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Proffered Paper session Proffered Paper session

96O - Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): A randomized, double-blind, multicenter, phase III trial

Presentation Number
96O
Lecture Time
14:35 - 14:45
Speakers
  • C. Zhou (Shanghai, China)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • C. Zhou (Shanghai, China)
  • S. Ren (Shanghai, China)
  • J. Chen (Changsha, China)
  • X. Xu (Yangzhou, China)
  • Y. Cheng (Changchun, China)
  • G. Chen (Harbin, China)
  • Y. Pan (Hefei, China)
  • Y. Fang (Hangzhou, China)
  • Q. Wang (Zhengzhou, China)
  • Y. Huang (Kunming, China)
  • W. Yao (Chengdu, China)
  • R. Wang (Hefei, China)
  • X. Li (Zhengzhou, China)
  • W. Zhang (Nanchang, China)
  • Y. Zhang (Xian, China)
  • S. Hu (Wuhan, China)
  • R. Guo (Nanjing, China)
  • Z. Yang (Shanghai, China)
  • L. Wang (Shanghai, China)

Abstract

Background

Cytotoxic agents may potentiate immune-checkpoint inhibitors with immunological effects. Camrelizumab plus pemetrexed and platinum is a current standard of care for Chinese patients (pts) with advanced non-squamous NSCLC and negative EGFR/ALK mutation. Here we evaluated first-line camrelizumab plus chemotherapy (chemo) for pts with squamous NSCLC.

Methods

In this double-blind, multicenter, phase III trial, previously untreated pts with histologically or cytologically confirmed stage IIIB-IV squamous NSCLC were randomized 1:1 to receive 4–6 cycles of carboplatin (AUC 5) plus paclitaxel (175 mg/m²) with camrelizumab (200 mg) or placebo every 3 weeks, followed by maintenance therapy with camrelizumab or placebo. The primary endpoint was PFS per IRC. Cross-over after disease progression was allowed for pts allocated placebo plus chemo

Results

Totally, 389 pts (camrelizumab plus chemo, n = 193; placebo plus chemo, n = 196) were included. As of Nov. 06, 2020, pts treated with camrelizumab plus chemo were associated with significantly prolonged IRC-assessed PFS versus placebo plus chemo (median, 8.5 [95% CI 6.9–10.4] vs 4.9 [95% CI 4.2–5.5] months; HR, 0.37 [95% CI 0.29–0.47], one-sided P < 0.0001), with benefit observed in pts with both PD-L1 TPS <1% (HR, 0.49 [95% CI 0.35–0.68]) and ≥1% (HR, 0.34 [95% CI 0.24–0.49]). There was also significant improvement in OS for the camrelizumab plus chemo group (median, NR [18.4–NR] vs 14.5 [95% CI 13.2–16.6] months; HR, 0.55 [95% CI 0.40–0.75], one-sided P < 0.0001). Consistently, confirmed ORR (64.8% [95% CI 57.6%–71.5%] vs 36.7% [95% CI 30.0%–43.9%], P < 0.0001) and DoR (median, 13.1 [95% CI 9.3–15.7] vs 4.4 [95% CI 4.2–4.9] months) per IRC favored the camrelizumab plus chemo group. Grade ≥3 treatment-related adverse events occurred in 73.6% of pts in the camrelizumab plus chemo group and 71.9% in the placebo plus chemo group, with no unexpected adverse effects.

Conclusions

The addition of camrelizumab to chemotherapy significantly prolonged PFS and OS in the first-line setting with an acceptable safety profile, supporting this combination as an additional first-line treatment option for pts with advanced squamous NSCLC.

Clinical trial identification

NCT03668496.

Legal entity responsible for the study

Jiangsu Hengrui Medicine Co., Ltd.

Funding

Jiangsu Hengrui Medicine Co., Ltd.

Disclosure

C. Zhou: Honoraria (self): Roche; Honoraria (self): Lily China; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck; Honoraria (self), Advisory/Consultancy: Hengrui; Honoraria (self), Advisory/Consultancy: Qilu; Honoraria (self): Sanofi; Honoraria (self): Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Innovent Biologics; Honoraria (self): C-Stone; Honoraria (self): Luye Pharma; Honoraria (self), Advisory/Consultancy: TopAlliance Biosciences; Honoraria (self): Amoy Diagnositics. Z. Yang: Full/Part-time employment: Jiangsu Hengrui Medicine. L. Wang: Full/Part-time employment: Jiangsu Hengrui Medicine. All other authors have declared no conflicts of interest.

