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. 2021 Jun 4;7(9):1-9.
doi: 10.1001/jamaoncol.2021.2301. Online ahead of print.

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial

Salma K Jabbour  1 , Ki Hyeong Lee  2 , Nikolaj Frost  3 , Valeriy Breder  4 , Dariusz M Kowalski  5 , Theodore Pollock  6 , Evgeny Levchenko  7 , Noemi Reguart  8 , Alex Martinez-Marti  9 , Baerin Houghton  10 , Jean-Baptiste Paoli  11 , Sufia Safina  12 , Keunchil Park  13 , Takefumi Komiya  14 , Amy Sanford  15 , Vishal Boolell  16 , Hong Liu  17 , Ayman Samkari  17 , Steven M Keller  17 , Martin Reck  18
Affiliations

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial

Salma K Jabbour et al. JAMA Oncol. .

Abstract

Importance: Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC).

Objective: To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC.

Design, setting, and participants: The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.

Interventions: Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab.

Main outcomes and measures: Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis.

Results: A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively.

Conclusions and relevance: The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jabbour reported receiving grants, personal fees, and nonfinancial support from Merck & Co during the conduct of the study; and receiving grants from the National Cancer Institute and grants to institution from Merck & Co outside the submitted work. Dr Lee reported receiving personal fees for advisory board meetings from Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Eli Lilly outside the submitted work. Dr Frost reported receiving personal fees and nonfinancial support from Merck Sharp & Dohme during the conduct of the study; and receiving personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Roche, Pfizer, Takeda, Novartis, and AbbVie, Berlin-Chemie, Sanofi, and BeiGene; travel grants from Takeda, AstraZeneca, Bristol Myers Squibb, AbbVie, and Eli Lilly; and nonfinancial support from Bristol Myers Squibb outside the submitted work. Dr Kowalski reported serving on advisory boards for Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Takeda, and Roche outside the submitted work. Dr Reguart reported receiving grants from Novartis and Pfizer, personal fees (advisory panels, invited speaker, congress registration) from Merck Sharp & Dohme, Eli Lilly, Roche, Takeda, Novartis, Pfizer, and Janssen, and personal fees (advisory panels, invited speaker) from Bristol Myers Squibb outside the submitted work. Dr Martinez-Marti reported receiving personal fees and travel expenses from Bristol Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme Oncology, and AstraZeneca outside the submitted work. Dr Houghton reported receiving personal fees (trial funding) from Merck during the conduct of the study; and receiving personal fees (advisory board) from Merck outside the submitted work. Dr Paoli reported receiving nonfinancial support from Merck Sharp & Dohme during the conduct of the study; and receiving personal fees from Bristol Myers Squibb and AstraZeneca and nonfinancial support from Merck Sharp & Dohme France, Fresenius Kabi France, Ipsen Pharma, Boehringer Ingelheim France, Pierre Fabre Medicament, Eisai SAS, Janssen-Cilag, Pfizer SAS, Roche SAS, Isis Méditerranée, Novartis Pharma SAS, Mundipharma, Vifor France SA, Sandoz, Kyowa Kirin, Bristol Myers Squibb, and AstraZeneca outside the submitted work. Dr Park reported receiving grants (research funding) from Merck Sharp & Dohme outside the submitted work; and serving as an advisor for Merck Sharp & Dohme outside the submitted work. Dr Sanford reported receiving grants to institution from Merck during the conduct of the study; and receiving grants from Eli Lilly, NantWorks, and QuantumLeap Health outside the submitted work. Drs Liu, Samkari, and Keller reported being an employee of Merck. Dr Reck reported receiving personal fees (honoraria for lectures and consultancy) from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung Bioepis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Disposition
aIncludes 11 patients in cohort A and 6 patients in cohort B who did not receive all of the planned radiotherapy treatment. This was due to inability to provide treatment per protocol (n = 6; of whom 5 discontinued on day 1, and 1 discontinued on day 23), physician decision (n = 3; discontinued treatment on day 1), patient withdrawal (n = 1; discontinued treatment on day 1), and adverse event (n = 1; discontinued treatment on day 22) in cohort A; and due to inability to provide treatment per protocol (n = 3; all of whom discontinued treatment on day 1), adverse event (n = 1; discontinued treatment on day 1), and protocol violation (n = 2; discontinued treatment on day 1 and day 42, respectively) in cohort B. bIncludes patients with clinical progression and progressive disease.
Figure 2.
Figure 2.. Kaplan-Meier Estimates of Duration of Confirmed Response by BICR per RECIST v1.1 in Cohorts A and B
A, Duration of confirmed response in cohort A. An estimated 88.2% of responders had a duration of response lasting at least 6 months and 79.7% at least 12 months. B, Duration of confirmed response in cohort B. An estimated 91.3% of responders had a duration of response lasting at least 6 months and 75.6% at least 12 months. Abbreviations: BICR, blinded independent central review; NR, not reached; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
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