Both CheckMate-649 and ATTRACTION-4 showed a statistically significant improvement in progression-free survival (PFS) for treatment of advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/oesophageal adenocarcinoma (EAC) with nivolumab.

 

Standard first-line chemotherapy options for advanced or metastatic HER2-negative GC/GEJC and EAC result in poor overall survival (OS; median less than 1 year). In recent years, nivolumab provided superior OS in heavily pretreated patients with GC/GEJC [1]. In addition, first-line treatment with nivolumab plus chemotherapy showed promising results in a phase 2 trial in patients with advanced/recurrent GC/GEJC [2].

 

CheckMate 649 is a randomized phase 3 trial designed to evaluate the efficacy of first-line treatment with nivolumab plus chemotherapy or nivolumab plus ipilimumab versus chemotherapy in patients with previously untreated, unresectable advanced or metastatic GC/GEJC/EAC. Prof. Markus Möller (Johannes-Gutenberg University Clinic, Germany) presented the first results of the trial, comparing nivolumab plus chemotherapy versus chemotherapy alone [3]. A total of 1,581 patients were 1:1 randomized to receive either nivolumab (240 mg) plus chemotherapy (FOLFOX Q2W or XELOX Q3W) or chemotherapy alone. Primary endpoints of the study were PFS and OS in patients with positive PD-L1 tumor expression (CPS≥5).

 

Both PFS and OS were significantly improved in the nivolumab plus chemotherapy arm versus chemotherapy alone. Median OS was 14.4 months in the nivolumab plus chemotherapy arm versus 11.1 in the chemotherapy arm (HR 0.71; P<0.0001). OS survival rates at 12 months were 57% versus 46%. Superior OS benefit for nivolumab plus chemotherapy was also seen in patients with PD-L1 CPS≥1 (HR 0.77) and in all randomized patients, irrespectively of PD/L1 expression (HR 0.80). The OS benefit of nivolumab plus chemotherapy was observed in all pre-specified subgroups, including race and region. Median PFS in patients with PD/L1 CPS≥5 was significantly improved by nivolumab: 7.7 months versus 6.0 months, respectively (HR 0.68; P<0.0001). In patients with PD-L1 CPS≥1 and all randomized patients HR was 0.74 and 0.77, respectively. Objective response rate was also in favor of nivolumab plus chemotherapy (60% vs 45%) as was median duration of response (9.5 vs 7.0 months. Nivolumab plus chemotherapy was associated with more adverse events (grade 3-4) compared with chemotherapy alone: 59% versus 44%. However, no new safety signals were identified.

 

The results of CheckMate-649 are in line with the results of the phase 3 part of the ATTRACTION-4 trial, presented at ESMO Virtual 2020 by Prof. Narakazi Boku (National Cancer Center Hospital, Japan) [4]. In this study, 724 Asian GC/GEJC/EAC patients were 1:1 randomized to receive nivolumab plus chemotherapy (CAPOX or oxaliplatin/S1) or chemotherapy alone.

 

After a median follow-up period of 11.6 months, PFS was significantly improved in the nivolumab plus chemotherapy arm: 10.5 months versus 8.4 months (HR 0.68; P=0.0007), meeting the primary endpoint. However, after a median follow-up of 26.6 months, there was no statistically significant difference in OS: 17.5 months versus 17.3 months (HR 0.90; P=0.257).

Commenting on the 2 presentations, Dr. Elizabeth Smythe (Cambridge University Hospitals, UK) suggested that more intense second- and third-line treatment in Asia could explain the non-significance of OS. In addition, Dr. Smythe cautioned not to extrapolate the benefit seen in patients with PD-L1 CPS≥5 in CheckMate 649 to all patients. Although a statistically significant benefit was also seen in all randomized patients, this outcome was predominantly driven by 60% of patients with PD-L1 CPS≥5 in the total population. A separate analysis of patients with PD-L1 CPS<5 should be performed to see whether nivolumab plus chemotherapy is also beneficial for these patients, Dr. Smythe concluded.

 

  1. Kang Y-K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390 :2461-2471.
  2. Boku N, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol. 2019; 30:250-258.
  3. Möhler M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. ESMO 2020 Virtual Meeting, abstract LBA6.
  4. Boku N, et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. ESMO 2020 Virtual Meeting, abstract LBA7.
  5. Smythe E. Immune checkpoint blockade in 1L gastroesophageal adenocarcinoma: a new door opens. ESMO 2020 Virtual Meeting, Presentation ID 5603.