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Proffered Paper session Proffered Paper session

97O - First-Line Pembrolizumab Plus Chemotherapy for Patients With Advanced Squamous NSCLC: 3-Year Follow-up From KEYNOTE-407

Presentation Number
97O
Lecture Time
14:45 - 14:55
Speakers
  • A. Robinson (Kingston, ON, Canada)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • A. Robinson (Kingston, ON, Canada)
  • D. Vicente Baz (Sevilla, Spain)
  • A. Tafreshi (Wollongong, NS, Australia)
  • H. Soto Parra (Catania, Italy)
  • J. Mazieres (Toulouse, France)
  • I. Cicin (Edirne, Turkey)
  • B. Medgyasszay (Farkasgyepu, Hungary)
  • J. Rodríguez-Cid (Mexico City, Mexico)
  • I. Okamoto (Fukuoka, Japan)
  • S. Lee (Busan, Korea, Republic of)
  • R. Ramlau (Poznan, Poland)
  • V. Vladimirov (Pyatigorsk, Russian Federation)
  • Y. Cheng (Changchun, China)
  • B. Halmos (Bronx, NY, United States of America)
  • C. Liu (Kenilworth, NJ, United States of America)
  • P. Schwarzenberger (Kenilworth, NJ, United States of America)
  • B. Piperdi (Kenilworth, NJ, United States of America)
  • L. Paz-Ares (Madrid, Spain)

Abstract

Background

Pembrolizumab (pembro) + carboplatin and paclitaxel/nab-paclitaxel significantly improved OS and PFS vs placebo in patients (pts) with previously untreated stage IV squamous NSCLC in the phase III KEYNOTE-407 study (NCT02775435). At protocol-specified final analysis (data cutoff May 9, 2019), HR for OS was 0.71 (95% CI, 0.58–0.88). We report long-term data and outcomes for pts who completed 35 cycles (∼2 y) of treatment.

Methods

Eligible pts were randomized 1:1 (stratified by paclitaxel vs nab-paclitaxel; East Asia vs rest of the world; and PD-L1 TPS ≥1% vs <1%) to receive pembro 200 mg + chemo or placebo + chemo Q3W for 4 cycles, then pembro or placebo for up to a total of 35 cycles. Primary endpoints were OS and PFS per RECIST v1.1 by blinded independent central review.

Results

278 pts were randomized to pembro + chemo and 281 to the placebo + chemo group. As of Sep 30, 2020, median time from randomization to data cutoff was 40.1 (range, 33.1–49.4) mo; 117 (41.6%) pts crossed over from the placebo + chemo group to receive pembro monotherapy. Median OS in the pembro + chemo group was 17.2 vs 11.6 mo for placebo + chemo; HR 0.71 (95% CI, 0.59–0.86). 3-year OS rate was 29.7% vs 18.2%, respectively. Median PFS2 was 13.8 vs 9.1 mo, respectively; HR 0.59 (95% CI, 0.49–0.71; Table). Grade 3–5 AEs occurred in 74.8% of pts in the pembro + chemo group and 70.0% in the placebo + chemo group. Among 55 pts who completed 35 cycles of pembro, ORR was 92.7% (5 CR, 46 PR) and 4 pts (7.3%) had SD. 51 pts (92.7%) were alive, and 1-year OS and PFS after completion of 35 cycles were 96.0% and 82.6%. 7 pts had initiated a second course of pembro at data cutoff.

