44 results on '"Hellmann, M D"'
Search Results
2. ‘Genotype/immunotype’ correlations in resected NSCLC
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Paik, P. K. and Hellmann, M. D.
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- 2017
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3. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing
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Yu, H. A., Arcila, M. E., Hellmann, M. D., Kris, M. G., Ladanyi, M., and Riely, G. J.
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- 2014
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4. Corrigendum: Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (Annals of Oncology (2018) 29 (iv192–iv237) DOI: 10.1093/annonc/mdy275)
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Planchard, D., Popat, S., Kerr, K., Novello, S., Smit, E. F., Faivre-Finn, C., Mok, T. S., Reck, M., Van Schil, P. E., Hellmann, M. D., and Peters, Solange
- Abstract
The following corrections are made: In the section "Management of advanced/metastatic NSCLC, First-line treatment of EGFR-and ALK-negative NSCLC disease, regardless of PD-L1 status" 1. In KEYNOTE-189, patients with metastatic non-squamous NSCLC, PS 0-1, without sensitising EGFR or ALK mutations, were randomised to receive pemetrexed and a platinum-based ChT plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy [96]. Is replaced with: In KEYNOTE-189, patients with metastatic non-squamous NSCLC, PS 0-1, without sensitising EGFR or ALK mutations, were randomised to receive pemetrexed and cisplatin or carboplatin plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy [96]. 2. Recently, the combination of carboplatin or cisplatin with pemetrexed and atezolizumab has been shown, in the context of the IMpower132 trial, to be superior to the ChT doublet. Is replaced with: Recently, the combination of carboplatin or cisplatin with pemetrexed and atezolizumab followed by maintenance pemetrexed and atezolizumab has been shown, in the context of the IMpower132 trial, to be superior to the ChT doublet followed by maintenance pemetrexed. 3. Atezolizumab was studied in patients with metastatic squamous NSCLC in the IMpower131 study. Patients were randomised to atezolizumab/ carboplatin/paclitaxel, atezolizumab/carboplatin/nab-P or carboplatin/nab-P (nab-PC) [100]. Atezolizumab/carboplatin/ nab-P had improved PFS compared with nab-PC (HR 0.715, P=0.0001), but no improvement in OS was seen at the first interim analysis (mOS 14 versus 13.9 months). More mature data are needed to evaluate long-Term benefit of the strategy; with the use of atezolizumab with nab-PC today representing an option in patients with metastatic squamous NSCLC [I, B; not EMA-Approved]. Is replaced with: Atezolizumab was studied in patients with metastatic squamous NSCLC in the IMpower131 study. Patients were randomised to atezolizumab/ carboplatin/paclitaxel, atezolizumab/carboplatin/nab-P or carboplatin/nab-P [100]. Atezolizumab/carboplatin/nab-P had improved PFS compared with carboplatin/nab-P (HR 0.715, P=0.0001), but no improvement in OS was seen at the first interim analysis (mOS 14 versus 13.9 months). More mature data are needed to evaluate the long-Term benefit of the strategy; with the use of atezolizumab with carboplatin and nab-P today representing an option in patients with metastatic squamous NSCLC [I, B; not EMAapproved]. In the section "First-line treatment of NSCLC without actionable oncogenic driver, with contraindications to use of immunotherapy" The nab-PC regimen has been shown in a large phase III trial to have a significantly higher ORR compared with solvent-based paclitaxel/ carboplatin (sb-PC), and less neurotoxicity [I, B] [113]. The benefits were observed in both SCC and non-SCC (NSCC), with a larger impact on response in SCC. For this reason, the nab-PC regimen could be considered a chemotherapeutic option in advanced NSCLC patients, particularly in patients with greater risk of neurotoxicity, pre-existing hypersensitivity to paclitaxel or contraindications for standard paclitaxel premedication [I, B]. Is replaced with: The carboplatin/nab-P regimen has been shown in a large phase III trial to have a significantly higher ORR compared with solventbased paclitaxel/carboplatin (sb-PC), and less neurotoxicity [I, B] [113]. The benefits were observed in both SCC and non-SCC (NSCC), with a larger impact on response in SCC. For this reason, the carboplatin/nab-P regimen could be considered a chemotherapeutic option in advanced NSCLC patients, particularly in patients with greater risk of neurotoxicity, pre-existing hypersensitivity to paclitaxel or contraindications for standard paclitaxel premedication [I, B]. (Figure Presented).
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- 2018
5. Metastatic non-small cell lung cancer : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
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Planchard, D., Popat, S., Kerr, K., Novello, S., Smit, E. F., Faivre-Finn, C., Mok, T. S., Reck, M., Van Schil, P. E., Hellmann, M. D., Peters, S., and ESMO Guidelines Comm
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0301 basic medicine ,Lung Neoplasms ,Biopsy ,Aftercare ,Survivorship ,Medical Oncology ,Radiosurgery ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Bronchoscopy ,Biomarkers, Tumor ,Humans ,Precision Medicine ,Pneumonectomy ,Lung ,Societies, Medical ,Neoplasm Staging ,Manchester Cancer Research Centre ,Brain Neoplasms ,ResearchInstitutes_Networks_Beacons/mcrc ,Incidence ,Hematology ,Prognosis ,Magnetic Resonance Imaging ,Europe ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Human medicine ,Tomography, X-Ray Computed - Published
- 2018
6. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.
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Hellmann, M D, Kim, T -W, Lee, C B, Goh, B -C, Miller, W H, Oh, D -Y, Jamal, R, Chee, C -E, Chow, L Q M, Gainor, J F, Desai, J, Solomon, B J, Thakur, M Das, Pitcher, B, Foster, P, Hernandez, G, Wongchenko, M J, Cha, E, Bang, Y -J, and Siu, L L
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RAS oncogenes , *NON-small-cell lung carcinoma , *APOPTOSIS , *MELANOMA , *PROGRESSION-free survival , *T cells , *COLON cancer - Abstract
Background Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. Patients and methods This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival. Results Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases. Conclusions Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study. ClinicalTrials.gov Identifier NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix , available at Annals of Oncology online). [ABSTRACT FROM AUTHOR]
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- 2019
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7. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.
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Derosa, L, Hellmann, M D, Spaziano, M, Halpenny, D, Fidelle, M, Rizvi, H, Long, N, Plodkowski, A J, Arbour, K C, and Chaft, J E
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ANTIBIOTICS , *CANCER treatment , *RENAL cell carcinoma , *NON-small-cell lung carcinoma , *GUT microbiome , *IMMUNE response - Abstract
Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progressionfree survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P<0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P<0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P=0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P=0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P=0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P<0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI. [ABSTRACT FROM AUTHOR]
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- 2018
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8. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
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Hellmann, M. D., Ciuleanu, T.-E., Pluzanski, A., Lee, J. S., Otterson, G. A., Audigier-Valette, C., Minenza, E., Linardou, H., Burgers, S., Salman, P., Borghaei, H., Ramalingam, S. S., Brahmer, J., Reck, M., O'Byrne, K. J., Geese, W. J., Green, G., Chang, H., Szustakowski, J., and Bhagavatheeswaran, P.
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IPILIMUMAB , *CANCER treatment , *NON-small-cell lung carcinoma , *CANCER chemotherapy , *TREATMENT effectiveness , *PROGRESSION-free survival , *GENETIC mutation , *PATIENT selection - Abstract
Background: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).Methods: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.Results: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .).Conclusions: Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut [ABSTRACT FROM AUTHOR]- Published
- 2018
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9. Chemotherapy remains an essential element of personalized care for persons with lung cancers.
