40 results on '"McCleland, M."'
Search Results
2. FP13.03 IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC
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Herbst, R., primary, De Marinis, F., additional, Giaccone, G., additional, Vergnenegre, A., additional, Barrios, C., additional, Morise, M., additional, Felip, E., additional, Oprean, C., additional, Kim, Y., additional, Andric, Z., additional, Mocci, S., additional, Enquist, I., additional, Komatsubara, K., additional, Mccleland, M., additional, Deng, Y., additional, Kuriki, H., additional, Villalobos, M., additional, Phan, S., additional, Spigel, D., additional, and Jassem, J., additional
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- 2021
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3. 375O Final efficacy results from IMpower132: First-line atezolizumab + chemotherapy in patients with stage IV non-squamous NSCLC
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Nishio, M., primary, Barlesi, F., additional, Ball, S., additional, Bordoni, R., additional, Cobo, M., additional, Dubray-Longeras, P., additional, Goldschmidt, J., additional, Novello, S., additional, Orlandi, F.J., additional, Sanborn, R., additional, Szalai, Z., additional, Ursol, G., additional, Mendus, D., additional, Wang, L., additional, Wen, X., additional, McCleland, M., additional, Hoang, T., additional, Phan, S., additional, and Socinski, M., additional
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- 2020
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4. 1781MO IMpower133: Characterisation of long-term survivors treated first-line with chemotherapy ± atezolizumab in extensive-stage small cell lung cancer
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Liu, S.V., primary, Horn, L., additional, Mok, T., additional, Mansfield, A., additional, De Boer, R., additional, Losonczy, G., additional, Sugawara, S., additional, Dziadziuszko, R., additional, Krzakowski, M., additional, Smolin, A., additional, Hochmair, M.J., additional, Garassino, M.C., additional, Lam, S., additional, McCleland, M., additional, Cardona, A., additional, Morris, S., additional, and Reck, M., additional
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- 2020
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5. 1265P IMpower150: A post hoc analysis of efficacy outcomes in patients with KRAS, STK11 and KEAP1 mutations
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West, H., primary, Cappuzzo, F., additional, Reck, M., additional, Mok, T., additional, Jotte, R.M., additional, Nishio, M., additional, Kim, E., additional, Morris, S., additional, Shankar, G., additional, Zou, W., additional, Shames, D., additional, McCleland, M., additional, and Socinski, M.A., additional
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- 2020
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6. LBA1 Clinical efficacy of atezolizumab (atezo) in biomarker subgroups by SP142, SP263 and 22C3 PD-L1 immunohistochemistry (IHC) assays and by blood tumour mutational burden (bTMB): Results from the IMpower110 study
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Herbst, R.S., primary, de Marinis, F., additional, Giaccone, G., additional, Reinmuth, N., additional, Vergnenegre, A., additional, Barrios, C.H., additional, Morise, M., additional, Felip, E., additional, Andric, Z., additional, Geater, S., additional, Ozguroglu, M., additional, Mocci, S., additional, McCleland, M., additional, Zou, W., additional, Enquist, I., additional, Komatsubara, K., additional, Deng, Y., additional, Kuriki, H., additional, Spigel, D.R., additional, and Jassem, J., additional
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- 2019
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7. OA14.02 IMpower131: Final OS Results of Carboplatin + Nab-Paclitaxel ± Atezolizumab in Advanced Squamous NSCLC
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Jotte, R., primary, Cappuzzo, F., additional, Vynnychenko, I., additional, Stroyakovskiy, D., additional, Abreu, D. Rodriguez, additional, Hussein, M., additional, Soo, R., additional, Conter, H., additional, Kozuki, T., additional, Huang, K., additional, Graupner, V., additional, Sun, S., additional, Hoang, T., additional, Jessop, H., additional, Mccleland, M., additional, Ballinger, M., additional, Sandler, A., additional, and Socinski, M., additional
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- 2019
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8. IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC
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Spigel, D., primary, de Marinis, F., additional, Giaccone, G., additional, Reinmuth, N., additional, Vergnenegre, A., additional, Barrios, C.H., additional, Morise, M., additional, Felip, E., additional, Andric, Z.G., additional, Geater, S., additional, Özgüroğlu, M., additional, Mocci, S., additional, McCleland, M., additional, Enquist, I., additional, Komatsubara, K.M., additional, Deng, Y., additional, Kuriki, H., additional, Wen, X., additional, Jassem, J., additional, and Herbst, R.S., additional
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- 2019
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9. IMpower133: Updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC)
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Reck, M., primary, Liu, S.V., additional, Mansfield, A.S., additional, Mok, T.S.K., additional, Scherpereel, A., additional, Reinmuth, N., additional, Garassino, M.C., additional, De Carpeno, JCastro, additional, Califano, R., additional, Nishio, M., additional, Orlandi, F., additional, Alexander, J A Alatorre, additional, Leal, T.A., additional, Cheng, Y., additional, Lee, J.-S., additional, Lam, S., additional, McCleland, M., additional, Deng, Y., additional, Phan, S., additional, and Horn, L., additional
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- 2019
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10. Clinical Efficacy of atezolizumab (atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study
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Rittmeyer, A, additional, Gadgeel, S, additional, Kowanetz, M, additional, Zou, W, additional, Hirsch, FR, additional, Kerr, KM, additional, Gandara, D, additional, Barlesi, F, additional, Park, K, additional, McCleland, M, additional, Koeppen, H, additional, Ballinger, M, additional, Sandler, A, additional, and Hegde, PS, additional
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- 2018
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11. MA 05.09 Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC
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Kowanetz, M., primary, Zou, W., additional, Mccleland, M., additional, Gandara, D.R., additional, Gadgeel, S., additional, Rittmeyer, A., additional, Barlesi, F., additional, Park, K., additional, Shames, D., additional, Koeppen, H., additional, Ballinger, M., additional, Sandler, A., additional, and Hegde, P., additional
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- 2017
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12. Clinical efficacy of atezolizumab (Atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study
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Gadgeel, S., primary, Kowanetz, M., additional, Zou, W., additional, Hirsch, F.R., additional, Kerr, K.M., additional, Gandara, D.R., additional, Barlesi, F., additional, Park, K., additional, McCleland, M., additional, Koeppen, H., additional, Ballinger, M., additional, Sandler, A., additional, Hegde, P.S., additional, and Rittmeyer, A., additional
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- 2017
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13. LBA78 - IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC
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Spigel, D., de Marinis, F., Giaccone, G., Reinmuth, N., Vergnenegre, A., Barrios, C.H., Morise, M., Felip, E., Andric, Z.G., Geater, S., Özgüroğlu, M., Mocci, S., McCleland, M., Enquist, I., Komatsubara, K.M., Deng, Y., Kuriki, H., Wen, X., Jassem, J., and Herbst, R.S.
