CheckMate 649: A randomized, multicenter, open-label, phase III study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesophageal junction (GEJ) cancer.

Abstract

TPS192 Background: Pts with adv G/GEJ cancer have an OS of ≈ 1 y, indicating an unmet medical need for new first-line treatments. Expression of PD-L1 is observed in up to 40% of pts with G/GEJ cancer and is associated with poor prognosis. In the randomized phase 3 ATTRACTION-2 study, NIVO demonstrated superior overall survival vs placebo with a 38% reduction of the risk of death (median OS, 5.3 vs 4.1 mo; HR, 0.62 P< 0.0001) and increased the OS rate at 12 mo (27% vs 12%; Boku N et al ESMO 2017) in pts with adv CTX-R (≥ 2 lines) G/GEJ cancer. In the phase 1/2 CheckMate-032 study in pts with CTX-R G/GEJ/esophageal cancer (79% ≥ 2 prior Tx lines), NIVO 1 mg/kg + IPI 3 mg/kg had a manageable safety profile and resulted in 24% ORR (40% ORR in pts with PD-L1+ tumors), a median OS of 6.9 mo, and a 35% OS rate at 12 mo (Janjigian Y et al ASCO 2017). In the phase 1 CheckMate-012 trial, NIVO + CTX had clinical activity and manageable safety in pts with NSCLC (Rizvi NA et al J Clin Oncol 2016). These positive results support investigation of NIVO, NIVO + IPI, and NIVO + CTX in earlier lines of treatment for G/GEJ cancer. The open-label, phase 3 CheckMate 649 trial will evaluate NIVO + IPI and NIVO + CTX vs CTX alone as first-line treatment for pts with adv G/GEJ cancer (NCT02872116). Methods: 1266 pts aged ≥ 18 y with untreated, inoperable adv/metastatic G/GEJ cancer (histologically confirmed adenocarcinoma) regardless of PD-L1 status will be randomized to receive either NIVO + IPI, NIVO + CTX (capecitabine/oxaliplatin [XELOX] or fluorouracil/leucovorin/oxaliplatin [FOLFOX]), or investigator choice of XELOX or FOLFOX. Tumor tissue for determination of PD-L1 status (Dako assay) must be provided from ≤ 6 mo before study treatment. No prior systemic treatment, including HER2 inhibitors, are allowed. Pts with known HER2+ status, suspected autoimmune disease, grade > 1 peripheral neuropathy, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ (≥ 1%) tumors. Other endpoints include OS in all pts; PFS and time to symptom deterioration in all pts and in pts with PD-L1+ tumors; and safety. Clinical trial information: NCT02872116.

Current treatment and recent progress in gastric cancer

“…Nivolumab alone and in combination with ipilimumab (a monoclonal antibody inhibiting CTLA‐4) has been studied in Western populations with chemotherapy‐refractory gastroesophageal adenocarcinoma and has been shown to have encouraging antitumor activity with an acceptable toxicity profile 59 . CheckMate‐649 (ClinicalTrials.gov identifier NCT02872116) is a phase 3 trial investigating nivolumab plus chemotherapy or nivolumab plus ipilimumab versus chemotherapy alone in the first‐line treatment of metastatic, HER2‐negative gastric cancer 60 . In initial results, patients with PD‐L1 CPS ≥5 receiving nivolumab plus chemotherapy compared with chemotherapy alone had improved OS (14.4 vs 11.1 months) at a prespecified interim analysis and improved PFS (7.7 vs 6.1 months) at final analysis 61 .…”

Current status and future potential of predictive biomarkers for immune checkpoint inhibitors in gastric cancer

“…Another phase III trial, CHECKMATE-649 (NCT02872116), has completed recruitment with over 2000 patients randomising patients to oxaliplatin-based chemotherapy alone or in combination with nivolumab or nivolumab plus ipilimumab. 32 The third arm of this study terminated recruitment early due to early safety signal.…”

“… 44 Thus, one of the coprimary patient population in the first-line CHECKMATE-649 study, that has recently completed recruitment, is including a subpopulation of patients with PD-L1 CPS ≥5. 32 …”

Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

“…We propose that at least half of the potential pharma gains would be used to finance the trial. [51] 1581 TNBC-triple-negative breast cancer; EC-esophageal cancer; GEJ-gastroesophageal junction; G-gastric cancer; QRCT; quality of randomized clinical trials; SRL; the slope of the regression line. r.; HRPFS/HROS.…”

“…Therefore, these considerations ideally should be endorsed by the FDA and EMA or National Health Systems. This specific evaluation has been highlighted and tested in Table 5 in TNBC and esophageal-gastric cancer trials, comparing chemotherapy plus checkpoint blockade vs. chemotherapy alone [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Remarkably major differences in ESMO-MCBS evaluation were observed between trials with subgroup analysis based on PD-L1 (Programmed Death-Ligand 1) expression analyzed with Combined positive score (CPS).…”