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Hellmann, M. D., Li, B. T., Chaft, J. E., and Kris, M. G.
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CANCER chemotherapy , *INDIVIDUALIZED medicine , *LUNG cancer treatment , *CANCER immunotherapy , *NEOVASCULARIZATION inhibitors - Abstract
Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates. [ABSTRACT FROM AUTHOR]
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- 2016
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10. A phase II trial of paclitaxel, pemetrexed and bevacizumab in patients with untreated, advanced lung cancers
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Pietanza, M. C., Hellmann, M. D., Rizvi, N., Azzoli, C. G., Stephanie Smith-Marrone, Fiore, J., Tyson, L. B., Sumner, D. K., Hergianto, A. B., Kass, S. L., Miller, C. P., Sima, C. S., Zhao, B. S., Ginsberg, M. S., Schwartz, L. H., and Kris, M. G.
11. Prevalence of germline BAP1 mutations in patients with malignant mesothelioma (MM)
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Hellmann, M. D., Borsu, L., Zehir, A., Cheng, D. T., Zha, Z., Siegel, B., Rohrer, R. W., Robson, M. E., Arnold, A. G., Fleischut, M. H., Cavatore, M., Gaskell, A. A., Gawel, C., Robertson, A., Viale, A., Valerie Rusch, Krug, L. M., Ladanyi, M., and Zauderer, M. G.
12. 'Intention-to-treat' outcomes of sequential patients with stage IIIA lung adenocarcinomas treated with neoadjuvant chemotherapy with intent of surgical resection
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Hellmann, M. D., Chaft, J. E., Hilden, P. D., Rusch, V. W., and Mark Kris
13. Alterations in two oncogenic drivers: Impact of concurrent PIK3CA or AKT1 mutations in patients with oncogene-driven lung adenocarcinomas
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Eng, J., Hellmann, M. D., Woo, K., Sima, C. S., Yu, H. A., Arcila, M. E., Ladanyi, M., Mark Kris, and Drilon, A. E.
14. NEOSCAN: Phase II trial of neoadjuvant chemotherapy for resectable lung cancers with switch to chemo alternative in F-18-FDG PET nonresponders
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Kris, M. G., Hellmann, M. D., Naidoo, J., Mark Dunphy, Sima, C. S., Downey, R. J., Travis, W. D., Azzoli, C. G., and Chaft, J. E.
15. Stage at diagnosis as a prognostic marker for patients with KRAS-mutant metastatic lung adenocarcinomas
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Yu, H. A., Hellmann, M. D., Sima, C. S., Busby, N., Rodriguez, K., Riely, G. J., and Mark Kris
16. Tumor expression of TTF1 is associated with a doubling of overall survival in patients with advanced lung adenocarcinomas
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Hellmann, M. D., Patrick Hilden, Sima, C. S., Kris, M. G., Rekhtman, N., and Chaft, J. E.
17. Major pathologic response (<= 10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas
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Chaft, J. E., Hellmann, M. D., Rusch, V. W., Travis, W. D., and Mark Kris
18. A phase II study of 18f-FDG PET guided optimization of neoadjuvant chemotherapy for resectable non-small cell lung cancer
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Chaft, J. E., Hellmann, M. D., Mark Dunphy, Jappe, W., Sima, C. S., Downey, R. J., Travis, W. D., Azzoli, C. G., and Kris, M. G.
19. How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer.
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Peters, S, Reck, M, Smit, E F, Mok, T, and Hellmann, M D
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NON-small-cell lung carcinoma , *THERAPEUTICS , *SMALL cell lung cancer , *PULMONARY fibrosis , *IMMUNOTHERAPY - Published
- 2019
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20. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
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Schoenfeld, A J, Arbour, K C, Rizvi, H, Iqbal, A N, Gadgeel, S M, Girshman, J, Kris, M G, Riely, G J, Yu, H A, and Hellmann, M D
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- 2019
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21. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
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Planchard, D, Popat, S, Kerr, K, Novello, S, Smit, E F, Faivre-Finn, C, Mok, T S, Reck, M, Schil, P E Van, Hellmann, M D, and Peters, S
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- 2019
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22. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.
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Forde, P. M., Chaft, J. E., Smith, K. N., Anagnostou, V., Cottrell, T. R., Hellmann, M. D., Zahurak, M., Yang, S. C., Jones, D. R., Broderick, S., Battafarano, R. J., Velez, M. J., Rekhtman, N., Olah, Z., Naidoo, J., Marrone, K. A., Verde, F., Guo, H., Zhang, J., and Caushi, J. X.
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LUNG cancer , *LUNG diseases , *LUNG tumors , *IMMUNOTHERAPY , *CANCER treatment , *ANTINEOPLASTIC agents - Abstract
Background: Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.Methods: In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.Results: Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .). [ABSTRACT FROM AUTHOR]- Published
- 2018
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23. Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.
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Hui, R., Garon, E. B., Goldman, J. W., Leighl, N. B., Hellmann, M. D., Patnaik, A., Gandhi, L., Eder, J. P., Ahn, M.-J., Horn, L., Felip, E., Carcereny, E., Rangwala, R., Lubiniecki, G. M., Zhang, J., Emancipator, K., Roach, C., and Rizvi, N. A.
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CANCER treatment , *NON-small-cell lung carcinoma , *PEMBROLIZUMAB , *APOPTOSIS , *CLINICAL trials , *LIGANDS (Biochemistry) , *THERAPEUTICS - Abstract
Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (=1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received =1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS =50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS =50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS = 50%. [ABSTRACT FROM AUTHOR]
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- 2017
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24. Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers.
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Drilon, A., Bergagnini, I., Delasos, L., Sabari, J., Woo, K. M., Plodkowski, A., Wang, L., Hellmann, M. D., Joubert, P., Sima, C. S., Smith, R., Somwar, R., Rekhtman, N., Ladanyi, M., Riely, G. J., and Kris, M. G.
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PEMETREXED , *LUNG cancer , *PROGRESSION-free survival , *GENOMICS - Abstract
Background: RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored. Patients and methods: A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers. Results: We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1-(23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers. Conclusion: Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered. [ABSTRACT FROM AUTHOR]
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- 2016
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25. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.
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Chatterjee, M., Turner, D. C., Felip, E., Lena, H., Cappuzzo, F., Horn, L., Garon, E. B., Hui, R., Arkenau, H.-T., Gubens, M. A., Hellmann, M. D., Dong, D., Li, C., Mayawala, K., Freshwater, T., Ahamadi, M., Stone, J., Lubiniecki, G. M., Zhang, J., and Im, E.
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NON-small-cell lung carcinoma , *PEMBROLIZUMAB , *ADVERSE health care events , *TUMORS , *REGRESSION analysis - Abstract
Background: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. Patients and methods: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. Results: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. Conclusions: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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26. Treatment outcomes of immune-related cutaneous adverse events
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Paul B. Chapman, Vanessa A Reed, Alina Markova, Azael Freites-Martinez, Wen-Hung Chung, Stephen W. Dusza, Oluwaseun Kukoyi, Gabriella Fabbrocini, Mario E. Lacouture, Adriana T. Lopez, Maria Carmela Annunziata, Jennifer Wu, Michael A. Postow, Robert J. Motzer, Margaret K. Callahan, Naiyer A. Rizvi, Matthew D. Hellmann, Donald Chan, Gregory S. Phillips, Chih-Hsun Yang, Aliyah Pabani, Larisa J. Geskin, Jonathan E. Rosenberg, Phillips, G. S., Wu, J., Hellmann, M. D., Postow, M. A., Rizvi, N. A., Freites-Martinez, A., Chan, D., Dusza, S., Motzer, R. J., Rosenberg, J. E., Callahan, M. K., Chapman, P. B., Geskin, L., Lopez, A. T., Reed, V. A., Fabbrocini, G., Annunziata, M. C., Kukoyi, O., Pabani, A., Yang, C. -H., Chung, W. -H., Markova, A., and Lacouture, M. E.