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- 2019
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14. 1736O - IMpower133: Updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC)
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Reck, M., Liu, S.V., Mansfield, A.S., Mok, T.S.K., Scherpereel, A., Reinmuth, N., Garassino, M.C., De Carpeno, JCastro, Califano, R., Nishio, M., Orlandi, F., Alexander, J A Alatorre, Leal, T.A., Cheng, Y., Lee, J.-S., Lam, S., McCleland, M., Deng, Y., Phan, S., and Horn, L.
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- 2019
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15. The SP142 PD-L1 IHC assay for atezolizumab (atezo) reflects pre-existing immune status in NSCLC and correlates with PD-L1 mRNA
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Williams, J., primary, Kowanetz, M., additional, Koeppen, H., additional, Boyd, Z., additional, Kadel, E.E., additional, Smith, D., additional, McCleland, M., additional, Zou, W., additional, and Hegde, P.S., additional
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- 2016
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16. 1296O - Clinical efficacy of atezolizumab (Atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study
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Gadgeel, S., Kowanetz, M., Zou, W., Hirsch, F.R., Kerr, K.M., Gandara, D.R., Barlesi, F., Park, K., McCleland, M., Koeppen, H., Ballinger, M., Sandler, A., Hegde, P.S., and Rittmeyer, A.
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- 2017
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17. 553 PRPF6, a tri-snRNP spliceosome protein, regulates the alternative splicing of a distinct oncogenic ZAK variant and promotes colon tumor growth
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Firestein, R., primary, Adler, A., additional, McCleland, M., additional, Yaylaoglu, M., additional, Zhang, Z., additional, Liu, J., additional, and Jiang, Z., additional
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- 2014
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18. 1171P - The SP142 PD-L1 IHC assay for atezolizumab (atezo) reflects pre-existing immune status in NSCLC and correlates with PD-L1 mRNA
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Williams, J., Kowanetz, M., Koeppen, H., Boyd, Z., Kadel, E.E., III, Smith, D., McCleland, M., Zou, W., and Hegde, P.S.
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- 2016
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19. Comparison of SP263 and 22C3 immunohistochemistry PD-L1 assays for clinical efficacy of adjuvant atezolizumab in non-small cell lung cancer: results from the randomized phase III IMpower010 trial.
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Zhou C, Srivastava MK, Xu H, Felip E, Wakelee H, Altorki N, Reck M, Liersch R, Kryzhanivska A, Oizumi S, Tanaka H, Hamm J, McCune SL, Bennett E, Gitlitz B, McNally V, Ballinger M, McCleland M, Zou W, Das Thakur M, and Novello S
- Subjects
- Humans, Immunohistochemistry, B7-H1 Antigen metabolism, Treatment Outcome, Adjuvants, Immunologic, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Small Cell Lung Carcinoma
- Abstract
Background: Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC)., Methods: PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining., Results: When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1-high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups., Conclusions: The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab., Trial Registration Number: NCT02486718., Competing Interests: Competing interests: CZ reports consulting fees from Innovent Biologics, Qilu, Hengrui, and TopAlliance Biosciences Inc; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eli Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone LUYE Pharma, TopAlliance Biosciences Inc, Amoy Diagnostics, and AnHeart. MS reports employment by Genentech and stockholding in Roche. HX reports stockholding in Roche as a former Roche employee. EF reports grants or contracts from Merck Healthcare KGaA and Fundación Merck Salud; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and is an independent member of the board for Grífols. HW reports grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; participation on a data safety monitoring board or advisory board for AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership or fiduciary role in other board, society, committee, or advocacy group (paid or unpaid) for International Association for the Study of Lung Cancer (IASLC) and ECOG-ARIN. MR reports consulting fees from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; and participation on a data safety monitoring board or advisory board for Sanofi and Daiichi Sankyo. SO reports grants or contracts from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceuticals, Daiichi Sankyo, Ono Pharmaceutical, Pfizer, MSD, Sanofi, Taiho, and Takeda. Hiroshi Tanaka reports grants or contracts from Chugai Pharmaceuticals, AstraZeneca, MSD, Ono Pharmaceutical, and Bristol Myers Squibb; and honoraria for Chugai Pharmaceuticals, AstraZeneca, MSD, Ono Pharmaceutical, and Bristol Myers Squibb. SLM reports support from Genentech as a research site for this trial. EB reports employment by Genentech and stockholding in Roche. BG reports employment by Genentech and stockholding in Roche. VM reports employment by Roche and stockholding in Roche. MB reports employment by Genentech and stockholding in Roche. MM reports being a former employee of Roche/Genentech. WZ reports employment by Roche and stockholding in Roche. MDT reports stock or stock options as a former employee of Roche/Genentech. SN reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Amgen, Boehringer Ingelheim, Roche, Pfizer, Takeda, Novartis, Sanofi, Janssen, and GSK; and participation on a data safety monitoring board or advisory board for AstraZeneca, Amgen, Boehringer Ingelheim, Roche, Pfizer, Takeda, Novartis, Sanofi, Janssen, and GSK. NA, RL, AK and JH declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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20. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11 , KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial.
