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635 KEYNOTE-495/KeyImPaCT: updated analysis of a biomarker-directed, randomized, phase 2 trial of pembrolizumab-based combination therapy for non-small cell lung cancer
  1. Roy Herbst1,
  2. Wei-Sen Lam2,
  3. Matthew Hellmann3,
  4. Matthew Gubens4,
  5. Charu Aggarwal5,
  6. Daniel Shao Weng Tan6,
  7. Enriqueta Felip7,
  8. Joanne Chiu8,
  9. Jong-Seok Lee9,
  10. James Chih-Hsin Yang10,
  11. Edward Garon11,
  12. Giovanna Finocchiaro12,
  13. Myung-Ju Ahn13,
  14. Alexander Luft14,
  15. Gregory Landers15,
  16. Andrea Basso16,
  17. Hua Ma16,
  18. Julie Kobie16,
  19. John Palcza16,
  20. Razvan Cristescu16,
  21. Lawrence Fong4,
  22. Alexandra Snyder16,
  23. Jianda Yuan16 and
  24. Martin Gutierrez17
  1. 1Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
  2. 2Fiona Stanley Hospital and Western Australia Country Health Service, Perth, Australia
  3. 3Memorial Sloan Kettering Cancer Center, New York, NY, USA
  4. 4UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
  5. 5Perelman School of Medicine, University, Philadelphia, PA, USA
  6. 6National Cancer Centre Singapore, Singapore, Singapore
  7. 7Vall d’Hebron University Hospital, Vall, Barcelona, Spain
  8. 8University of Hong Kong, Queen Mary Hosp, Pok Fu Lam, Hong Kong
  9. 9Seoul National University Bundang Hospit, Seongnam, Republic of Korea
  10. 10National Taiwan University Hospital and, Taipei City, Taiwan
  11. 11David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  12. 12IRCCS Humanitas Research Hospital, Milan, Italy
  13. 13Samsung Medical Center, Sungkyunkwan Uni, Seoul, Republic of Korea
  14. 14Leningrad Regional Clinical Hospital, Saint Petersburg, Russian Federation
  15. 15The Oncology Centre, KwaZulu-Natal, South Africa
  16. 16Merck and Co., Inc., Rahway, NJ, USA
  17. 17Hackensack University Medical Center, Hackensack, NJ, USA


Background The group sequential, adaptively randomized, open-label, phase 2 KEYNOTE-495/KeyImPaCT trial (NCT03516981) demonstrated the feasibility of using prospective T-cell–inflamed gene expression profile (TcellinfGEP) and tumor mutation burden (TMB) dual biomarker status to assess the clinical activity of first-line pembrolizumab-based combination therapies in advanced non−small-cell lung cancer (NSCLC). Here, we present updated efficacy data relative to prespecified biomarker-defined subgroups for each treatment arm.

Methods Patients with previously untreated stage IV NSCLC were categorized by TcellinfGEP and TMB dual biomarker status (TcellinfGEPlowTMBnon-high, TcellinfGEPlowTMBhigh, TcellinfGEPnon-lowTMBnon-high, TcellinfGEPnon-lowTMBhigh) then randomly assigned 1:1:1 to receive pembrolizumab (200 mg IV Q3W) plus the multikinase inhibitor (targeting VEGFRs 1-3, FGFRs 1-4, PDGFRα, RET, and KIT) lenvatinib (20 mg oral QD), CTLA-4 inhibitor quavonlimab (75 mg IV Q6W), or LAG-3 inhibitor favezelimab (initially 200 mg and then 800 mg IV Q3W). Adaptive randomization based on objective response rate (ORR) was employed, and frequent interim analyses were performed to quantify efficacy and assess for futility. The primary end point of investigator-assessed ORR per RECIST v1.1 was assessed using prespecified efficacy thresholds for each biomarker-defined subgroup: an ORR of >5% within the TcellinfGEPlowTMBnon-high subgroup, >20% within the TcellinfGEPlowTMBhigh subgroup and TcellinfGEPnon-lowTMBnon-high subgroup, and >45% within the TcellinfGEPnon-lowTMBhigh subgroup evaluated using a Bayesian posterior probability. Secondary end points included progression-free survival (PFS) per RECIST v1.1, overall survival (OS), and safety.

Results At data cutoff (March 21, 2022), 243 patients had been treated (pembrolizumab+lenvatinib, n=80; pembrolizumab+quavonlimab, n=82; pembrolizumab+favezelimab 200 mg, n=30; pembrolizumab+favezelimab 800 mg, n=51). Efficacy data are presented in table 1. ORR with pembrolizumab+lenvatinib in the TcellinfGEPnon-lowTMBnon-high subgroup met the prespecified efficacy threshold. The safety profile of each treatment arm was consistent with the known safety profile of each combination.

Conclusions Pembrolizumab-based combination therapy continued to show promising antitumor activity and durable response in the TcellinfGEPnon-lowTMBhigh subgroup across all combinations. Response in the TcellinfGEPnon-lowTMBnon-high subgroup treated with pembrolizumab+lenvatinib met the prespecified efficacy threshold. Although response in the pembrolizumab+favezelimab arm did not reach the efficacy bar, there was a trend toward improved ORR in the TcellinfGEPnon-lowTMBhigh subgroup versus the other 3 biomarker-defined subgroups; median PFS and OS were also numerically longer in the TcellinfGEPnon-lowTMBhigh subgroup compared with the other 3 biomarker-defined subgroups. Prospective assessment of dual biomarkers, as performed in this study, may help identify patients with NSCLC most likely to respond to pembrolizumab-based combination therapies.

Acknowledgements Medical writing and/or editorial assistance was provided by Mehak Aggarwal, PharmD, and Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Trial Registration NCT03516981

Consent The study protocol and all amendments were approved by the institutional review board or ethics committee at each institution. All patients provided written informed consent

Abstract 635 Table 1

Efficacy by treatment and dual biomarker status

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