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Adolescent ,Immune checkpoint inhibitors ,Treatment outcome ,MEDLINE ,Skin Diseases ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Immune system ,Immunologic Factor ,Internal medicine ,Original Reports ,Humans ,Immunologic Factors ,Medicine ,Young adult ,Adverse effect ,Aged ,Aged, 80 and over ,Extramural ,business.industry ,Skin Disease ,Middle Aged ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,Drug-Related Side Effects and Adverse Reaction ,Human - Abstract
PURPOSE The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics. METHODS A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed. RESULTS A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype ( P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043). CONCLUSION Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
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- 2019
27. Erratum to "Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project": [Annals of Oncology 32 (2021) 1626-1636].
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Vega DM, Yee LM, McShane LM, Williams PM, Chen L, Vilimas T, Fabrizio D, Funari V, Newberg J, Bruce LK, Chen SJ, Baden J, Carl Barrett J, Beer P, Butler M, Cheng JH, Conroy J, Cyanam D, Eyring K, Garcia E, Green G, Gregersen VR, Hellmann MD, Keefer LA, Lasiter L, Lazar AJ, Li MC, MacConaill LE, Meier K, Mellert H, Pabla S, Pallavajjalla A, Pestano G, Salgado R, Samara R, Sokol ES, Stafford P, Budczies J, Stenzinger A, Tom W, Valkenburg KC, Wang XZ, Weigman V, Xie M, Xie Q, Zehir A, Zhao C, Zhao Y, Stewart MD, and Allen J
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- 2024
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28. Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis.
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Borghaei H, Ciuleanu TE, Lee JS, Pluzanski A, Caro RB, Gutierrez M, Ohe Y, Nishio M, Goldman J, Ready N, Spigel DR, Ramalingam SS, Paz-Ares LG, Gainor JF, Ahmed S, Reck M, Maio M, O'Byrne KJ, Memaj A, Nathan F, Tran P, Hellmann MD, and Brahmer JR
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- Humans, Nivolumab therapeutic use, Ipilimumab adverse effects, Progression-Free Survival, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
- Abstract
Background: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival., Patients and Methods: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed., Results: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population., Conclusion: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC., Competing Interests: Disclosure HB reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, Genentech, Lilly, Merck, and Novartis; advisory/consulting fees from AbbVie, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Cantargia AB, EMD Serono, Genmab, HUYA Bioscience International, Nuclaei, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet, Takeda, and Trovagene; honoraria from Amgen, Axiom Biotechnologies, Bristol Myers Squibb, Celgene, and Pfizer; research funding from Bristol Myers Squibb, Celgene, Lilly, Merck, and Millennium; stock interest with Nuclaei, Rgenix, and Sonnet; travel, accommodation, and expenses from Clovis Oncology; data safety monitoring board with Incyte and University of Pennsylvania; and ad boards with Guardant, Natera, and OncoCyte. TEC reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. J-SL reports advisory/consulting fees from AstraZeneca and Ono Pharmaceutical. AP reports speaker fees, expert testimony, travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, and MSD; speaker fees and expert testimony from Roche, speaker fees from Pfizer; and speaker fees, travel, accommodation, and expenses from AstraZeneca. RBC reports advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Takeda. MG reports advisory fees from Celularity and Guardant 360; and speaker fees from Guardant 360. YO reports advisory/consulting fees, honoraria, and research funding from AstraZeneca and Ono Pharmaceutical; and honoraria and research funding from Bristol Myers Squibb Japan. MN reports advisory/consulting fees, honoraria, and research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Ono Pharmaceuticals, Taiho Pharmaceutical, and Takeda; advisory/consulting fees from AbbVie and Teijin Pharma; honoraria and research funding from Janssen, Merck, Novartis, and Pfizer; and honoraria from Boehringer Ingelheim and Nippon Kayaku. JG reports grant support from Advaxis, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Pfizer; consulting and writing fees from Bristol Myers Squibb; and consulting fees from AstraZeneca, Genentech, and Pfizer. NR reports consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Genentech, Merck, and Roche; research funding from Merck; honoraria from Novartis and Celgene; expert testimony fees from Bristol Myers Squibb and Celgene; speaker’s bureau fees from Bristol Myers Squibb; personal fees from AbbVie, Amgen, Jazz, Regeneron, and Sanofi; other fees from AbbVie; and a grant from Amgen. DRS reports grant support from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas Pharma, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicine, Calithera, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Eli Lilly, EMD Serono, Evelo, G1 Therapeutics, GlaxoSmithKline, GRAIL, Hutchinson MediPharma, ImClone Systems, ImmunoGen, Incyte, Ipsen, Janssen, Kronos Bio, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novocure, Oncologie, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, University of Texas-Southwestern, and Verastem; and consulting support from Amgen, BeiGene, Curio Science, Eli Lilly, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Molecular Templates, Novocure, Puma Biotechnology, Regeneron, and Sanofi-Aventis. SSR reports advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyo, Eisai, Genentech/Roche, GlaxoSmithKline, Lilly, Merck, Sanofi, Takeda; and research funding from Advaxis, AstraZeneca, Bristol Myers Squibb, EMD Serono, Genmab, GlaxoSmithKline, Merck, Takeda, Tesaro. LGPA reports travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Merck Serono, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche/Genetech, Sanofi, Servier, and Takeda; speaker fees from Bristol Myers Squibb, Lilly, Merck Serono, MSD Oncology, Pfizer, and Roche/Genentech; research funding from AstraZeneca, Bristol Myers Squibb, MSD, PharmaMar; and personal fees from Altum Sequencing and Genomica. JFG reports consulting fees and honoraria from AstraZeneca, Blueprint, Bristol Myers Squibb, EMD Serono, Gilead, Glyde Bio, iTeos, Karyopharm, Loxo/Lilly, Merck, Moderna, Novartis, Oncorus, Pfizer, Regeneron, Silverback Therapeutics, and Takeda; grant support from Adaptimmune, Alexo, Array Biopharma, Blueprint, Bristol Myers Squibb, Jounce, Merck, Moderna, Novartis, and Tesaro; and an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. MR reports advisory/consulting fees, travel, accommodation, and expenses from AbbVie and Amgen; advisory/consulting fees, speaker fees, expert testimony, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, MSD, Novartis, Pfizer, and Roche; and advisory/consulting fees from Samsung. MM reports advisory/consulting fees Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, iOnctura, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and SciClone. KJO reports advisory/consulting fees, speaker fees, expert testimony, honoraria, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly Oncology, MSD, Pfizer, and Roche; advisory/consulting fees, speaker fees, expert testimony and honoraria from Novartis; advisory/consulting fees, speaker fees, and honoraria from Teva; advisory/consulting fees and honoraria from Natera, Takeda, Tristar, and Yuhan; and being a shareholder at Carpe Vitae Pharmaceuticals, DGC diagnostics, Foundation Medicine, and RepLuca Pharmaceuticals. AM reports employment and stock interest with Bristol Myers Squibb. FN reports employment at Bristol Myers Squibb; and ownership/stock interest with AstraZeneca, Johnson & Johnson, and Eli Lilly. PT reports employment and stock interest with Bristol Myers Squibb. MDH reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. JRB reports advisory/consultancy fees and research funding from Bristol Myers Squibb; advisory/consultancy fees from Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Merck, Regeneron, and Sanofi; consultancy fees and honoraria from Janssen; and advisory/consultancy fees and other from Roche/Genentech. SA has declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2023
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29. Deciphering radiological stable disease to immune checkpoint inhibitors.