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West HJ, McCleland M, Cappuzzo F, Reck M, Mok TS, Jotte RM, Nishio M, Kim E, Morris S, Zou W, Shames D, Das Thakur M, Shankar G, and Socinski MA
- Subjects
- Adult, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bevacizumab pharmacology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Middle Aged, Mutation, Prognosis, Progression-Free Survival, Retrospective Studies, AMP-Activated Protein Kinase Kinases metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bevacizumab therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Kelch-Like ECH-Associated Protein 1 metabolism, Lung Neoplasms drug therapy, Tumor Suppressor Protein p53 metabolism
- Abstract
Background: The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (m KRAS ) and co-occurring STK11 , KEAP1, or TP53 mutations., Methods: Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774)., Results: Within the m KRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)-greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in m KRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS -WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11 , KEAP1, and TP53 ; these subgroups conferred different prognostic outcomes. Within the m KRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11 -WT and/or KEAP 1-WT. In m KRAS patients with co-occurring m STK11 and/or m KEAP1 (44.9%) or m TP53 (49.3%), survival was longer with ABCP than with ACP or BCP., Conclusions: These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the m KRAS and KEAP1 -WT and STK11 -WT population vs m KRAS and m KEAP1 and m STK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with m KRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression., Competing Interests: Competing interests: FC reports nonfinancial support from Roche/Genentech during the conduct of the study and personal fees from Roche/Genentech, AstraZeneca, Takeda, Pfizer, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, and Bayer, outside the submitted work. RMJ reports nonfinancial support from Roche/Genentech during the conduct of the study and personal fees from Bristol Myers Squibb and Roche/Genentech, outside the submitted work. EK reports stock ownership from Genentech Inc outside the submitted work and employment by Genentech. MM reports other from Roche/Genentech outside the submitted work and employment by Roche/Genentech. TSKM reports personal fees from Abbvie, InMed Medical Communication, MD Health (Brazil), Medscape/WebMD, MoreHealth, PeerVoice, Physicians' Education Resource, P. Permanyer SL, PrIME Oncology, Research to Practice, Touch Medical Media, Curio Science, Inivata, and Berry Oncology. He reports personal fees and other from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Blueprint Medicines, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Ignyta, IQVIA, Incyte, Janssen, Lilly, Loxo-Oncology, Lunit, Mirati Therapeutics, OrigiMed, Puma Technology, Roche, Sanofi-Aventis R&D, Takeda, and Yuhan. He reports grants from Clovis Oncology, SFJ Pharmaceuticals, and XCovery; grants and personal fees from G1 Therapeutics; and grants, personal fees, and other from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, and Pfizer. He reports other from Aurora, Virtus Medical Group, AstraZeneca, Hutchison Chi-Med, Sanomics, and geneDecode, outside the submitted work. SM reports employment by and stock ownership in F. Hoffmann-La Roche. MN reports grants and personal fees from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Merck Sharp & Dohme, Novartis, Daiichi Sankyo, and Takeda Pharmaceutical Company; and personal fees from Boehringer-Ingelheim, Merck Biopharma, Teijin Pharma, and AbbVie, outside the submitted work. MR reports personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Bioepis, outside the submitted work. DS reports employment by Genentech and stock ownership in F. Hoffmann-La Roche. MDT reports employment by Genentech and stock ownership in F. Hoffmann-La Roche. GS reports previous employment by Genentech. MAS reports nonfinancial support from Roche/Genentech during the conduct of the study; grants and personal fees from Roche/Genentech and AstraZeneca; personal fees from Merck, Guardant, Bristol Myers Squibb, and Bayer; and grants from Novartis, outside the submitted work. HJW reports personal fees from Genentech/Roche, AstraZeneca, Merck, Takeda, and Bristol Myers Squibb, outside the submitted work. WZ reports employment by Genentech., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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21. Comparison of SP142 and 22C3 Immunohistochemistry PD-L1 Assays for Clinical Efficacy of Atezolizumab in Non-Small Cell Lung Cancer: Results From the Randomized OAK Trial.