Efficacy outcomes in the ITT population

Pembro + Chemo (n = 278)Placebo + Chemo (n = 281)
Median OS, mo (95% CI)17.2 (14.4–19.7)11.6 (10.1–13.7)
OS HR (95% CI)0.71 (0.59–0.86)
3-y OS rate, % (95% CI)29.7 (24.5–35.2)18.2 (13.8–23.0)
Median PFS, mo (95% CI)8.0 (6.3–8.5)5.1 (4.3–6.0)
PFS HR (95% CI)0.59 (0.49–0.71)
3-y PFS rate, % (95% CI)16.1 (12.0–20.8)6.5 (3.9–10.0)
Median PFS2,a mo (95% CI)13.8 (12.2–15.9)9.1 (8.0–10.3)
PFS2 HR (95% CI)0.59 (0.49–0.71)
ORR, % (95% CI)62.6 (56.6–68.3)38.8 (33.1–44.8)
Median DOR, mo (range)9.0 (1.3+ to 45.0+)4.9 (1.3+ to 44.8+)

+, indicates no PD at last disease assessment. aTime from randomization to second/subsequent PD on next-line treatment/death.

Conclusions

With ∼3 y of follow-up, pembro + chemo continued to demonstrate durable benefit vs chemo alone without additional toxicity. Most pts who completed 35 cycles had objective responses and were alive at data cutoff. These data continue to support pembro + chemo as first-line treatment in pts with metastatic squamous NSCLC.

Clinical trial identification

NCT02775435.

Editorial acknowledgement

Writing support was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A.G. Robinson: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche. D. Vicente: Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: AstraZeneca; Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: BMS; Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: Boehringer Ingelheim; Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: MSD; Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: Pfizer; Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: Roche. A. Tafreshi: Research grant/Funding (institution), received funding to their institutions from Merck to support study conduct: Merck. H. Soto Parra: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Roche. J. Mazieres: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Blueprint; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Pfizer; Honoraria (self): PharmaMar; Honoraria (self): Pierre Fabre; Honoraria (self), Research grant/Funding (institution): Roche. I. Cicin: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Advisory/Consultancy: F. Hoffmann-La Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses: Quintiles; Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Parexel; Research grant/Funding (institution): Taiho. B. Medgyasszay: Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Parexel; Research grant/Funding (institution): Quintiles; Research grant/Funding (institution): Taiho. J. Rodríguez-Cid: Research grant/Funding (institution): MSD; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Novartis. I. Okamoto: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): BMS; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (self): Chugai Pharma; Honoraria (self), Research grant/Funding (self): Eli Lilly; Honoraria (self), Research grant/Funding (self): MSD Oncology; Honoraria (self), Research grant/Funding (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (self): Taiho; Honoraria (self): Pfizer; Research grant/Funding (self): AbbVie; Research grant/Funding (self): Astellas Pharma; Research grant/Funding (self): Novartis. S. Lee: Research grant/Funding (institution), received funding to their institutions from Merck to support study conduct: Merck. R. Ramlau: Honoraria (self), received honoraria to self/spouse for scientific advice or as a speaker: Amgen; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: AstraZeneca; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: BMS; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: Boehringer Ingelheim; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: Eli Lilly; Honoraria (self), received honoraria to self/spouse for scientific advice or as a speaker: Merck; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: MSD; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: Novartis; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: Pfizer; Honoraria (self), Leadership role, received honoraria to self/spouse for scientific advice or as a speaker: Roche; Honoraria (self), received honoraria to self/spouse for scientific advice or as a speaker: Sanofi; Leadership role, Board member: AbbVie; Leadership role, Board member: Takeda. V. Vladimirov: Research grant/Funding (institution), received funding to their institutions from Merck to support study conduct: Merck. Y. Cheng: Research grant/Funding (institution), received funding to their institutions from Merck to support study conduct: Merck. B. Halmos: Research grant/Funding (institution): AbbVie; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): GSK; Advisory/Consultancy, Research grant/Funding (institution): Guardant Health; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Mirati; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Takeda; Advisory/Consultancy: Genentech; Advisory/Consultancy: Genentech. C-C. Liu: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. P. Schwarzenberger: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. B. Piperdi: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. L. Paz-Ares: Honoraria (self): Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Speaker Bureau/Expert testimony: Roche, Lilly, AstraZeneca, MSD, BMS; Leadership role: Altum Sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme; Officer/Board of Directors: Genómica; Spouse/Financial dependant: AAA, Advanz Pharma, Bayer, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi.