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Luo J, Wu S, Rizvi H, Zhang Q, Egger JV, Osorio JC, Schoenfeld AJ, Plodkowski AJ, Ginsberg MS, Callahan MK, Maher C, Shoushtari AN, Postow MA, Voss MH, Kotecha RR, Gupta A, Raja R, Kris MG, and Hellmann MD
- Subjects
- Biomarkers, Tumor genetics, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Background: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research., Patients and Methods: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts., Results: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated., Conclusions: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research., Competing Interests: Disclosure JL has received honoraria from Targeted Oncology and Physicians’ Education Resource. SW and QZ are former employees of AstraZeneca. MKC receives institutional research funding from Bristol-Myers Squibb; and has received personal fees from Merck, InCyte, Moderna, ImmunoCore, and AstraZeneca. ANS reports advisory board positions with Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences; and institutional research support from BMS, Immunocore, Xcovery, Polaris, Novartis, Pfizer, Checkmate Pharmaceuticals, and Foghorn Therapeutics. MAP reports consulting fees from Bristol-Myers Squibb, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Pfizer, and Aduro; honoraria from BMS and Merck; and institutional research support from Rgenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. MHV reports receiving commercial research support from Bristol-Myers Squibb, Pfizer, and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation from Astra Zeneca, Eisai, Novartis, and Takeda; and consultant/advisory board member for Aveo, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Merck, Onquality Pharmaceuticals, Novartis, and Pfizer. MSG has been a compensated consultant for Ultimate Opinions in Medicine LLC and MORE Health, Inc. AG and RR are employees of AstraZeneca. RR has a patent pending related to tumor mutation burden. MGK receives personal fees from AstraZeneca, Pfizer, Regeneron, and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; and received travel support from AstraZeneca, Pfizer, Regeneron, and Genentech; is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech/Roche, and PUMA Biotechnology for research conducted by MGK. MSK has licensed testing for EGFR T790M to MolecularMD. MDH, as of November 2021, is an employee of AstraZeneca; has received personal fees from Achilles, Adagene, Adicet, Arcus, Blueprint Medicines, Bristol-Myers Squibb, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs, and Regeneron; has options from Factorial, Shattuck Labs, Immunai, and Arcus; and has a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2022
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30. Insights from prospective multi-omic profiling of lymphocytes in resected lung cancer.
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Chow A and Hellmann MD
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- Humans, Lymphocytes, Prospective Studies, Genomics, Lung Neoplasms genetics, Lung Neoplasms surgery
- Abstract
Competing Interests: Disclosure MDH reports grants from Bristol Myers Squibb; nonfinancial support from AstraZeneca and Bristol Myers Squibb; and personal fees from Achilles; Arcus AstraZeneca; Blueprint Medicines; Bristol Myers Squibb; Genentech/Roche; Immunai; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Mirati; Nektar; Pact Pharma; Shattuck Labs; Syndax; Janssen; and Regeneron; as well as equity options from Immunai, Shattuck Labs, and Arcus. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. AC has declared no conflicts of interest.
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- 2022
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31. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer.
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Schoenfeld AJ, Antonia SJ, Awad MM, Felip E, Gainor J, Gettinger SN, Hodi FS, Johnson ML, Leighl NB, Lovly CM, Mok T, Perol M, Reck M, Solomon B, Soria JC, Tan DSW, Peters S, and Hellmann MD
- Subjects
- B7-H1 Antigen, Humans, Immunotherapy, Programmed Cell Death 1 Receptor, Prospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months., Competing Interests: Disclosure AJS reports consulting/advising role to J&J and Perceptive Advisors. SJA reports consulting/advising role from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis; expenses from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis. MMA reports grants and personal fees from Genentech, grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, grants from Lilly, personal fees from Maverick, personal fees from Blueprint Medicine, personal fees from Syndax, personal fees from Ariad, personal fees from Nektar, personal fees from Gritstone, personal fees from ArcherDx, personal fees from Mirati, personal fees from NextCure, personal fees from EMD Serono. EF reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Blue Print Medicines, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from GSK, personal fees from Janssen, personal fees from Medscape, personal fees from Merck KGaA, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Roche, personal fees from PeerVoice, personal fees from Pfizer, personal fees from prIME Oncology, personal fees from Puma Biotechnology, personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from Springer, personal fees from Takeda, personal fees from TouchIME, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, outside the submitted work; and Grífols: Independent Member of the Board. JG reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Takeda, grants and personal fees from Blueprint, grants and personal fees from Loxo, personal fees from Oncorus, personal fees from Regeneron, personal fees from Pfizer, personal fees from Incyte, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from Agios, personal fees from Amgen, grants from Array, grants from Tesaro, grants from Moderna, grants from Adaptimmune, grants from Alexo, personal fees from Ironwood Pharmaceuticals, personal fees from Gilead, personal fees from EMD Serono, personal fees from AstraZeneca, personal fees from Mirati. SNG reports personal fees and other from Bristol Myers Squibb, personal fees from Nektar, other from Genentech, other from Ariad/Takeda, other from Iovance Biotherapeutics, during the conduct of the study. FSH reports grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Aduro, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Verastem, personal fees from Torque, personal fees from Rheos, personal fees from Kairos, personal fees from Bicara, from Psioxus Therapeutics, other from Pieris Pharmaceutical, from Zumutor, from Corner Therapeutics, personal fees from Eisai, personal fees from Checkpoint Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent Therapeutic Peptides Patent number: 9402905 issued, a patent Methods of using pembrolizumab and trebananib pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, and a patent Anti- galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses. Publication number: 20170343552 pending. MLJ reports other from Achilles Therapeutics, grants and other from AstraZeneca, grants and other from Atreca, grants and other from Boehringer Ingelheim, grants and other from Calithera Biosciences, grants and other from EMD Serono, grants and other from Roche/Genentech, grants and other from GlaxoSmithKline, grants and other from Gritstone Oncology, grants and other from Guardant Health, grants and other from Incyte, grants and other from Janssen Research and Development, grants and other from Lilly, grants and other from Merck, grants and other from Mirati Therapeutics, grants and other from Novartis, grants and other from Pfizer, grants and other from Sanofi-Aventis, grants from AbbVie, grants from Acerta Pharma, grants from Adaptimmune, grants and other from Amgen, grants from Apexigen, grants from Array BioPharma, grants from BeiGene, grants from Checkpoint Therapeutics, grants from Corvus Pharmaceuticals, grants from CytomX, grants and other from Daiichi Sankyo, grants from Dynavax Technologies, grants from Genmab, grants from Genocea Biosciences, grants from Hengrui Therapeutics, grants from Immunocore, grants from Jounce Therapeutics, grants from Kadmon Pharmaceuticals, grants from Loxo Oncology, grants from Lycera, grants from Neovia Oncology, grants from OncoMed Pharmaceuticals, grants from Regeneron Pharmaceuticals, grants from Shattuck Labs, grants from Stem CentRx, grants from Syndax Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Tarveda, grants from University of Michigan, grants and other from WindMIL Therapeutics, grants from TCR2 Therapeutics, grants from Arcus Biosciences, grants and other from Ribon Therapeutics, grants from Seven and Eight Biopharmaceuticals, other from Bristol-Myers Squibb, personal fees from Astellas, personal fees from Otsuka, grants from BerGenBio, grants from Foundation Medicine, other from G1 Therapeutics, grants from Tmunity Therapeutics. NBL reports grants and personal fees for CME lectures from MSD and BMS. CML reports other from Cepheid, other from Syros, other from Foundation Medicine, other from Novartis, other from