- Author
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Gadgeel S, Hirsch FR, Kerr K, Barlesi F, Park K, Rittmeyer A, Zou W, Bhatia N, Koeppen H, Paul SM, Shames D, Yi J, Matheny C, Ballinger M, McCleland M, and Gandara DR
- Subjects
- Antineoplastic Agents therapeutic use, Docetaxel therapeutic use, Humans, Retrospective Studies, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, B7-H1 Antigen, Carcinoma, Non-Small-Cell Lung drug therapy, Immune Checkpoint Inhibitors therapeutic use, Immunohistochemistry, Lung Neoplasms drug therapy
- Abstract
Background: This phase III OAK trial (NCT02008227) subgroup analysis (data cutoff, January 9, 2019) evaluated the predictive value of 2 PD-L1 IHC tests (VENTANA SP142 and Dako 22C3) for benefit from atezolizumab versus docetaxel by programmed death ligand 1 (PD-L1) status in patients with previously treated metastatic non-small cell lung cancer., Methods: PD-L1 expression was assessed prospectively with SP142 on tumor cells (TC) and tumor-infiltrating immune cells (IC) and retrospectively with 22C3 using a tumor proportion score (TPS) based on TC membrane staining. Efficacy was assessed in the 22C3 biomarker-evaluable population (22C3-BEP) (n = 577; 47.1% of SP142-intention-to-treat population) and non-22C3-BEP (n = 648) in PD-L1 subgroups (high, low, and negative) and according to selection by 1 or both assays., Results: In the 22C3-BEP, overall survival benefits with atezolizumab versus docetaxel were observed across PD-L1 subgroups; benefits were greatest in SP142-defined PD-L1-high (TC3 or IC3: hazard ratio [HR], 0.39 [95% confidence interval (CI), 0.25-0.63]) and 22C3-defined PD-L1-high (TPS ≥ 50%: HR, 0.56 [95% CI, 0.38-0.82]) and low (TPS, 1% to < 50%: HR, 0.55 [95% CI, 0.37-0.82]) groups. Progression-free survival improved with increasing PD-L1 expression for both assays. SP142 and 22C3 assays identified overlapping and unique patient populations in PD-L1-high, positive, and negative subgroups. Overall survival and progression-free survival benefits favored atezolizumab over docetaxel in double PD-L1-positive and negative groups; patients with both SP142- and 22C3-positive tumors derived the greatest benefit., Conclusions: Despite different scoring algorithms and differing sensitivity levels, the SP142 and 22C3 assays similarly predicted atezolizumab benefit at validated PD-L1 thresholds in patients with non-small cell lung cancer., Competing Interests: Disclosure Dr. Gadgeel reports personal fees from Genentech/Roche, AstraZeneca, Merck, Bristol Myers Squibb, Novartis, Daichii-Sanyko, Boehringer-Ingelheim, Xcovery, Jazz Pharmaceuticals, Pfizer, and Janssen, outside the submitted work. Dr. Hirsch reports scientific advisory board for Genentech/Roche, Merck, Bristol Myers Squibb, Novartis, AstraZeneca/Daiichi, Regeneron/Sanofi, and Amgen, outside the submitted work. Dr. Kerr reports personal fees from AbbVie, Amgen, AstraZeneca, Archer Diagnostics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Roche Diagnostics/Ventana, outside the submitted work. Dr. Barlesi reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. Dr. Park has nothing to disclose. Dr. Rittmeyer reports grants from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche, and Novartis, outside the submitted work. Dr. Zou reports employment from Genentech, outside the submitted work. Dr. Bhatia reports employment from Genentech, outside the submitted work. Dr. Koeppen reports employment from Genentech, outside the submitted work. Dr. Paul reports employment from Genentech, outside the submitted work. David Shames reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Yi reports employment and spousal employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Matheny reports employment from Genentech, during the conduct of the study, and employment from Genentech, outside the submitted work. Dr. Ballinger reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. McCleland reports employment from Genentech, outside the submitted work. Dr. Gandara reports personal fees and institutional grants from Genentech, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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22. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC.
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Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, and Herbst RS
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- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Humans, Platinum therapeutic use, Survival Analysis, B7-H1 Antigen therapeutic use, Lung Neoplasms drug therapy
- Abstract
Introduction: IMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group., Methods: This open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC)., Results: The any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months' additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66-1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54-1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab., Conclusions: Statistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression., (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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23. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC.
