Four-year outcomes and circulating tumor DNA (ctDNA) analysis of pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in unresectable, locally advanced, stage III non–small-cell lung cancer (NSCLC): From KEYNOTE-799.

Martin Reck LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany info_outline Martin Reck, Ki Hyeong Lee, Nikolaj Frost, Valeriy Vladimirovich Breder, Dariusz M. Kowalski, Evgeny Levchenko, Noemi Reguart, Alex Martinez-Marti, Baerin Houghton, Jean-Baptiste Paoli, Sufiia Safina, Hong Liu, Vladimir Novinskiy, E.J. Dettman, Julie Kobie, Salma K. Jabbour

Authors Martin Reck LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany info_outline Martin Reck, Ki Hyeong Lee, Nikolaj Frost, Valeriy Vladimirovich Breder, Dariusz M. Kowalski, Evgeny Levchenko, Noemi Reguart, Alex Martinez-Marti, Baerin Houghton, Jean-Baptiste Paoli, Sufiia Safina, Hong Liu, Vladimir Novinskiy, E.J. Dettman, Julie Kobie, Salma K. Jabbour Organizations LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, Thoracic Oncology Unit, Department of Medical Oncology, IDIBAPS, Hospital Clínic, Barcelona, Spain, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Barcelona, Spain, Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, NSW, Australia, Radiotherapie, Clinique Clairval, Marseille, France, Medical Oncology, Republican Dispensary of Tatarstan MoH, Kazan, Russian Federation, Merck & Co., Inc., Rahway, NJ, MSD (UK) Limited, London, United Kingdom, Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ Abstract Disclosures Research Funding Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Background: The nonrandomized phase 2 KEYNOTE-799 study (NCT03631784) of pembro + cCRT in previously untreated unresectable, locally advanced, stage III NSCLC demonstrated an ORR of 70.5% in cohort A (squamous and nonsquamous) and 70.6% in cohort B (nonsquamous only) after median follow-up of 18.5 mo and 13.7 mo, respectively. We present outcomes with ⁓4 y of follow-up and analysis of ctDNA. Methods: Eligible patients (pts) were aged ≥18 y with unresectable confirmed stage IIIA–C NSCLC (per AJCC v8), measurable disease per RECIST v1.1, and ECOG PS 0 or 1. Pts in cohort A (squamous and nonsquamous) received carboplatin + paclitaxel and pembro 200 mg for one 3-wk cycle, followed by carboplatin + paclitaxel QW for 6 wks + 2 cycles of pembro 200 mg Q3W + standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous only) received 3 cycles of cisplatin, pemetrexed, and pembro 200 mg Q3W + standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro. Primary endpoints were ORR per RECIST v1.1 by BICR and incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). As an exploratory endpoint, tumor ctDNA was assessed in available plasma samples collected at baseline and cycle 7 using the Signatera ctDNA assay. Results: Of 214 pts enrolled, including 112 in cohort A and 102 in cohort B. Median (range) time from first dose to database cutoff (Oct 16, 2023) was 54.1 (49.2–59.4) and 49.3 (38.4–59.1) mo, respectively. ORR was 71.4% in cohort A and 74.5% in cohort B (Table). Grade ≥3 pneumonitis (primary endpoint) occurred in 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Grade 3–5 treatment-related AEs occurred in 73 pts (65.2%) in cohort A and 52 (51.0%) in cohort B. Of ~136 samples sent for sequencing, 73 pts (~53.7%) had samples evaluable for ctDNA at baseline. ORR was 68.7% in pts with ctDNA detectable (n = 67) vs 50.0% in pts with ctDNA non-detectable samples (n = 6) at baseline. Among 46 pts with ctDNA detectable at baseline and evaluated at cycle 7, 32 (69.6%) had cleared ctDNA at cycle 7; these pts had better trends in PFS and OS vs pts who had not cleared ctDNA at cycle 7 (n = 14). Conclusions: With ~4 y of follow-up, pembro + cCRT continues to demonstrate durable antitumor activity and manageable safety in previously untreated unresectable, locally advanced stage III NSCLC. ctDNA was evaluable in ~half of the samples assessed; most pts with detectable ctDNA at baseline had cleared ctDNA at cycle 7. Clinical trial information: NCT03631784. Cohort A N = 112 Cohort B N = 102 ORR (95% CI), % 71.4 (62.1–79.6) 74.5 (64.9–82.6) Median DOR (range), mo 46.5 (1.9+ to 54.5+) NR (1.6+ to 54.6+) Median PFS (95% CI), mo 29.0 (16.6–48.5) 37.9 (17.9–NR) 48-mo PFS rate (95% CI), % 40.6 (28.9–52.0) 46.4 (33.7–58.1) Median OS (95% CI), mo 35.6 (26.1–44.2) NR (41.1–NR) 48-mo OS rate (95% CI), % 40.2 (31.1–49.1) 54.6 (43.9–64.0) ‘+’ indicates no PD by the time of last assessment.

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