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Proffered Paper session Proffered Paper session

98O - First-line nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles chemotherapy (chemo) vs 4 cycles chemo in advanced non-small cell lung cancer (aNSCLC): association of blood and tissue tumor mutational burden (TMB) with efficacy in CheckMate 9LA

Presentation Number
98O
Lecture Time
14:55 - 15:05
Speakers
  • L. Paz-Ares (Madrid, Spain)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • L. Paz-Ares (Madrid, Spain)
  • T. Ciuleanu (Cluj-Napoca, Romania)
  • M. Cobo Dols (Malaga, Spain)
  • M. Schenker (Craiova, Romania)
  • B. Zurawski (Bydgoszcz, Poland)
  • J. Menezes (Porto Alegre, Brazil)
  • E. Richardet (Córdoba, Argentina)
  • J. Bennouna (Nantes, France)
  • E. Felip (Barcelona, Ca, Spain)
  • O. Juan-Vidal (Valencia, Spain)
  • A. Alexandru (Bucharest, Romania)
  • H. Sakai (Saitama, Japan)
  • A. Scherpereel (Lille, France)
  • M. Reck (Grosshansdorf, Germany)
  • S. Lu (Shanghai, China)
  • T. John (Heidelberg, VI, Australia)
  • S. Meadows-Shropshire (Princeton, NJ, United States of America)
  • D. Balli (Princeton, NJ, United States of America)
  • S. Agrawal (Princeton, NJ, United States of America)
  • D. Carbone (Columbus, OH, United States of America)

Abstract

Background

In CheckMate 9LA (NCT03215706), 1L NIVO + IPI + chemo (2 cycles) significantly improved overall survival (OS) vs chemo (4 cycles) in patients (pts) with aNSCLC regardless of tumor histology or PD-L1 expression. TMB is potentially associated with the clinical efficacy of immune checkpoint inhibitors. We evaluated efficacy by tissue and blood TMB (tTMB/bTMB) in CheckMate 9LA.

Methods

tTMB was evaluated using the FoundationOne CDxTM assay from tissue samples collected prior to enrollment. Plasma samples collected at baseline were used for isolation of circulating cell-free tumor DNA and evaluation of bTMB using the Guardant OMNI platform. TMB was not a stratification factor for randomization. Analyses of OS, progression-free survival (PFS), and objective response rate (ORR) were based on prespecified TMB thresholds (tTMB, 10 mut/Mb; bTMB, 16 and 20 mut/Mb). Analyses were based on the March 9, 2020 database lock (DBL; minimum OS follow-up, 12.7 mo).

Results

Of 711 randomized pts with available TMB data at DBL, 64% had evaluable tTMB and 73% had evaluable bTMB. Baseline characteristics were generally well balanced between all randomized, TMB-evaluable and non-evaluable, as well as TMB-high and TMB-low subgroups (both bTMB and tTMB). Overall, clinical benefit (OS, PFS, ORR) was observed with NIVO + IPI + chemo vs chemo in both TMB-high and TMB-low subgroups (Table). The OS benefit with NIVO + IPI + chemo vs chemo was similar between tTMB ≥10 and <10 mut/Mb, and between bTMB ≥16 and <16 mut/Mb subgroups; a numerically higher OS benefit was seen in bTMB ≥20 vs <20 mut/Mb subgroups. For PFS and ORR, the magnitude of benefit was higher in TMB-high versus TMB-low subgroups for both tTMB and bTMB.

Efficacy outcomes in subgroups based on blood and tissue TMB

TMB cut-off (mut/Mb)
tTMB ≥10tTMB <10bTMB ≥16bTMB <16bTMB ≥20bTMB <20
N + I + chemo n = 101Chemo n = 82N + I + chemo n = 135Chemo n = 138N + I + chemo n = 113Chemo n = 85N + I + chemo n = 165Chemo n = 156N + I + chemo n = 80Chemo n = 61N + I + chemo n = 196Chemo n = 180
Median OS, mo15.010.816.812.415.410.415.011.219.411.414.110.8
HR (95% CI)0.74 (0.51–1.08)0.75 (0.55–1.02)0.60 (0.42–0.86)0.73 (0.55–0.96)0.54 (0.35–0.84)0.74 (0.57–0.95)
Median PFS, mo8.94.75.65.07.25.35.64.59.75.35.64.5
HR (95% CI)0.49 (0.34–0.70)0.83 (0.63–1.10)0.55 (0.39–0.78)0.78 (0.60–1.00)0.48 (0.32–0.73)0.78 (0.62–0.99)
ORR, %462833274927332855313327

Conclusions

Higher TMB appeared to be associated with improved PFS and ORR benefits of NIVO + IPI + chemo over chemo. OS benefit was generally similar between high and low TMB.