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Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, and Reck M
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- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bevacizumab therapeutic use, Carboplatin therapeutic use, Humans, Paclitaxel therapeutic use, Survival Analysis, Lung Neoplasms drug therapy
- Abstract
Introduction: We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143)., Methods: In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays., Results: At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018)., Conclusions: At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2021
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24. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
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Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, and Wakelee H
- Subjects
- Aged, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung surgery, Chemotherapy, Adjuvant, Disease-Free Survival, Female, Humans, Male, Middle Aged, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients., Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting)., Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%)., Interpretation: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial support from F Hoffmann-La Roche. EF received advisory or consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme (MSD), Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, and Takeda; received honoraria from Amgen, AstraZeneca, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, Janssen, Medscape, Medical Trends, MSD, Merck Serono, Peervoice, Pfizer, Springer, and Touch Medical; and is an independent member of the board for and has received personal fees from GRIFOLS. NA received grants or contracts from AstraZeneca, the National Cancer Institute, New York Genome Center P1000 and LC200388 the US Department of Defense; and received honoraria from AstraZeneca and Regeneron. CZ received honoraria from Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent, C-Stone, LUYE Pharma, TopAlliance Bioscience, and Amoy Diagnostics; and participated in a data safety monitoring board or advisory board for Innovent Biologics, Hengrui, Qilu, and TopAlliance Bioscience. AM-M received personal fees and travel expenses from Bristol–Myers Squibb, F Hoffmann-La Roche, MSD, Pfizer, Boehringer Ingelheim, MSD Oncology, and AstraZeneca, outside the submitted work. HK received research funding from Chugai Pharmaceutical, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK; and received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly KK, Kyowa Hakko Kirin, Bristol–Myers Squibb, MSD, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK, Pfizer, and Taiho Pharma. SS received honoraria from Chugai Pharma. DV, YD, and MM are employed by Genentech. FW is employed by Roche (China). JY, EB, and BG are employed by Genentech and have stock ownership of F Hoffmann-La Roche. HW received research funding (to institution) from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol–Myers Squibb, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, SeaGen, Xcovery, and Eli Lilly; received honoraria from Novartis and AstraZeneca; received compensation for advisory boards from AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, and Helsinn; served in an uncompensated role for advisory boards for Merck, Takeda, Genentech/Roche, and Cellworks; and reports an uncompensated leadership role with the International Association for the Study of Lung Cancer. All other authors have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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25. Microenvironmental regulation of tumour immunity and response to immunotherapy.
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Kockx MM, McCleland M, and Koeppen H
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- Animals, Humans, Biomarkers, Tumor immunology, Immunotherapy, Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
The confluence of immunology and oncology has led to a lot of uncertainty and questions about relevant biomarkers. Despite the complexity of the tumour microenvironment, most clinical studies have relied on a single-parameter immunohistochemical assay to prospectively select patients for checkpoint inhibitor therapy; the results of this strategy have been highly variable and often less than optimal. While great efforts have been made to identify additional or alternative biomarkers, pathologists, drug developers, and clinicians alike have faced technical, logistical, and regulatory challenges on how to implement them successfully. In this review, we will discuss these challenges; we will also highlight recent advances in dissecting the functional diversity of immune cell populations within the tumour microenvironment and their potential for improved, biomarker-driven therapeutic strategies. The dynamic nature and cellular diversity of the tumour microenvironment may challenge past models of a single biomarker predicting patient response and clinical outcome. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2021
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26. Molecular determinants of response to PD-L1 blockade across tumor types.
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Banchereau R, Leng N, Zill O, Sokol E, Liu G, Pavlick D, Maund S, Liu LF, Kadel E 3rd, Baldwin N, Jhunjhunwala S, Nickles D, Assaf ZJ, Bower D, Patil N, McCleland M, Shames D, Molinero L, Huseni M, Sanjabi S, Cummings C, Mellman I, Mariathasan S, Hegde P, and Powles T
- Subjects
- Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Renal Cell drug therapy, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Humans, Immune Checkpoint Inhibitors therapeutic use, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Mutation, Treatment Outcome, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics, Whole Genome Sequencing, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic drug effects, Immune Checkpoint Inhibitors pharmacology
- Abstract
Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1
+ tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.- Published
- 2021
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27. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial.
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Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, and Socinski MA
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- Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin therapeutic use, Cisplatin therapeutic use, Humans, Pemetrexed therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Introduction: We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC., Methods: Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS)., Results: The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively., Conclusions: IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2021
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28. Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade.
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Banchereau R, Chitre AS, Scherl A, Wu TD, Patil NS, de Almeida P, Kadel Iii EE, Madireddi S, Au-Yeung A, Takahashi C, Chen YJ, Modrusan Z, McBride J, Nersesian R, El-Gabry EA, Robida MD, Hung JC, Kowanetz M, Zou W, McCleland M, Caplazi P, Eshgi ST, Koeppen H, Hegde PS, Mellman I, Mathews WR, Powles T, Mariathasan S, Grogan J, and O'Gorman WE
- Subjects
- Antibodies, Monoclonal, Humanized adverse effects, B7-H1 Antigen immunology, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Databases, Genetic, Gene Expression Profiling, Humans, Immune Checkpoint Inhibitors adverse effects, Lung Neoplasms genetics, Lung Neoplasms immunology, Phenotype, Randomized Controlled Trials as Topic, Time Factors, Treatment Outcome, Tumor Microenvironment, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms immunology, Antibodies, Monoclonal, Humanized therapeutic use, Antigens, CD genetics, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor genetics, CD8-Positive T-Lymphocytes immunology, Immune Checkpoint Inhibitors therapeutic use, Integrin alpha Chains genetics, Lung Neoplasms drug therapy, Lymphocytes, Tumor-Infiltrating immunology, Urinary Bladder Neoplasms drug therapy
- Abstract
Background: CD8+ tissue-resident memory T (T
RM ) cells, marked by CD103 ( ITGAE ) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy., Methods: Here, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1))., Results: ITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion., Conclusions: Our analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response., Competing Interests: Competing interests: All authors except Thomas Powles are current or former employees of Roche., (© 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.)- Published
- 2021
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29. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133).
