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BACKGROUND No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoffl). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaKlOO ClinicalTrials.gov number, NCT03600883). [ABSTRACT FROM AUTHOR]

Objective: To provide a review of the science and applicability of current multi-cancer early detection (MCED) tests for otolaryngologists., Data Sources: PubMed, clinicaltrials.gov, company websites., Review Methods: Using PRISMA methodology, primary literature regarding MCED tests was queried from April 26 to May 12, 2024 using MCED search terms. Ongoing clinical trials incorporating MCED screens were identified via the National Institutes of Health clinicaltrials.gov website. Company websites for available or upcoming MCED tests were reviewed., Conclusion: Long-term robust data regarding the performance characteristics, effects on clinical outcomes, and cost-utility of MCED tests for head and neck cancer are currently lacking. Otolaryngologists should be aware of the implications of MCED tests as these assays become more widely used., Implications for Practice: Although not FDA-approved or covered by insurances at the time of writing of this manuscript, MCED testing is rapidly gaining interest, and patients with positive tests are presenting to otolaryngologists for evaluation. While MCED technologies hold great promise for early detection of disease and potential reduction of morbidity and mortality, more study is needed about their utility for head and neck cancer and optimal diagnostic workflows., Competing Interests: GD: None related to MCED, however, Dr. Durm has grant and research support from Merck, BMS, and Astra Zeneca, and has honoraria from Dava Oncology, Curio Science, and Astra Zeneca., (© 2024 The Author(s). OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology‐Head and Neck Surgery Foundation.)

Purpose/objective(s): The addition of immunotherapy (IO) after concurrent chemoradiation (CCRT) for unresectable non-small cell lung cancer (NSCLC) has become common practice in eligible patients. Approaches to further improve outcomes and reduce treatment-related toxicity for these patients are needed. This study evaluates the risk of radiation pneumonitis after CCRT and its correlation with the radiation dose distribution, immunotherapy regimen (nivolumab vs nivolumab plus ipilimumab), and patient demographics across BTCRC-LUN16-081., Materials/methods: Patients with unresectable stage III NSCLC after completion of CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial to assess efficacy and tolerability of consolidative nivolumab versus nivolumab plus ipilimumab for six months. Radiation dose parameters, patient demographics, and toxicity events were evaluated among treatment arms for risk and severity of pneumonitis., Results: One-hundred and five patients were enrolled into two treatment arms, 54 patients received nivolumab alone and 51 patients received nivolumab plus ipilimumab. Of these, 104 patients had dose volume histogram (DVH) information available. Within this cohort, 65 patients (62.5%) had stage IIIA and 39 patients (37.5%) had stage IIIB NSCLC disease per AJCC 7 th edition. During the study, 29 patients (27.9%) were diagnosed with grade 2 or greater pneumonitis. Utilizing logistic regression and evaluating different cut-offs for lung V20, patients with V20 >23% demonstrated significantly higher grade 2 or greater pneumonitis rates (37.1% vs. 16.2%, P = .031). No significant difference in rates of pneumonitis between arms were identified. Traditional lung DVH cut-offs (V5 of >65%, V20 of >35%, mean >20 Gy) were not associated with pneumonitis., Conclusion: In patients receiving nivolumab or nivolumab plus ipilimumab after definitive CCRT, lung V20 of >23% was associated with an increased risk of grade 2 or greater pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible., Competing Interests: Declaration of competing interest MS previously served on the speaker bureau for Jazz Pharmaceuticals. MS has received consulting advisory fees from AstraZeneca and Jazz Pharmaceuticals. GD receives Research Funding from Astra Zeneca, Merck, Bristol Myers Squib and honoraria from Curio Science, Dava Oncology. HN has received research funding support for institutional investigator initiatives from Genentech, Bristol Myers Squibb, Merck, and Natera. During the preparation of this work the author used ChatGPT in order to proofread sentences at times. After using this tool/service, the author reviewed and edited the content as needed and take full responsibility for the content of the publication., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The current standard of care for patients with inoperable stage III non-small cell lung cancer includes chemoradiotherapy (CRT) followed by 1 year of checkpoint inhibitor (CPI) therapy. Nevertheless, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of patients with unresectable locally advanced non-small cell lung cancer treated on a phase 2 trial of short-course consolidation immunotherapy after CRT, with the goal of testing whether ctDNA may be able to identify patients who do not require a full year of treatment., Methods: Plasma samples for ctDNA analysis were collected from patients on the Big Ten Cancer Research Consortium LUN 16-081 trial after completion of CRT, before day 1 of cycle 2 (C2D1) of CPI (i.e., 1 mo after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using cancer personalized profiling by deep sequencing. Levels of ctDNA at each time point were correlated with clinical outcomes., Results: Detection of ctDNA predicted significantly inferior progression-free survival after completion of CRT (24-mo 29% versus 65%, p = 0.0048), before C2D1 of CPI (24-mo 0% versus 72%, p < 0.0001) and at the end of CPI (24-mo 15% versus 67%, p = 0.0011). In addition, patients with decreasing or undetectable ctDNA levels after 1 cycle of CPI had improved outcomes compared with patients with increasing ctDNA levels (24-mo progression-free survival 72% versus 0%, p < 0.0001). Progression of disease occurred within less than 12 months of starting CPI in all patients with increasing ctDNA levels at C2D1., Conclusions: Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment., Competing Interests: Disclosure Dr. Durm receives support from Bristol-Myers Squibb; grants or contracts from AstraZeneca, Merck, and Mirati; consulting fees from Cook Biotech; payments or honoraria from Curio Science, DAVA Oncology, and AstraZeneca; and participates on an advisory board for Curio Science, DAVA oncology, and AstraZeneca. Dr. Ganti receives research grants or contracts from VA Office of Research and Development, Merck, TAB Biosciences, NEKTAR Therapeutics, Mirati Therapeutics, IOVANCE Therapeutics, and Apexigen; royalties or licenses from Oxford University Press; consulting fees from AstraZeneca, Flagship Biosciences, G1 Therapeutics, Jazz Pharmaceuticals, Cardinal Health, Mirati Therapeutics, Beigene Ltd., Sanofi Genzyme, Blueprint Medicines, and Regeneron Pharmaceuticals; payments or honoraria from MedLearning Group and Plexus Communications; participates on a data safety monitoring board for YmAbs Therapeutics; holds leadership or fiduciary roles at Academic and Community Cancer Research United and A Breath of Hope for Lung Cancer; and has received equipment or materials from Takeda Pharmaceuticals and Chimerx. Dr. Alizadeh receives research grants or contracts from the National Cancer Institute, National Heart, Lung and Blood Institute, National Institutes of Health, Celgene, Bristol-Myers Squibb, and Pfizer; consulting fees from ADCT, Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche; has patents planned, issued, or pending with FortySeven Inc., Foresight Diagnostics, CiberMed Inc., and Roche; participates on a data safety monitoring board for Lymphoma Research Foundation; holds leadership or fiduciary roles at the American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, and Leukemia & Lymphoma Society; and has equity ownership interests in CiberMed Inc., Foresight Diagnostics, FortySeven Inc., and CARGO Therapeutics. Dr. Hanna receives grants or contracts from Merck, Genentech, Bristol-Myers Squibb, and Natera. Dr. Diehn receives grants or contracts from AstraZeneca and Varian Medical Systems; royalties or licenses from Roche and Foresight Diagnostics; consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Illumina, Gritstone Bio, and Regeneron; payments or honoraria from Bristol-Myers Squibb, Japan, and Novartis; support for attending meetings or travel from Foresight Diagnostics and Regeneron; has patents planned, issued, or pending with Stanford University; holds leadership or fiduciary roles at Foresight Diagnostics; and holds stock or stock options in CiberMed Inc., Foresight Diagnostics, and Gritstone Bio. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

PD-L1 IHC 22C3 pharmDx is an FDA-approved companion test to select patients for anti-PD-L1 immunotherapy. In head and neck squamous cell carcinoma PD-L1 expression is determined using a Combined Positive Score (CPS), which evaluates expression in tumor cells and tumor-associated leukocytes. We hypothesized that in nodal metastasis, the CPS should be higher given their inherent higher proportion of leukocytes. A significant difference in CPS between sites would mean that the tissue chosen for PD-L1 testing would impact patient eligibility for therapy. Currently, guidelines about which tissue should be tested do not exist. PD-L1 22C3 IHC was performed in the primary and nodal metastases of 35 head and neck squamous cell carcinoma, and a CPS was generated by 3 pathologists. Mean CPS was higher at the primary than the nodal