Clinical trial identification: NCT03215706.

Editorial acknowledgement

Writing and editorial assistance were provided by Nick Patterson, of Caudex, London, UK, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

L. Paz-Ares: Honoraria (self): Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Speaker Bureau/Expert testimony: Roche, Lilly, AstraZeneca, MSD, BMS; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme; Officer/Board of Directors: Genómica; Spouse/Financial dependant: AAA, Advanz Pharma, Bayer, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi. T-E. Ciuleanu: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca, Amgen, Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Pfizer, Roche, Sanofi, Servier. M. Schenker: Research grant/Funding (self), Fees for clinical trial activities : Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Merck, MSD, Mylan, Novartis, Pfizer, Pharma Mar, Regeneron, Roche, Serono. B. Zurawski: Research grant/Funding (self): Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, MSD, Roche. J. Bennouna: Honoraria (self), Advisory/Consultancy: Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, MSD, Servier, Bayer, Roche; Research grant/Funding (self): AstraZeneca; Travel/Accommodation/Expenses: AstraZeneca, Roche. E. Felip: Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Mediines, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Merck, MSD, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi Genzyme, Takeda; Speaker Bureau/Expert testimony: AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Medscape, MSD, Novartis, Peervoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, Touchime, CME OUtfitters; Research grant/Funding (self): Fundacion Merck Salud; Officer/Board of Directors: Orifols. O. Juan-Vidal: Advisory/Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Roche/Genentech, AstraZeneca, AbbVie, Pfizer, Takeda and Eli Lilly; Speaker Bureau/Expert testimony: Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Roche/Genentech, AstraZeneca; Travel/Accommodation/Expenses: Roche and Merck Sharp and Dohme. A. Alexandru: Advisory/Consultancy: Roche, Boehringer Ingelheim; Speaker Bureau/Expert testimony: Sandoz, Novartis, Bristol Myers Squibb; Travel/Accommodation/Expenses: Boehringer Ingelheim, Sanofi, Pfizer, Roche, AstraZeneca, Bristol Myers Squibb. H. Sakai: Advisory/Consultancy: Bristol Myers Squibb, Merck KGaA; Speaker Bureau/Expert testimony: Bristol Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Merck & Co, Merck KGaA. A. Scherpereel: Advisory/Consultancy: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Speaker Bureau/Expert testimony: AstraZeneca, Bristol Myers Squibb, MSD; Research grant/Funding (institution): Bristol Myers Squibb; Travel/Accommodation/Expenses: AstraZeneca, Bristol Myers Squibb, MSD, Roche. M. Reck: Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung; Speaker Bureau/Expert testimony: AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Research grant/Funding (self): Bristol Myers Squibb, Boehringer-Ingelheim; Travel/Accommodation/Expenses: AbbVie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Lu: Advisory/Consultancy: AstraZeneca, Boehringer-Ingelheim, Hutchison MediPharma, Simcere, ZaiLab, GenomiCare and Roche; Speaker Bureau/Expert testimony: AstraZeneca, Roche, Hansoh. T. John: Honoraria (self): Bristol Myers Squibb, AstraZeneca, Roche, Merck, MSD, Boehringer Ingelheim, Bayer; Honoraria (institution): Specialised Therapeutics, Pfizer, Novartis; Advisory/Consultancy: MSD, Merck, Roche, AstraZeneca, Bristol Myers Squibb, Takeda, BI, Bayer. S. Meadows-Shropshire: Research grant/Funding (self), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. D. Balli: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. S. Agrawal: Full/Part-time employment: Bristol Myers Squibb. D.P. Carbone: Honoraria (self): AstraZeneca, Pfizer, Bristol Myers Squibb, Eisai; Advisory/Consultancy: AstraZeneca, EMD Serono/Merck, GI Therapeutics (Intellisphere), Gritstone Oncology, GSK, Inivata, Roche China, Oncocyte, GenePlus, Gloria Biosciences, Roche, BMS, Daiichi Sankyo Inc, Boehringer-Ingelheim, Seattle Genetics, Flame Biosciences, Novocure; Leadership role, Chair of the Lung Biology subcommittee for the Eastern Cooperative Oncology Group and on the Thoracic Core committees for both the Alliance and ECOG/ACRIN. I am also Past-President of the International Association for the Study of Lung Cancer (IASLC).: ECOG, ECOG/ACRIN, IASLC; Research grant/Funding (institution): Bristol Myers Squibb; Travel/Accommodation/Expenses: AbbVie, AstraZeneca, Bristol Myers Squibb, EMD Serono, Inivata, Inovio, Janssen, Loxo Oncology, Merck, MSD, Pfizer, Roche/Genentech, Takeda Oncology, Trinity, Incyte, Kyowa Kirin, Novartis, Gritstone Oncology, GSK, Roche China GenePlus, Daiichi Sankyo Inc; Officer/Board of Directors: IASLC, LCFA, LUNGevity, ALCMI, Joan's Legacy Foundation, Lance Armstrong Foundation, Wendy Wyrick Foundation, Wendy Will Case Foundation, Jack Roth Foundation. All other authors have declared no conflicts of interest.