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Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, Garassino MC, De Castro Carpeno J, Califano R, Nishio M, Orlandi F, Alatorre-Alexander J, Leal T, Cheng Y, Lee JS, Lam S, McCleland M, Deng Y, Phan S, and Horn L
- Subjects
- Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, B7-H1 Antigen pharmacology, Carboplatin pharmacology, Disease Progression, Double-Blind Method, Etoposide pharmacology, Female, Humans, Male, Middle Aged, Neoplasm Staging, Survival Analysis, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B7-H1 Antigen therapeutic use, Carboplatin therapeutic use, Etoposide therapeutic use, Lung Neoplasms drug therapy, Small Cell Lung Carcinoma drug therapy
- Abstract
Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported., Patients and Methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m
2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted., Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status., Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.- Published
- 2021
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30. NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes.
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Singh A, Daemen A, Nickles D, Jeon SM, Foreman O, Sudini K, Gnad F, Lajoie S, Gour N, Mitzner W, Chatterjee S, Choi EJ, Ravishankar B, Rappaport A, Patil N, McCleland M, Johnson L, Acquaah-Mensah G, Gabrielson E, Biswal S, and Hatzivassiliou G
- Subjects
- AMP-Activated Protein Kinase Kinases genetics, AMP-Activated Protein Kinases genetics, Animals, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Disease Models, Animal, Drug Resistance, Neoplasm genetics, Gene Expression Profiling, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Kaplan-Meier Estimate, Kelch-Like ECH-Associated Protein 1 genetics, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Lung Neoplasms pathology, Mice, NF-E2-Related Factor 2 genetics, Prognosis, Proto-Oncogene Proteins p21(ras) genetics, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, NF-E2-Related Factor 2 metabolism
- Abstract
Purpose: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, KEAP1 loss often co-occurs with STK11 loss and KRAS -activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined., Experimental Design: We model NRF2 activation, STK11 loss, and KRAS activation in vivo using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials., Results: Our in vivo data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS -mutant, STK11 -null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment., Conclusions: Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment., (©2020 American Association for Cancer Research.)
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- 2021
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31. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC.
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Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, and Spigel DR
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Squamous Cell drug therapy, Cisplatin administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms mortality, Male, Middle Aged, Mutation, Survival Analysis, Gemcitabine, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known., Methods: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden., Results: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden., Conclusions: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.)., (Copyright © 2020 Massachusetts Medical Society.)
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- 2020
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32. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial.
- Author
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Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, Soo R, Conter HJ, Kozuki T, Huang KC, Graupner V, Sun SW, Hoang T, Jessop H, McCleland M, Ballinger M, Sandler A, and Socinski MA
- Subjects
- Albumins, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin, Humans, Paclitaxel therapeutic use, Carcinoma, Squamous Cell drug therapy, Lung Neoplasms drug therapy
- Abstract
Introduction: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC., Methods: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported., Results: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively., Conclusions: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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33. Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations.
- Author
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Reck M, Shankar G, Lee A, Coleman S, McCleland M, Papadimitrakopoulou VA, Socinski MA, and Sandler A
- Subjects
- Bevacizumab therapeutic use, Carboplatin therapeutic use, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung therapy, ErbB Receptors genetics, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms therapy, Male, Mutation, Paclitaxel therapeutic use, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Immunotherapy, Lung Neoplasms drug therapy
- Abstract
Introduction : Cancer immunotherapy has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). However, specific patient groups (e.g. patients with activating epidermal growth factor receptor [ EGFR] mutations) do not appear to derive benefit from immune checkpoint inhibitor (ICI) monotherapy. Combining ICIs, such as atezolizumab, with chemotherapy and/or targeted therapies may help to address this unmet need. Areas covered : Atezolizumab is an anti-programmed death-ligand 1 therapy for several tumor types. We review its clinical efficacy and safety in the treatment of advanced or metastatic NSCLC, with a specific focus on the combination of atezolizumab with bevacizumab, carboplatin, and paclitaxel (ABCP). Data from IMpower150 show that the ABCP regimen provided clinical benefit to patients with non-squamous NSCLC, including those with EGFR mutations. Expert opinion : Combining ICIs with chemotherapy has proven to be superior to chemotherapy alone. However, tumor resistance to ICIs will likely increase as these drugs enter earlier lines of therapy, underscoring a need for effective treatments when immunotherapy fails. Data suggest that the ABCP regimen may circumvent ICI resistance mechanisms. Continued investigation into the regimen's mechanisms, improved patient profiling/selection, and treatment personalization will drive further development/discoveries.
- Published
- 2020
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34. SUV420H2 is an epigenetic regulator of epithelial/mesenchymal states in pancreatic cancer.
