First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Trial registration: ClinicalTrials.gov NCT02872116.

FIG 1.

Kaplan-Meier estimates of OS, PFS, and duration of response in (A, C, and E) patients with PD-L1 CPS ≥5 and (B, D, and F) all randomly assigned patients. ^aNumber of responders; ^bPer BICR assessment. BICR, blinded independent central review; Chemo, chemotherapy; CPS, combined positive score; HR, hazard ratio; NIVO, nivolumab; OS, overall survival; PFS, progression-free survival.

FIG 2.

Forest plot of OS in prespecified subgroups with (A) PD-L1 CPS ≥5 and (B) all randomly assigned patients. ^aNot reported, n = 29; ^bindeterminate, nonevaluable, or not reported, n = 1; ^cinvalid/not available, n = 74; ^dECOG PS 2, n = 4; ^enot reported, n = 49; ^findeterminate, nonevaluable, or not reported, n = 4; ^ginvalid/not available, n = 159. Chemo, chemotherapy; CPS, combined positive score; EAC, esophageal adenocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, fluorouracil plus leucovorin plus oxaliplatin; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HR, hazard ratio; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NIVO, nivolumab; OS, overall survival; ROW, rest of the world; XELOX, capecitabine plus oxaliplatin.

FIG A1.

CONSORT diagram. ^aEnrolled patients included all concurrently randomly assigned patients to nivolumab plus chemotherapy and chemotherapy as well as patients enrolled before the nivolumab plus ipilimumab arm was closed and not randomly assigned to any of the treatment arms. ^bIncluded death (n = 35), AEs (n = 24), poor/noncompliance (n = 15), and additional reasons (n = 54). ^cIncludes patients concurrently randomly assigned to the nivolumab plus chemotherapy and chemotherapy arms. ^dIncluded completion of treatment (n = 55), maximum clinical benefit (n = 12), lost to follow-up (n = 2), no longer met study criteria (n = 1), poor/noncompliance (n = 1), and other (n = 11). ^eIncluded maximum clinical benefit (n = 30), poor/noncompliance (n = 4), lost to follow-up (n = 2), death (n = 1), and other (n = 9). AE, adverse event; CPS, combined positive score; OS, overall survival; PFS, progression-free survival.

FIG A2.

Subgroup analysis by PD-L1 CPS subpopulation for (A) OS and (B) objective rate response. ^aPD-L1 CPS expression indeterminate/not reported, n = 19; ^bPD-L1 CPS expression indeterminate/not reported, n = 14; ^crandomly assigned patients who had target lesion measurements at baseline, per BICR; ^dpercentages may not reflect an exact difference because of rounding. BICR, blinded independent central review; Chemo, chemotherapy; CPS, combined positive score; HR, hazard ratio; NIVO, nivolumab; ORR, objective response rate; OS, overall survival.

FIG A3.

OS by response status at week 18 landmark in patients with (A) PD-L1 CPS ≥5, (B) PD-L1 CPS <5, and (C) all randomly assigned patients. Patients had measurable disease per BICR at baseline, had a tumor evaluation before or at 18 weeks, and were alive, evaluable, and not censored before 18 weeks. ^aPatients who had achieved confirmed partial response or complete response per BICR before or at the time of landmark. BICR, blinded independent central review; Chemo, chemotherapy; CPS, combined positive score; NIVO, nivolumab; OS, overall survival.

FIG A4.

Least squares mean change (95% CI) in FACT-Ga total score and FACT-Ga GP5 (“I am bothered by side effects of treatment”) item values in (A and C) patients with PD-L1 CPS ≥5 and (B and D) the overall population. Least squares mean (95% CI) change from baseline in FACT-Ga total score with nivolumab plus chemotherapy versus chemotherapy in (A) patients with PD-L1 CPS ≥5 (completion at baseline: nivolumab plus chemotherapy, n = 412; chemotherapy, n = 386) and (B) the overall population (completion at baseline: nivolumab plus chemotherapy, n = 679; chemotherapy, n = 639). Data in A and B are presented as least squares mean change from baseline and 95% CI. Top and bottom dotted and dashed lines indicate minimally important difference in score. The primary meaningful change threshold is 15.1 (dotted lines) and the sensitivity threshold is 10.4 (dashed lines). The P value for the difference in least squares means was computed as the two-tailed probability using the t distribution. No adjustments were made for multiple comparisons. *P < .05 for contrast between nivolumab plus chemotherapy versus chemotherapy; not formally tested. FACT-Ga GP5 (“I am bothered by side effects of treatment”) item values in (C) patients with PD-L1 CPS ≥5 and (D) the overall population. Chemo, chemotherapy; CPS, combined positive score; FACT-Ga, Functional Assessment of Cancer Therapy-Gastric; NIVO, nivolumab.