Astra Zeneca, other from Takeda, other from Amgen, other from Blueprints Medicine, other from Genentech, other from Eli Lilly/Loxo, other from Pfizer, other from Roche, other from Achilles, from null, outside the submitted work. TM reports personal fees from AbbVie, Inc., personal fees and other from ACEA Pharma, personal fees and other from Alpha Biopharma Co. Ltd., personal fees and other from Amgen, personal fees and other from Amoy Diagnostics Co. Ltd., grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, personal fees and other from Boehringer Ingelheim, grants, personal fees and other from Bristol-Myers Squibb, personal fees and other from Blueprint Medicines Corporation, personal fees and other from CStone Pharmaceuticals, personal fees and other from Daiichi Sankyo, personal fees and other from Eisai, personal fees and other from Fishawack Facilitate Ltd., other from geneDecode, personal fees and other from Gritstone Oncology Inc., personal fees and other from Guardant Health, personal fees and other from Hengrui Therapeutics, personal fees and other from Ignyta Inc., personal fees and other from IQVIA, personal fees and other from Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, personal fees and other from Lilly, personal fees and other from Loxo-Oncology, personal fees and other from Lunit, Inc., personal fees from MD Health (Brazil), personal fees from Medscape/WebMD, grants, personal fees and other from Merck Serono, grants, personal fees and other from Merck Sharp & Dohme, personal fees and other from Mirati Therapeutics Inc., personal fees from MoreHealth, grants, personal fees and other from Novartis, personal fees and other from OrigiMed, personal fees from PeerVoice, personal fees from Physicians' Education Resource, personal fees from P. Permanyer SL, grants, personal fees and other from Pfizer, Inc, personal fees from prIME Oncology, personal fees and other from Puma Technology Inc, personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, personal fees and other from Takeda, personal fees from Touch Medical Media, other from Virtus Medical Group, personal fees and other from Yuhan Corporation, other from AstraZeneca PLC, other from Hutchison Chi-Med, other from Sanomics Ltd., grants from Clovis Oncology, grants from SFJ Pharmaceuticals, grants from XCovery, outside the submitted work. MP reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from AstraZeneca, personal fees from ELI LILLY, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from B Bristol Myers Squibb, personal fees and non-financial support from Merck Sharp & Dohme, personal fees from Novartis, grants and personal fees from Takeda, personal fees and non-financial support from Chugai, personal fees from Amgen, personal fees from Illumina, personal fees from Gritstone, outside the submitted work. MR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from BMS, personal fees from Boehringer-Ingelheim, personal fees from Lilly, personal fees from Merck, personal fees from MSD, personal fees from Mirati, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Samsung, outside the submitted work. BS reports personal fees from Roche/Genentech, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Amgen, personal fees from Eli Lilly, personal fees from Loxo Oncology, personal fees from Merck, personal fees from Bristol Myers Squibb, personal fees from PharmaMar, personal fees from Pfizer, outside the submitted work. J-CS reports other from AstraZeneca, other from AstraZeneca, during the conduct of the study; other from Gritstone Oncology, other from Daiichi Sankyo, other from Relay Therapeutics, outside the submitted work. DSWT reports grants and personal fees from Novartis, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Celgene, grants and personal fees from Astra Zeneca, personal fees from Eli Lilly, personal fees from LOXO, personal fees from Merck, grants and personal fees from Pfizer, personal fees from Roche, personal fees from Takeda, grants from GlaxoSmithKline, personal fees from Merrimack, outside the submitted work. SP reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, personal fees from Boehringer-Ingelheim, personal fees from Bistrol-Myers Squibb, personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Foundation Medicine, personal fees from Illumina, personal fees from Janssen, personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack, personal fees from Novartis, personal fees from Pharma Mar, personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics and Takeda, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Merck Sharp and Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, non-financial support from Sponsored by Amgen, non-financial support from AstraZeneca, non-financial support from Boehringer-Ingelheim, non-financial support from Bristol-Meyers Squibb, non-financial support from Clovis, non-financial support from F. Hoffmann-La Roche, non-financial support from Illumina, non-financial support from Merck Sharp and Dohme, non-financial support from Merck Serono, non-financial support from Novartis, non-financial support from Pfizer, non-financial support from Sanofi, personal fees from Bioinvent, outside the submitted work. All fees to institution. MDH reports personal fees from Merck, personal fees from Genentech/Roche, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and other from Shattuck Labs, personal fees from Nektar, personal fees and other from Immunai, personal fees and other from Arcus, from Eli Lilly, during the conduct of the study; In addition, Dr. Hellmann has a patent A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) licensed to PGDx., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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32. Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.
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Vega DM, Yee LM, McShane LM, Williams PM, Chen L, Vilimas T, Fabrizio D, Funari V, Newberg J, Bruce LK, Chen SJ, Baden J, Carl Barrett J, Beer P, Butler M, Cheng JH, Conroy J, Cyanam D, Eyring K, Garcia E, Green G, Gregersen VR, Hellmann MD, Keefer LA, Lasiter L, Lazar AJ, Li MC, MacConaill LE, Meier K, Mellert H, Pabla S, Pallavajjalla A, Pestano G, Salgado R, Samara R, Sokol ES, Stafford P, Budczies J, Stenzinger A, Tom W, Valkenburg KC, Wang XZ, Weigman V, Xie M, Xie Q, Zehir A, Zhao C, Zhao Y, Stewart MD, and Allen J
- Subjects
- Biomarkers, Tumor, Humans, Reproducibility of Results, Tumor Burden, Mutation, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Background: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications., Materials and Methods: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values., Results: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples., Conclusions: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available., Competing Interests: Disclosure XZW is an employee of EMD Serono Research and Development Institute. JN, DF, and ESS are all employees of Foundation Medicine, and ESS is a shareholder in Roche. VF and LKB are employees of Neogenomics and stockholders in NeoGenomics Inc. S-JC and J-HC are employees of ACT Genomics and stockholder in ACT Genomics. JB is employed with BMS, shareholder in BMS, and a shareholder in Johnson & Johnson. JC and SP are employed by OmniSeq, Inc. and hold restricted stock in OmniSeq, Inc. DC and WT are employed with Thermo Fisher Scientific and stockholder in Thermo Fisher Scientific. KE is an employee of Intermountain Genome Diagnostics. GG is employed by BMS and a stockholder in BMS. VRG and R. Samara are employed with QIAGEN. LAK and KCV are employed with Personal Genome Diagnostics. PS is employed by Caris Life Sciences. AS serves on advisory boards and/or receives speech honoraria from AIGnostics, Bayer, Thermo Fisher, Illumina, Astra Zeneca, Novartis, Pfizer, Roche, Seattle Genetics, MSD, BMS, Takeda, Janssen, and Eli-Lily; and research funding from: Chugai and Bristol Myers Squibb. MB is employed by LGC SeraCare. VW is employed with Q Squared Solutions. JCB and MX are employed by AstraZeneca. JCB is employed and holds shares of AstraZeneca. KM and CZ are employees of Illumina Inc and stockholders in Illumina Inc. HM and GP are employees and shareholders in Biodesix Inc. MDH has stock and other ownership interests in Shattuck Labs, Immunai, and Arcus Biosciences; reports honoraria from AstraZeneca and Bristol Myers Squibb; has a consulting or advisory role with Bristol Myers Squibb, Merck, Genentech/Roche, AstraZeneca, Nektar, Syndax, Mirati Therapeutics, Shattuck Labs, Immunai, Blueprint Medicines, Achilles Therapeutics, and Arcus Biosciences; receives research funding from Bristol Myers Squibb (Inst); has patents, royalties, and other intellectual property [a patent has been filed by Memorial Sloan Kettering (PCT/US2015/062208) for the use of TMB for prediction of immunotherapy efficacy, which is licensed to Personal Genome Diagnostics]; and receives travel and accommodation expense reimbursement from AstraZeneca, Bristol Myers Squibb, and Eli Lilly. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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33. Lesion-level heterogeneity of radiologic progression in patients treated with pembrolizumab.