- Author
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Viotti M, Wilson C, McCleland M, Koeppen H, Haley B, Jhunjhunwala S, Klijn C, Modrusan Z, Arnott D, Classon M, Stephan JP, and Mellman I
- Subjects
- Cell Line, Tumor, Epigenesis, Genetic genetics, Gene Expression Regulation, Neoplastic genetics, Histone-Lysine N-Methyltransferase genetics, Humans, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Epithelial-Mesenchymal Transition, Histone-Lysine N-Methyltransferase metabolism, Pancreatic Neoplasms metabolism
- Abstract
Epithelial-to-mesenchymal transition is implicated in metastasis, where carcinoma cells lose sessile epithelial traits and acquire mesenchymal migratory potential. The mesenchymal state is also associated with cancer stem cells and resistance to chemotherapy. It might therefore be therapeutically beneficial to promote epithelial identity in cancer. Because large-scale cell identity shifts are often orchestrated on an epigenetic level, we screened for candidate epigenetic factors and identified the histone methyltransferase SUV420H2 (KMT5C) as favoring the mesenchymal identity in pancreatic cancer cell lines. Through its repressive mark H4K20me3, SUV420H2 silences several key drivers of the epithelial state. Its knockdown elicited mesenchymal-to-epithelial transition on a molecular and functional level, and cells displayed decreased stemness and increased drug sensitivity. An analysis of human pancreatic cancer biopsies was concordant with these findings, because high levels of SUV420H2 correlated with a loss of epithelial characteristics in progressively invasive cancer. Together, these data indicate that SUV420H2 is an upstream epigenetic regulator of epithelial/mesenchymal state control., (© 2018 Viotti et al.)
- Published
- 2018
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35. USP7 small-molecule inhibitors interfere with ubiquitin binding.
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Kategaya L, Di Lello P, Rougé L, Pastor R, Clark KR, Drummond J, Kleinheinz T, Lin E, Upton JP, Prakash S, Heideker J, McCleland M, Ritorto MS, Alessi DR, Trost M, Bainbridge TW, Kwok MCM, Ma TP, Stiffler Z, Brasher B, Tang Y, Jaishankar P, Hearn BR, Renslo AR, Arkin MR, Cohen F, Yu K, Peale F, Gnad F, Chang MT, Klijn C, Blackwood E, Martin SE, Forrest WF, Ernst JA, Ndubaku C, Wang X, Beresini MH, Tsui V, Schwerdtfeger C, Blake RA, Murray J, Maurer T, and Wertz IE
- Subjects
- Animals, Binding, Competitive, Cell Line, Tumor, Drug Synergism, Female, Humans, Mice, Mice, SCID, Models, Molecular, Neoplasms drug therapy, Neoplasms enzymology, Neoplasms pathology, Protein Binding, Proto-Oncogene Proteins c-mdm2 metabolism, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Substrate Specificity, Tumor Suppressor Protein p53 deficiency, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Ubiquitin chemistry, Ubiquitin-Specific Peptidase 7 chemistry, Ubiquitin-Specific Peptidase 7 deficiency, Ubiquitin-Specific Peptidase 7 metabolism, Aminopyridines chemistry, Aminopyridines pharmacology, Indazoles chemistry, Indazoles pharmacology, Phenols chemistry, Phenols pharmacology, Pyridines chemistry, Pyridines pharmacology, Ubiquitin metabolism, Ubiquitin-Specific Peptidase 7 antagonists & inhibitors
- Abstract
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival. However, developing selective deubiquitinase inhibitors has been challenging and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors. Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 Å distant from the catalytic cysteine. The compounds attenuate ubiquitin binding and thus inhibit USP7 deubiquitinase activity. GNE-6640 and GNE-6776 interact with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains. We investigated this idea by engineering di-ubiquitin chains containing differential proximal and distal isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquitin binding for full functional activity.
- Published
- 2017
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36. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
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Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S, Kwong M, Hong R, Gao M, Del Nagro C, Pusapati R, Ma S, Salphati L, Pang J, Zhou A, Lai T, Li Y, Chen Z, Wei B, Yen I, Sideris S, McCleland M, Firestein R, Corson L, Vanderbilt A, Williams S, Daemen A, Belvin M, Eigenbrot C, Jackson PK, Malek S, Hatzivassiliou G, Sampath D, Evangelista M, and O'Brien T
- Subjects
- Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, Humans, L-Lactate Dehydrogenase metabolism, Models, Molecular, Molecular Structure, Pyridones chemistry, Structure-Activity Relationship, Thiophenes chemistry, Cell Plasticity drug effects, Enzyme Inhibitors pharmacology, L-Lactate Dehydrogenase antagonists & inhibitors, Pyridones pharmacology, Thiophenes pharmacology
- Abstract
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.
- Published
- 2016
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37. Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Putten Strain CRJJGF_00159 (Phylum Gammaproteobacteria).
- Author
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Gupta SK, McMillan EA, Jackson CR, Desai PT, Porwollik S, McCleland M, Hiott LM, Humayoun SB, and Frye JG
- Abstract
Here, we report a 4.90 Mbp draft genome sequence of Salmonella enterica subsp. enterica serovar Putten strain CRJJGF_00159 isolated from food animal in 2004., (Copyright © 2016 Gupta et al.)
- Published
- 2016
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38. Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer.