metastasis: 47.2 versus 42.2; however, the difference was not statistically significant: P=0.259 . By therapeutic groups: negative (CPS <1), low (CPS 1-19) and high (CPS≥20), low-expression was more common in the primary: 40 vs. 26%, and high-expression in the nodal metastasis: 74 vs. 60% but this difference was not statistically significant: P=0.180. Stratified by positive versus negative (CPS <1 vs. ≥1), there were no differences between sites. Interobserver agreement for CPS among the 3 raters was slight for both sites: ƙ = 0.117 and 0.025, fair if stratified by therapeutic group: ƙ = 0.371 and 0.318, and near perfect if stratified as negative versus positive: ƙ = 0.652 and 1. There were no statistically significant differences in CPS between primary and nodal metastases independent of how the CPS was stratified., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community., Objective: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community., Methods: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non-case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers' practice., Results: A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians' practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new., Conclusions: Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians' practices, significantly impact patient care in community practices, and be a source of new knowledge and education., (©Maitri Kalra, Elizabeth Henry, Kelly McCann, Meghan S Karuturi, Jean G Bustamante Alvarez, Amanda Parkes, Robert Wesolowski, Mei Wei, Sarah S Mougalian, Gregory Durm, Angel Qin, Caitlin Schonewolf, Meghna Trivedi, Avan J Armaghani, Frederick H Wilson, Wade T Iams, Anita A Turk, Praveen Vikas, Michael Cecchini, Sam Lubner, Priyadarshini Pathak, Kristen Spencer, Vadim S Koshkin, Matthew K Labriola, Catherine H Marshall, Katy E Beckermann, theMednet.org NCI-CCC Tumor Board Program Collaborative Group, Marina N Sharifi, Anthony C Bejjani, Varsha Hotchandani, Samir Housri, Nadine Housri. Originally published in JMIR Cancer (https://cancer.jmir.org), 19.05.2022.)

Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy., Competing Interests: The authors have following conflicts of interest within the past 2 years, none of which influenced the work being submitted. HM: Advisory role – Zentalis. GD: Research grant - BMS, AstraZeneca, Merck; Honoraria - AstraZeneca, Curio Science. SJ: Research grant - AstraZeneca, Astex, Tesaro; Consultant – Adaptimmune. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mamdani, Matosevic, Khalid, Durm and Jalal.)

Purpose: Little research has assessed cancer patients' success criteria and priorities for symptom improvement to inform patient-centered care. Thus, we modified and tested a measure of these constructs for advanced lung cancer patients. We compared acceptable severity levels following symptom treatment across eight symptoms and identified patient subgroups based on symptom importance., Methods: Advanced lung cancer patients (N=102) completed a one-time survey, including the modified Patient-Centered Outcomes Questionnaire (PCOQ), standard symptom measures, and other clinical characteristics., Results: The modified PCOQ showed evidence of construct validity through associations with theoretically related constructs. Symptom severity and importance were moderately correlated. Levels of acceptable symptom severity were low and did not differ across the eight symptoms. Four patient subgroups were identified: (1) those who rated all symptoms as low in importance (n=12); (2) those who rated bronchial symptoms and sleep problems as low in importance and all other symptoms as moderately important (n=29); (3) those who rated nausea and emotional distress as low in importance and all other symptoms as moderately important (n=23); and (4) those who rated all symptoms as highly important (n=33). Subgroups were unrelated to clinical characteristics, except for functional status., Conclusion: The modified PCOQ showed evidence of construct validity. Patients considered low symptom severity to be acceptable, irrespective of the symptom. Findings suggest that symptom severity and importance are related yet distinct aspects of the advanced lung cancer symptom experience. Patients have heterogeneous priorities for symptom improvement, which has implications for tailoring treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Nikhil ShuklaPatents, Royalties, Other Intellectual Property: Combination of SapC-DOPS and AS1411 for the treatment of glioblastoma multiforme Nasser HannaHonoraria: UpToDateResearch Funding: Merck KGaA, Bristol Myers Squibb, AstraZeneca/MedImmune, GenentechOther Relationship: BeyondSpring Pharmaceuticals Greg DurmHonoraria: AstraZeneca, Curio ScienceResearch Funding: Merck, Bristol Myers Squibb, AstraZenecaNo other potential conflicts of interest were reported.