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Proffered Paper session Proffered Paper session

99O_PR - KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non-Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation

Presentation Number
99O_PR
Lecture Time
15:20 - 15:30
Speakers
  • G. Riely (New York, NY, United States of America)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • G. Riely (New York, NY, United States of America)
  • S. Ou (Orange, CA, United States of America)
  • I. Rybkin (Detroit, United States of America)
  • A. Spira (Fairfax, United States of America)
  • K. Papadopoulos (San Antonio, TX, United States of America)
  • J. Sabari (New York, NY, United States of America)
  • M. Johnson (Nashville, TN, United States of America)
  • R. Heist (Boston, MA, United States of America)
  • L. Bazhenova (La Jolla, CA, United States of America)
  • M. Barve (Dallas, TX, United States of America)
  • J. Pacheco (Aurora, United States of America)
  • K. Velastegui (San Diego, CA, United States of America)
  • C. Cilliers (San Diego, CA, United States of America)
  • P. Olson (San Diego, CA, United States of America)
  • J. Christensen (San Diego, CA, United States of America)
  • T. Kheoh (San Diego, CA, United States of America)
  • R. Chao (San Diego, CA, United States of America)
  • P. Janne (Boston, MA, United States of America)

Abstract

Background

KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (∼24 h), and extensive tissue distribution.

Methods

KRYSTAL-1 (NCT03785249) is a multi-cohort phase I/II study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRASG12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.

Results

As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14). Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n = 3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.

Conclusions

Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRASG12C-mutant NSCLC. Additional PD and mechanistic data will be presented.

Clinical trial identification

NCT03785249.