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Topp BG, Thiagarajan K, De Alwis DP, Snyder A, and Hellmann MD
- Subjects
- Antibodies, Monoclonal, Humanized, Humans, Retrospective Studies, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms diagnostic imaging, Lung Neoplasms drug therapy
- Abstract
Background: Disease progression is often considered a binary state reflecting presence or absence of response. Meaningful heterogeneity between metastatic sites of a given patient may exist, however, and may impact therapeutic outcomes. To characterize the heterogeneity of progression with immunotherapy, we evaluated lesion-level dynamics of pembrolizumab-treated patients across three tumor types., Patients and Methods: Individual metastatic lesion dynamics were analyzed retrospectively in patients with advanced melanoma, non-small-cell lung cancer (NSCLC), and gastric or gastroesophageal junction (G/GEJ) cancer who received pembrolizumab in KEYNOTE-001 or KEYNOTE-059. Primary progression was defined as radiologic progression as per RECIST v1.1 occurring at the first on-treatment study scan (∼9-12 weeks, +2-week window) and secondary progression as progression occurring beyond the first scan (∼14 weeks and beyond). The change in sum of target lesions and of individual lesions was examined, as were patterns and timing of progression., Results: 9239 individual lesions from 1194 patients were analyzed. Among patients with primary progression [39% (200/511) of patients with melanoma, 41% (179/432) with NSCLC, 61% (154/251) with G/GEJ cancer], most patients (51%-63%) had a mixture of growing, stable, and shrinking lesions. Despite overall primary progression, a minority of patients (19%-25%) had tumor growth at every metastatic site and 17%-32% had ≥1 shrinking lesion. Among patients with secondary progression [22% (113/511) of patients with melanoma, 27% (117/432) with NSCLC, 18% (44/251) with G/GEJ cancer], few patients had rebound growth (>20% increase in diameter from nadir) in all lesions whereas the majority (74%-84%) had sustained regression in ≥1 lesion., Conclusions: Lesion-level heterogeneity at the time of disease progression was common in pembrolizumab-treated patients, with many patients demonstrating ongoing disease control in a subset of tumor sites. These results may inform clinical decision-making, trial design, and tumor sampling in the future., Competing Interests: Disclosure BGT reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. KT has declared no conflicts of interest. DPDA reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. AS reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. MDH reports grants from Bristol Myers Squibb; nonfinancial support from AstraZeneca and Bristol Myers Squibb; and personal fees from Achilles; Arcus AstraZeneca; Blueprint Medicines; Bristol Myers Squibb; Genentech/Roche; Immunai; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Mirati; Nektar; Pact Pharma; Shattuck Labs; Syndax; Janssen; and Regeneron; as well as equity options from Immunai, Shattuck Labs, and Arcus. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx., (Copyright © 2021 Merck Sharp & Dohme Corp., The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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34. IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.
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Barrios DM, Phillips GS, Geisler AN, Trelles SR, Markova A, Noor SJ, Quigley EA, Haliasos HC, Moy AP, Schram AM, Bromberg J, Funt SA, Voss MH, Drilon A, Hellmann MD, Comen EA, Narala S, Patel AB, Wetzel M, Jung JY, Leung DYM, and Lacouture ME
- Subjects
- Aged, Female, Humans, Immune Checkpoint Inhibitors, Male, Pruritus chemically induced, Pruritus drug therapy, Retrospective Studies, Immunoglobulin E, Omalizumab adverse effects
- Abstract
Background: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents., Patients and Methods: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0., Results: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab., Conclusions: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies., Competing Interests: Disclosure AM has an advisory board role in AstraZeneca, receives research funding from Incyte, and is supported by a Dermatology Foundation Career Development Award. EQ receives royalties from UpToDate. SAF receives research funding from AstraZeneca and Genentech/Roche, has a consulting/advisory relationship with Merck, and has ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, InconOVir and Vida Ventures. MHV reports receiving commercial research support from Pfizer and honoraria from Pfizer, Exelixis, Eisai, Calithera Biosciences, and Corvus Pharmaceuticals. AD discloses honoraria/advisory board participation for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; associated research funding paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research for Foundation Medicine; royalties from Wolters Kluwer; expenses from Merck and Puma; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice. MDH receives research funding from Bristol Myers Squibb; is a paid consultant to Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Achilles Therapeutics, PACT Pharma, Immunai, and Shattuck Labs; receives travel support/honoraria from AstraZeneca, Eli Lilly, Merck, and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EAC reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, and Heron Therapeutics. DYML has been a consultant for Genentech and Novartis. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, NCODA, Apricity, Oncoderm Labs, Hoth Therapeutics. Dr. Lacouture also receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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35. Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.
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Shaverdian N, Beattie J, Thor M, Offin M, Shepherd AF, Gelblum DY, Wu AJ, Simone CB 2nd, Hellmann MD, Chaft JE, Rimner A, and Gomez DR
- Subjects
- Humans, Immune Checkpoint Inhibitors, Retrospective Studies, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Radiation Pneumonitis epidemiology, Radiation Pneumonitis etiology
- Abstract
Background: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined., Patients and Methods: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled., Results: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP., Conclusion: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients., Competing Interests: Disclosure MO: Reports advisory role for PharMar, Novartis and Targeted Oncology. Reports honoraria from Bristol Myers Squibb and Merck Sharp & Dohme. AFS: Reports honoraria from ASCO. AJW: Reports research support from CivaTech Oncology, Inc., non-financial support from AlphaTau Medical, personal fees from MoreHealth and personal fees from AstraZeneca. CBS II: Reports honoraria from Varian Medical Systems. MDH: Reports personal fees from Genentech, grants, personal fees and non-financial support from Bristol Myers Squibb, personal fees from Merck, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and equity from Shattuck Labs, personal fees and equity from Immunai, personal fees from Nektar, personal fees from Blueprint Medicines. In addition, MDH has a pending patent Determinants of Cancer Response to Immunotherapy by PD-1 Blockade (PCT/US2015/062208) licensed to PGDx. JEC: Reports both research funding and consulting roles with Bristol Myers Squibb, Merck, Genentech and AstraZeneca. AR: Reports grants from Varian Medical Systems, grants from Boehringer Ingelheim, grants from Pfizer, grants and personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Research to Practice, personal fees from Cybrexa, non-financial support from Philips/Elekta, personal fees from MoreHealth. DRG: Reports honoraria from Merck, Bristol Myers Squibb, AstraZeneca, Reflexion, Medscape, Vindico, US Oncology, and Varian. Reports research support from Merck, Bristol Myers Squibb, AstraZeneca and Varian. Serves on advisory board for AstraZeneca. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2020
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36. COVID-19 in patients with lung cancer.