Background: Probody ® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1)., Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1)., Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1)., Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression., Trial Registration Number: NCT03013491., Competing Interests: Competing interests: AN: Research funding from Amplimmune, Arcus Biosciences, ARMO BioSciences, Atterocor, BMS, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD, HealiosOnc, ImmuneOncia, Incyte, Karyopharm Therapeutics, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Nutrition, Pfizer, PsiOxus, Regeneron, Serono, Surface Oncology, and TopAlliance Biosciences. Advisory boards for CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, and STCube Pharmaceuticals. Travel expenses from ARMO BioSciences. AN’s spouse has received research funding from Baxalta, Chao physician-scientist, Immune Deficiency Foundation, and Jeffery Modell Foundation; and has served on advisory boards for Behring, CSL, Horizon, Pharming, and Takeda. FT: Research funding and conference registration from Novartis. Consultancy/advisory role for Achilles Therapeutics, Bayer, BMS, Enara Bio, GSK, T-Knife, and Zelluna. EGEDV: Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and Sanofi; all outside the submitted work. FALME: Consultancy/advisory role for Servier, Novartis, Eisai, and Ipsen. NU: Consultant for AstraZeneca, Eli Lilly, Ipsen, QED, and Taiho. Research support from EMD, Ipsen, Serono, and Taiho. Holds stock in Exact Sciences and Natera. PAO: Research funding from and advisory role for Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol-Meyers Squibb, Celldex, CytomX, Merck, Neon Therapeutics, Novartis, Pfizer, and Roche/Genentech. PL: Consultant/advisory board for AbbVie, ABL Bio, Agenus, Agios, Astellas, AstraZeneca, Black Diamond, Cybrexa, CytomX, EMD Serono, GenMab, Genentech, Glaxo-Smith Kline, ImmunoMet, IQVIA, Kineta Inc., Kyowa Kirin Pharmaceutical Development, MacroGenics, Molecular Templates, Pfizer, QED Therapeutics, Salarius, Shattuck, Silverback, SK Life Science, SOTIO, STCube Pharmaceuticals, Takeda, TRIGR, and Zentalis Pharmaceuticals. Data safety monitoring committee for Five Prime, Halozyme, and Tyme. Participant in imCORE Alliance (Roche/Genentech). JG-C: Speaker’s bureau for Bayer; fees to support registration and attending scientific meetings from BMS and Novartis. VB: Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences, Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Boston Therapeutics, Cytomx Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Macrogenics, Menarini, Merck, Mersana, Merus, Millenium, MSD, Nanobiotix, Nektar, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: Institutional financial support for clinical trials or contracted research from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech/Roche, Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks. Institutional financial support for advisory boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, Genentech/Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech/Roche, Gilead, Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: Advisory board for CytomX (unpaid). Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, Pfizer, and Tizona. MR: Honoraria from Bayer. GD: Research funding from AstraZeneca, Bristol Myers Squibb, and Merck. Honoraria from AstraZeneca. Advisory board for Curio Science. MG-M: Speaker’s bureau for Astra Zeneca, Pharmamar, and Roche. Financial support for registration and attendance at scientific meetings from MDS, Pharmamar, and Roche. MS is a former employee and ALH is a current employee of CytomX Therapeutics, Inc. Both are stockowners in CytomX Therapeutics Inc. H-TA: Advisor for