Editorial acknowledgement

Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

G.J. Riely: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Advisory/Consultancy: Mirati Therapeutics. S-H.I. Ou: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: TP Therapeutics; Speaker Bureau/Expert testimony: Genentech; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Takeda; Shareholder/Stockholder/Stock options: Turning Point Therapeutics. I. Rybkin: Advisory/Consultancy: AstraZeneca. A. Spira: Shareholder/Stockholder/Stock options: Lilly; Advisory/Consultancy: Incyte; Advisory/Consultancy: Amgen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Gritstone; Advisory/Consultancy: Jazz Pharmaceuticals; Honoraria (self): CytomX Therapeutics; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Amgen; Honoraria (self): Janssen Oncology; Honoraria (self): Novartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Bayer. K. Papadopoulos: Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Basilea. M. Johnson: Spouse/Financial dependant: Otsuka; Travel/Accommodation/Expenses: AbbVie; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Incyte; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Sanofi. R.S. Heist: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Tarveda; Advisory/Consultancy: Apollonia; Honoraria (self): Chugai/Roche. L. Bazhenova: Shareholder/Stockholder/Stock options: Epic Sciences; Advisory/Consultancy, Research grant/Funding (self): Beyond Spring Pharmaceuticals; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: G1; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Merck; Advisory/Consultancy: Johnson & Johnson; Advisory/Consultancy: BMSi; Advisory/Consultancy: Daichi Sankyo; Advisory/Consultancy: Neuvogen. J.M. Pacheco: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Gerson Lehrman; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Takeda. K. Velastegui: Full/Part-time employment: Mirati Therapeutics, Inc. C. Cilliers: Full/Part-time employment: Mirati Therapeutics, Inc. P. Olson: Full/Part-time employment: Mirati Therapeutics, Inc. J.G. Christensen: Leadership role, Shareholder/Stockholder/Stock options, Officer/Board of Directors: Mirati Therapeutics, Inc; Advisory/Consultancy: BridgeBio; Leadership role, Shareholder/Stockholder/Stock options: BCTG Acquisition; Shareholder/Stockholder/Stock options: Bluebird Bio. T. Kheoh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc; Shareholder/Stockholder/Stock options: Tocagen. R.C. Chao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc. P.A. Jänne: Shareholder/Stockholder/Stock options: Gatekeeper Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo; Research grant/Funding (self): Revolution Medicines; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Daichi Sankyo; Research grant/Funding (self): Astellas; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Chugai; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Araxes; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Silicon Therapeutics. All other authors have declared no conflicts of interest.

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Proffered Paper session Proffered Paper session

Invited Discussant 99O

Lecture Time
15:30 - 15:40
Speakers
  • A. Greystoke (Newcastle-upon-Tyne, United Kingdom)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • A. Greystoke (Newcastle-upon-Tyne, United Kingdom)
Proffered Paper session Proffered Paper session

Q&A and live discussion

Lecture Time
15:40 - 15:55
Speakers
  • A. Speakers (, Switzerland)
Room
Channel 1
Date
Thu, 25.03.2021
Time
14:35 - 15:55
Authors
  • A. Speakers (, Switzerland)
Heine H. Hansen Award lecture 2020 Keynote lecture

Biopsies, biomarkers and biology

Lecture Time
09:20 - 09:45
Speakers
  • F. Blackhall (Manchester, United Kingdom)
Room
Channel 1
Date
Fri, 26.03.2021
Time
09:15 - 09:45
Authors
  • F. Blackhall (Manchester, United Kingdom)
Why are there so many approaches to oligometastatic disease? Educational session

How can we define oligometastasis and how is it different from oligoprogression?

Lecture Time
10:00 - 10:15
Speakers
  • A. Dingemans (Rotterdam, Netherlands)
Room
Channel 1
Date
Fri, 26.03.2021
Time
10:00 - 11:00
Authors
  • A. Dingemans (Rotterdam, Netherlands)
Why are there so many approaches to oligometastatic disease? Educational session

Is there a role for surgery?

Lecture Time
10:15 - 10:30
Speakers
  • P. Van Schil (Edegem, Belgium)
Room
Channel 1
Date
Fri, 26.03.2021
Time
10:00 - 11:00
Authors
  • P. Van Schil (Edegem, Belgium)
Why are there so many approaches to oligometastatic disease? Educational session

When should I initiate, stop and resume systemic treatment?

Lecture Time
10:30 - 10:45
Speakers
  • B. Besse (Villejuif, CE, France)
Room
Channel 1
Date
Fri, 26.03.2021
Time
10:00 - 11:00
Authors
  • B. Besse (Villejuif, CE, France)
Why are there so many approaches to oligometastatic disease? Educational session

Current status of radiation therapy for oligometastasis

Lecture Time
10:45 - 11:00
Speakers
  • F. McDonald (London, United Kingdom)
Room
Channel 1
Date
Fri, 26.03.2021
Time
10:00 - 11:00
Authors
  • F. McDonald (London, United Kingdom)
Thymic malignancies: New treatments Educational session

Surgery: How to improve our standard - From minimally-invasive approaches to chemo-hyperthermia

Lecture Time
10:00 - 10:15
Speakers
  • E. Ruffini (Torino, Italy)
Room
Channel 2
Date
Fri, 26.03.2021
Time
10:00 - 11:00
Authors
  • E. Ruffini (Torino, Italy)