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Liu J, McCleland M, Stawiski EW, Gnad F, Mayba O, Haverty PM, Durinck S, Chen YJ, Klijn C, Jhunjhunwala S, Lawrence M, Liu H, Wan Y, Chopra V, Yaylaoglu MB, Yuan W, Ha C, Gilbert HN, Reeder J, Pau G, Stinson J, Stern HM, Manning G, Wu TD, Neve RM, de Sauvage FJ, Modrusan Z, Seshagiri S, Firestein R, and Zhang Z
- Subjects
- Base Sequence, Cell Line, Cell Proliferation genetics, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, MAP Kinase Kinase Kinases, Microsatellite Instability, Microsatellite Repeats genetics, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Receptor, ErbB-2 genetics, Sequence Analysis, DNA, Transcriptome genetics, Protein Isoforms genetics, Protein Kinases genetics, Stomach Neoplasms genetics
- Abstract
Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumours and 32 cell lines. Meta-analysis of exome data and previously published data sets reveals 24 significantly mutated genes in microsatellite stable (MSS) tumours and 16 in microsatellite instable (MSI) tumours. Over half the patients in our collection could potentially benefit from targeted therapies. We identify 55 splice site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumours. ZAK kinase isoform TV1 is preferentially upregulated in gastric tumours and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder and breast cancers. Overexpression of this particular isoform activates multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibits proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.
- Published
- 2014
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39. Improved muscle-derived expression of human coagulation factor IX from a skeletal actin/CMV hybrid enhancer/promoter.
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Hagstrom JN, Couto LB, Scallan C, Burton M, McCleland ML, Fields PA, Arruda VR, Herzog RW, and High KA
- Subjects
- Actins genetics, Animals, Cytomegalovirus genetics, Dogs, Enhancer Elements, Genetic genetics, Factor IX biosynthesis, Gene Expression, Humans, Mice, Muscle, Skeletal, Factor IX genetics, Gene Transfer Techniques, Genetic Vectors
- Abstract
Hemophilia B is caused by the absence of functional coagulation factor IX (F.IX) and represents an important model for treatment of genetic diseases by gene therapy. Recent studies have shown that intramuscular injection of an adeno-associated viral (AAV) vector into mice and hemophilia B dogs results in vector dose-dependent, long-term expression of biologically active F.IX at therapeutic levels. In this study, we demonstrate that levels of expression of approximately 300 ng/mL (6% of normal human F.IX levels) can be reached by intramuscular injection of mice using a 2- to 4-fold lower vector dose (1 x 10(11) vector genomes/mouse, injected into 4 intramuscular sites) than previously described. This was accomplished through the use of an improved expression cassette that uses the cytomegalovirus (CMV) immediate early enhancer/promoter in combination with a 1.2-kilobase portion of human skeletal actin promoter. These results correlated with enhanced levels of F.IX transcript and secreted F.IX protein in transduced murine C2C12 myotubes. Systemic F.IX expression from constructs containing the CMV enhancer/promoter alone was 120 to 200 ng/mL in mice injected with 1 x 10(11) vector genomes. Muscle-specific promoters performed poorly for F.IX transgene expression in vitro and in vivo. However, the incorporation of a sequence from the alpha-skeletal actin promoter containing at least 1 muscle-specific enhancer and 1 enhancer-like element further improved muscle-derived expression of F.IX from a CMV enhancer/promoter-driven expression cassette over previously published results. These findings will allow the design of a clinical protocol for therapeutic levels of F.IX expression with lower vector doses, thus enhancing efficacy and safety of the protocol. (Blood. 2000;95:2536-2542)
- Published
- 2000
40. Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX.
- Author
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Fields PA, Kowalczyk DW, Arruda VR, Armstrong E, McCleland ML, Hagstrom JN, Pasi KJ, Ertl HC, Herzog RW, and High KA
- Subjects
- Adenoviridae genetics, Adoptive Transfer, Animals, Cytokines metabolism, Factor IX genetics, Factor IX immunology, Fluorescent Antibody Technique, Hemophilia B immunology, Hemophilia B metabolism, Immunoglobulin G biosynthesis, Immunoglobulin G immunology, Mice, Mice, Inbred C57BL, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, Th1 Cells immunology, Th1 Cells metabolism, Th2 Cells immunology, Th2 Cells metabolism, Factor IX metabolism, Gene Transfer Techniques adverse effects, Genetic Vectors immunology, T-Lymphocyte Subsets immunology, Transgenes
- Abstract
Defining immune responses against the secreted transgene product in a gene therapy setting is critical for treatment of genetic diseases such as hemophilia B (coagulation factor IX deficiency). We have previously shown that intramuscular administration of an adeno-associated viral (AAV) vector results in stable expression of therapeutic levels of factor IX (F.IX) and may be associated with humoral immune responses against F.IX. This study demonstrates that intramuscular injection of an AAV vector expressing F.IX fails to activate F.IX-specific cytotoxic T lymphocytes (CTLs) in hemostatically normal or in hemophilia B mice, so that there is an absence of cellular immune responses against F.IX. However, transgene-derived F.IX can cause B cell responses characterized by production of T helper cell-dependent antibodies (predominantly IgG1, but also IgG2 subclasses) resulting from activation of CD4+ T helper cells primarily of the Th2 subset. In contrast, administration of an adenoviral vector efficiently activated F.IX-specific CTLs and T helper cells of both Th1 and Th2 subsets, leading to inflammation and destruction of transduced muscle tissue and activation of B cells as well. Therefore, vector sequences fundamentally influence T cell responses against transgene-encoded F.IX. In conclusion, activation of the immune system in AAV-mediated gene transfer is restricted to pathways mediated by F.IX antigen presentation through MHC class II determinants resulting in T and B cell responses that are more comparable to responses in the setting of protein infusion rather than of viral infection/gene transfer.
- Published
- 2000
- Full Text
- View/download PDF
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