Bayer, Beigene, Bicycle, Engitix, Guardant, iOnctura, Roche, and Servier. Employed by HCA Healthcare UK and Sarah Cannon Research Institute. AS: Consultant for Amgen, AstraZeneca, BMS, Merck, Mirati, and Novartis. Institutional financial support for clinical trials or contracted research from CytomX., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Many patients with non-small-cell lung cancer (NSCLC) treated with immunotherapy experience immune-related adverse events (irAEs). Patients with metastatic NSCLC who receive checkpoint inhibitors (CPI) and experience irAEs generally receive fewer cycles of CPI without decreased efficacy. However, the association between irAEs and efficacy outcomes in patients with locally advanced NSCLC treated with curative intent with CPI after chemoradiation has never been reported. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the Hoosier Cancer Research Network (HCRN) LUN 14-179 single-arm phase 2 trial of consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC., Patients and Methods: A total of 92 eligible patients were enrolled from March 2015 to November 2016. Demographics, disease characteristics, and number of pembrolizumab cycles received were reported in patients with and without irAEs. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS). A log-rank test was used to compare groups., Results: Any grade irAEs occurred in 55.4% of patients. There was no significant difference in number of pembrolizumab cycles received, TMDD, OS, or PFS in patients with and without irAEs. Patients who discontinued pembrolizumab early because of irAEs received significantly fewer cycles of pembrolizumab (5 vs 15, P = .0016) without a significant difference in TMDD, PFS, or OS. Similarly, patients who received immunosuppressive therapy received fewer numbers of cycles of pembrolizumab (4 vs 16, P < .001) without significantly reduced TMDD, PFS, or OS., Conclusion: irAEs due to pembrolizumab, regardless of grade or number of irAEs, were not associated with decreased efficacy outcomes. Furthermore, early discontinuation of pembrolizumab because of irAEs and/or treatment of irAEs with immunosuppressive therapy was not associated with a decrease in treatment efficacy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background Palbociclib is a selective inhibitor of CDK4/6 approved in metastatic breast cancer as well as evidence of activity in malignancies with CDK4-amplifications. Extensive preclinical evidence has demonstrated synergy of CDK4/6 inhibitors with platinum chemotherapy suggesting a potential role for clinical synthetic lethality. Given the sensitivity to platinum therapy as well as the landscape of genomic alterations, concurrent treatment with platinum chemotherapy and palbociclib is of significant interest as a novel treatment approach. Patients and Methods Patients with unresectable, recurrent, or metastatic head and neck cancer (R/M HNC) were enrolled. Eligible patients were required to have no previous treatment with cytotoxic chemotherapy in the recurrent/metastatic setting. This was a multicenter phase II trial in which patients were administered carboplatin in addition to concurrent palbociclib. The primary endpoint of this trial was 12-week disease control rate (DCR). Results Twenty-one patients were enrolled and 18 were evaluable for response. Grade 3/4 treatment related toxicities were seen in 79% of patients of which the most common were related to myelosuppression. 12-week DCR was 33% (5 patients with stable disease, 1 with a partial response). Median progression free survival was 2.9 months (range: 1.2-13.3) and overall survival was 4.6 months (range: 1.4-14.8). Conclusion The combination of carboplatin and palbociclib is associated with significant treatment related toxicity and insufficient anti-tumor activity.