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Luo J, Rizvi H, Preeshagul IR, Egger JV, Hoyos D, Bandlamudi C, McCarthy CG, Falcon CJ, Schoenfeld AJ, Arbour KC, Chaft JE, Daly RM, Drilon A, Eng J, Iqbal A, Lai WV, Li BT, Lito P, Namakydoust A, Ng K, Offin M, Paik PK, Riely GJ, Rudin CM, Yu HA, Zauderer MG, Donoghue MTA, Łuksza M, Greenbaum BD, Kris MG, and Hellmann MD
- Subjects
- Adult, Aged, Aged, 80 and over, B7-H1 Antigen immunology, B7-H1 Antigen therapeutic use, COVID-19, Coronavirus Infections drug therapy, Coronavirus Infections immunology, Female, Follow-Up Studies, Hospitalization trends, Humans, Hydroxychloroquine therapeutic use, Lung Neoplasms immunology, Male, Middle Aged, Pandemics, Pneumonia, Viral immunology, Retrospective Studies, SARS-CoV-2, COVID-19 Drug Treatment, Betacoronavirus, Coronavirus Infections epidemiology, Coronavirus Infections therapy, Lung Neoplasms epidemiology, Lung Neoplasms therapy, Pneumonia, Viral epidemiology, Pneumonia, Viral therapy
- Abstract
Background: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic., Patients and Methods: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166)., Results: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes., Conclusion: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity., Competing Interests: Disclosure JL has received honoraria from Targeted Oncology. IRP has been a compensated consultant for Pfizer and AstraZeneca. KCA reports compensated consulting for AstraZeneca. She has received non-monetary research support from Novartis and Takeda (to her institution). JEC reports compensated consulting for AstraZeneca, Bristol-Myers Squibb, Merck, and Genentech; and research funding to institution from AstraZeneca, Bristol-Myers Squibb, Merck, and Genentech. RMD reports personal equity ownership in CVS Caremark and Roche and immediate family member with equity ownership in Pfizer, Eli Lilly, Cigna Corporation, and Baxter Bioscience. AED reports honoraria/advisory boards for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros; associated research paid to institution from Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; research funding from Foundation Medicine; royalties from Wolters Kluwer; other support from Merck (food/beverage), Puma (food/beverage), Merus, Boehringer Ingelheim; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD. WVL receives institutional research funding from Daiichi Sankyo, Amgen, and Abbvie; has been a compensated consultant for PharmaMar, G1 Therapeutics, AstraZeneca, Jazz Pharmaceuticals. BTL receives institutional research funding from Genentech, Lilly, Amgen, Daiichi Sankyo, AstraZeneca, Hengrui Therapeutics, BioMedValley Discoveries, Illumina, GRAIL, Guardant Health and MORE Health; has two institutional patents at Memorial Sloan Kettering Cancer Center (US62/685,057, US62/514,661); has been a compensated consultant/advisor for Roche/Genentech, Thermo Fisher Scientific, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, and Lilly; received travel support from Resolution Bioscience and MORE Health. AN has been a compensated consultant for Bayer. MDO has been a compensated consultant for PharmMar, Novartis, and Targeted Oncology; received travel support from Bristol-Myers Squibb and Merck; received honoraria from OncLive. PKP reports honoraria/advisory boards for Boehringer Ingelheim, Celgene, EMD Serono, Celithera, AstraZeneca, Abbvie, and Lilly Oncology; was compensated for participation in an independent data safety monitoring committee for Takeda. GJR receives institutional research funding from Mirati, Merck, Pfizer, Novartis, Roche, and Takeda. CMR has been a compensated consultant regarding oncology drug development with AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, Celgene, Daiichi-Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, Pharmamar, Syros, and Vavotek; serves on the scientific advisory boards of Bridge Medicines and Harpoon Therapeutics. HAY receives institutional research funding from AstraZeneca, Novartis, Pfizer, Lilly, Cullinan, and Daiichi-Sankyo; has been a compensated consultant for AstraZeneca and Daiichi-Sankyo. MGZ has received consulting fees from GlaxoSmithKline (2020), Epizyme (2017), Aldeyra Therapeutics (2019), Novocure (2019), and Atara (2018) and honoraria from Medical Learning Institute (2019) and OncLive (2019). Memorial Sloan Kettering receives research funding from the Department of Defense, the National Institutes of Health, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium/Takeda, Curis, and Roche for research conducted by MGZ. MGZ serves as Chair of the Board of Directors of the Mesothelioma Applied Research Foundation. MGZ reports grants from National Institutes of Health/National Cancer Institute. Memorial Sloan Kettering has an institutional agreement with IBM for Watson for Oncology and receives royalties from IBM. MGZ is an employee of Memorial Sloan Kettering. BDG has received honoraria for speaking engagements from Merck, Bristol-Myers Squibb, and Chugai Pharmaceuticals; has been a compensated consultant for PMV Pharma and Rome Therapeutics of which he is a cofounder. MGK receives personal fees from AstraZeneca, Pfizer, Regeneron, and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; received travel support from AstraZeneca, Pfizer, Regeneron, and Genentech. MGK is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech Roche, and PUMA Biotechnology for research conducted by MGK. MSK has licensed testing for EGFR T790M to MolecularMD. MDH receives institutional research funding from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai, and Arcus; has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. The remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2020
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37. Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas.
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Schoenfeld AJ, Rizvi H, Bandlamudi C, Sauter JL, Travis WD, Rekhtman N, Plodkowski AJ, Perez-Johnston R, Sawan P, Beras A, Egger JV, Ladanyi M, Arbour KC, Rudin CM, Riely GJ, Taylor BS, Donoghue MTA, and Hellmann MD
- Subjects
- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, High-Throughput Nucleotide Sequencing, Humans, Mutation, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Background: Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI., Patients and Methods: We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted next-generation sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy., Results: A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q = 0.01; P = 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P = 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response., Conclusion: PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs., Competing Interests: Disclosure JLS reports stock ownership in the following companies: Pfizer, Thermo Fischer Scientific, Inc., Merck & Co Inc., and Chemed Corp. KCA has been a compensated consultant for AstraZeneca. MAE is a consultant for AstraZeneca and received support from AstraZeneca, Invivoscribe, and Raindance Technologies. ML has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda, and Bayer and research support from Loxo Oncology and Helsinn Healthcare. CML is a consultant for AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Chugai, Daiichi Sankyo, Genentech/Roche, GI Therapeutics, Loxo, Novartis, PharmaMar, and Seattle Genetics; serves on the scientific advisory boards of Elucida and Harpoon; and reports personal fees from Bristol-Myers Squibb and Ipsen. GJR has research funding for his institution from Pfizer, Novartis, Takeda, and Roche. MDH receives research funding from Bristol-Myers Squibb; is a paid consultant to Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs; receives travel support/honoraria from AstraZeneca and Bristol-Myers Squibb; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. All other authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2020
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38. Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50.
