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.

Abstract

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.