Introduction: The Hoosier Cancer Research Network (HCRN) LUN 14-179 is a phase II trial of consolidation pembrolizumab after concurrent chemoradiation for the treatment of patients with stage III non-small-cell lung cancer (NSCLC). Time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS) appear to be superior to that in historical controls of chemoradiation alone. Unfortunately, not all patients benefit from consolidation immunotherapy. We performed a univariate analysis to evaluate variables associated with PFS, metastatic disease, and OS., Patients and Methods: We conducted a retrospective analysis of patients enrolled in HCRN LUN 14-179. Data collected included age, sex, stage, smoking status, programmed death ligand 1 status, Grade (G) ≥ 2 versus G ≤ 1 adverse event, G ≤ 2 versus G ≥ 3 pneumonitis, duration of pembrolizumab (< 4 vs. ≥ 4 cycles), chemotherapy regimen, performance status 0 versus 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), volume of lung receiving at least 20 Gy of radiation (V 20 ; < 20% vs. ≥ 20%). Univariable Cox regression was performed to determine the variables associated with 3 end points: TMDD, PFS, and OS., Results: From April 2015 to December 2016, 93 patients were enrolled and 92 were included in the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes might be associated (P < .1) with stage IIIA and ≥ 4 cycles of pembrolizumab. For PFS, improved outcomes (P < .1) might be seen for ≥ 4 cycles of pembrolizumab, stage IIIA and V 20  < 20%. For OS, improved outcomes (P < .1) might be seen for stage IIIA and ≥ 4 cycles of pembrolizumab., Conclusion: Stage IIIA and longer duration of pembrolizumab treatment might be associated with prolonged TMDD, PFS, and OS for patients with stage III NSCLC treated with chemoradiation followed by pembrolizumab., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Advanced lung cancer patients typically have a poor prognosis and many symptoms that interfere with functioning, contributing to high rates of emotional distress in both patients and family caregivers. There remains a need for evidence-based interventions to improve functional outcomes and distress in this population., Objectives: This pilot trial examined the feasibility and preliminary efficacy of telephone-based Acceptance and Commitment Therapy (ACT) for symptomatic, advanced lung cancer patients and their distressed family caregivers. Primary outcomes were patient symptom interference with functioning and patient and caregiver distress., Methods: Symptomatic, advanced lung cancer patients and distressed caregivers (n = 50 dyads) were randomly assigned to six sessions of ACT or an education/support condition. Patients completed measures of symptom interference and measures assessing the severity of fatigue, pain, sleep disturbance, and breathlessness. Patients and caregivers completed measures of distress and illness acceptance and struggle., Results: The eligibility screening rate (51%) and retention rate (76% at six weeks postintervention) demonstrated feasibility. No group differences were found with respect to patient and caregiver outcomes. Both groups showed a small, significant decrease in struggle with the illness over the study period, but did not show meaningful change in other outcomes., Conclusion: Findings suggest that telephone-based ACT is feasible for many advanced lung cancer patients and caregivers, but may not substantially reduce symptom interference and distress. Low baseline levels of certain symptoms may have contributed to null findings. Next steps include applying ACT to specific, clinically meaningful symptom interference and varying intervention dose and modality., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

The landscape for the second- and third-line treatment of advanced non-small cell lung cancer has changed dramatically over the last two decades. Immunotherapeutic agents have become a preferred choice following progression on platinum-based first-line chemotherapy. However, there remains a role for cytotoxic chemotherapy and pemetrexed and docetaxel (with or without ramucirumab) are approved for single-agent use in the second-line setting. With the discovery of new genetic alterations and the development of novel targeted drugs, the treatment of advanced non-small cell lung cancer following progression on first-line therapy continues to become more complicated as new treatment algorithms evolve., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Angiogenesis plays a major role in the growth and progression of non-small-cell lung cancer (NSCLC), and there is increasing interest in the development of therapies that block this particular aspect of tumorigenesis. Bevacizumab was the first US FDA-approved inhibitor of angiogenesis after demonstrating improved progression-free survival and overall survival in combination with chemotherapy in treating NSCLC. However, the benefit of bevacizumab is only modest and transient as the tumors inevitably develop resistance to this particular treatment. Therefore, new therapies are being developed that attempt to inhibit angiogenesis through several different pathways. One promising new drug, nintedanib, is an oral triple angiokinase inhibitor that acts by blocking not only VEGFR, but also FGFR and PDGFR, which are involved in the development of resistance to bevacizumab. This article discusses the rationale for this approach and summarizes the clinical trial data on nintedanib, including the two most recent Phase III trials.