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Gainor JF, Rizvi H, Jimenez Aguilar E, Skoulidis F, Yeap BY, Naidoo J, Khosrowjerdi S, Mooradian M, Lydon C, Illei P, Zhang J, Peterson R, Ricciuti B, Nishino M, Zhang J, Roth JA, Grishman J, Anderson D, Little BP, Carter BW, Arbour K, Sauter JL, Mino-Kenudson M, Heymach JV, Digumarthy S, Shaw AT, Awad MM, and Hellmann MD
- Subjects
- Apoptosis, B7-H1 Antigen genetics, Humans, Programmed Cell Death 1 Receptor, Retrospective Studies, Smokers, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Phospholipase D metabolism
- Abstract
Background: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined., Patients and Methods: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB., Results: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]., Conclusions: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade., Competing Interests: Disclosure JFG: consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Regeneron, Oncorus, Array, Jounce, and Clovis Oncology, research support from Novartis, Genentech/Roche, and Ariad/Takeda, and institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo. JAR: consultant and equity in Genprex. BPL: Elsevier textbook author and editor, and receives royalties for his work. KA: consultant or received honoraria from AstraZeneca and Jackson Laboratory. JA: owns stock in Merck, Pfizer, and Thermo Fischer Scientific. MMK: consultant for Merimack Pharmaceuticals and H3 Biomedicine. ATS: consultant or received honoraria from Pfizer, Novartis, Chugai, Genentech/Roche, Ariad/Takeda, Ignyta, LOXO, Blueprint Medicines, KSQ Therapeutics, Daiichi Sankyo, EMD Serono, Taiho Pharmaceutical, TP Therapeutics, Bayer, Foundation Medicine, Guardant, and Natera. Institutional research funding from: Pfizer, Novartis, Roche/Genentech, Ariad, Ignyta, and TP Therapeutics. MMA: consultant or received honoraria from Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Blueprint, Maverick, and Syndax and research support from Bristol-Myers Squibb, AstraZeneca, Lilly, and Genentech. MDH: has received research funding from Bristol-Myers Squibb; is a paid consultant to Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, and Immunai; has received travel support/honoraria from AztraZeneca and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. The remaining authors have no conflicts of interest to disclose., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2020
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39. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.
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Aguilar EJ, Ricciuti B, Gainor JF, Kehl KL, Kravets S, Dahlberg S, Nishino M, Sholl LM, Adeni A, Subegdjo S, Khosrowjerdi S, Peterson RM, Digumarthy S, Liu C, Sauter J, Rizvi H, Arbour KC, Carter BW, Heymach JV, Altan M, Hellmann MD, and Awad MM
- Subjects
- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung pathology, Adult, Aged, Aged, 80 and over, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor immunology, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell pathology, Female, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Lung Neoplasms pathology, Male, Middle Aged, Patient Selection, Prognosis, Retrospective Studies, Survival Rate, Adenocarcinoma of Lung mortality, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Squamous Cell mortality, Lung Neoplasms mortality
- Abstract
Background: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown., Patients and Methods: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes ., Results: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002]., Conclusion: Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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40. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.
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Hastings K, Yu HA, Wei W, Sanchez-Vega F, DeVeaux M, Choi J, Rizvi H, Lisberg A, Truini A, Lydon CA, Liu Z, Henick BS, Wurtz A, Cai G, Plodkowski AJ, Long NM, Halpenny DF, Killam J, Oliva I, Schultz N, Riely GJ, Arcila ME, Ladanyi M, Zelterman D, Herbst RS, Goldberg SB, Awad MM, Garon EB, Gettinger S, Hellmann MD, and Politi K
- Subjects
- Aged, Alleles, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen immunology, B7-H1 Antigen metabolism, Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung mortality, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Genetic Heterogeneity, Humans, Lung immunology, Lung pathology, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms mortality, Male, Middle Aged, Mutation, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Progression-Free Survival, Retrospective Studies, Tobacco Smoking adverse effects, Tobacco Smoking epidemiology, Antineoplastic Agents, Immunological pharmacology, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade., Patients and Methods: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations., Results: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history., Conclusions: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)
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- 2019
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41. Correction to: "Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up".
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Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, and Peters S
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- 2019
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42. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
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Sabari JK, Leonardi GC, Shu CA, Umeton R, Montecalvo J, Ni A, Chen R, Dienstag J, Mrad C, Bergagnini I, Lai WV, Offin M, Arbour KC, Plodkowski AJ, Halpenny DF, Paik PK, Li BT, Riely GJ, Kris MG, Rudin CM, Sholl LM, Nishino M, Hellmann MD, Rekhtman N, Awad MM, and Drilon A
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma metabolism, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cohort Studies, Female, Follow-Up Studies, High-Throughput Nucleotide Sequencing, Humans, Immunotherapy methods, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Male, Middle Aged, Prognosis, Survival Rate, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung pathology, Exons genetics, Lung Neoplasms pathology, Mutation, Proto-Oncogene Proteins c-met genetics
- Abstract
Background: MET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized., Patients and Methods: Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels., Results: We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1%-49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase (P < 0.001, n = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase (P < 0.001, n = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearman's rho=0.18, P = 0.069). In response-evaluable patients (n = 24), the objective response rate was 17% (95% CI 6% to 36%) and the median progression-free survival was 1.9 months (95% CI 1.7-2.7). Responses were not enriched in tumors with PD-L1 expression ≥50% nor high TMB., Conclusion: A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.
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- 2018
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43. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).
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Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, Rekhtman N, Anders RA, Cuda JD, Illei PB, Gabrielson E, Askin FB, Niknafs N, Smith KN, Velez MJ, Sauter JL, Isbell JM, Jones DR, Battafarano RJ, Yang SC, Danilova L, Wolchok JD, Topalian SL, Velculescu VE, Pardoll DM, Brahmer JR, Hellmann MD, Chaft JE, Cimino-Mathews A, and Taube JM
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- Adult, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Feasibility Studies, Humans, Ipilimumab pharmacology, Ipilimumab therapeutic use, Lung immunology, Lung surgery, Lung Neoplasms immunology, Lung Neoplasms pathology, Neoadjuvant Therapy methods, Neoplasm, Residual, Nivolumab pharmacology, Nivolumab therapeutic use, Pneumonectomy, Prognosis, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Reproducibility of Results, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung therapy, Lung pathology, Lung Neoplasms therapy
- Abstract
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed., Patients and Methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed., Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002)., Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
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- 2018
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44. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.
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Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, Motzer RJ, Wu S, Busam KJ, Wolchok JD, and Lacouture ME
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cell Cycle Checkpoints drug effects, Clinical Trials as Topic, Exanthema chemically induced, Female, Humans, Male, Middle Aged, Nivolumab, Programmed Cell Death 1 Receptor antagonists & inhibitors, Pruritus chemically induced, Vitiligo chemically induced, Young Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Drug Eruptions etiology, Neoplasms drug therapy
- Abstract
Background: Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known., Methods: We conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented., Results: Rash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab., Conclusion: We found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors., Competing Interests: STATEMENT VRB, BB, MDH, NHS, RJM, and KJB have no conflicts of interest to declare. MAP has had a consulting or advisory role with Amgen and Bristol-Myers Squibb, and receives research support from Bristol-Myers Squibb and Novartis (Inst). AML has a consulting or advisory role with Bristol-Myers Squibb, Janssen, Aduro, Efranat, Jounce, and Novartis, and receives research funding from Bristol-Myers Squibb (Inst), Janssen (Inst.), and Genentech (Inst). SW has a speaking arrangement with Novartis, Bayer-Onyx, Pfizer, and Mediavation. JDW has a consulting or advisory role with Bristol-Myers Squibb, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, GlaxoSmithKline; receives honoraria from EMD Serono, Janssen Oncology, and research funding from Bristol-Myers Squibb (Inst), MedImmune (Inst), GlaxoSmithKline (Inst), Merck (Inst). MEL has consulted for BMS and Merck, and received research support from Bristol-Myers Squibb (Inst)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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