Editor’s pick of Sylvie Rottey, MD, PhD, medical oncologist, UZ Gent
The phase III CheckMate 649 study evaluated nivolumab in combination with chemotherapy, compared to chemotherapy alone, in patients with HER-2 negative gastro-oesophageal cancers. Nivolumab was found to be the first PD-1 inhibitor to demonstrate superior overall survival, a clinically meaningful progression-free survival benefit, a maintained health-related quality of life and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone.
Gastric cancer, including gastro-oesophageal junction cancer, represents the fourth most common cause of cancer-related deaths worldwide. Unfortunately, treatment with fluoropyrimidine plus platinum-based chemotherapy, the most frequently used first-line treatment for unresectable advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric and gastro-oesophageal junction adenocarcinoma, results in poor survival (median overall survival [mOS]) of less than 1 year). In addition, no targeted therapies have significantly improved survival relative to chemotherapy. The programmed cell death (PD)-1 inhibitor nivolumab has demonstrated a superior mOS compared to placebo in heavily pre-treated advanced/recurrent gastric and gastro-oesophageal junction cancers in the phase III ATTRACTION-2 study. In addition to direct cytotoxic properties, chemotherapy might contribute to the anti-tumour immune response elicited by nivolumab through induction of immunogenic cell death. The phase III CheckMate 649 study therefore evaluates the safety and efficacy of nivolumab plus standard of care (SoC) chemotherapy in previously untreated, advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma.
This multicentre, randomised, open-label phase III trial enrolled and randomised (1:1:1 while all three groups were open) 1,581 patients with previously untreated, unresectable, HER2-negative gastric, gastro-oesophageal junction or oesophageal adenocarcinoma to receive either nivolumab (NIVO) (360mg every 3 weeks [Q3W] or 240mg Q2W) plus chemotherapy (chemo) (capecitabine and oxaliplatin Q3W, or leucovorin, fluorouracil and oxaliplatin Q2W), nivolumab plus ipilimumab, or chemotherapy alone. Patients were required to be 18 years or older and were enrolled irrespective of PD-L1 expression status. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. Nivolumab was given for a maximum of 2 years and chemotherapy was given per local protocols. For the NIVO + chemo (N= 789) and chemo-alone groups (N= 792), the dual primary endpoints were OS and progression-free survival (PFS) in patients with a PD-L1 combined positive score (CPS) ≥5. Secondary endpoints included OS in the overall population as well as safety.
Baseline characteristics were well balanced across both the primary population (CPS ≥5) and the overall population. In total, 60% of the NIVO + chemo arm and 61% of the chemo-only arm had a PD-L1 CPS score ≥5. Most patients (70%) had gastric cancer, while 16% had gastro-oesophageal junction cancer and 13% had oesophageal adenocarcinoma. At a minimum follow-up of 12.1 months, both primary endpoints were met. The combination of NIVO + chemo significantly improved median OS, compared to chemo-only, in patients with a PD-L1 CPS score ≥5 (14.4 months vs. 11.1 months; HR[95%CI]: 0.71[0.59-0.86], P< 0.0001). Similarly, a clinically meaningful improvement in median PFS was observed (7.7 months vs. 6.0 months; HR[95%CI]: 0.68[0.56-0.81], P< 0.0001). Furthermore, also patients with a PD-L1 CPS score ≥1 benefitted from the immunochemotherapy combination compared to chemo-alone (mOS: 14.0 months vs. 11.3 months; HR[95%CI]: 0.77[0.64-0.92], P< 0.0001 and mPFS: 7.5 months vs. 6.9 months; HR[95%CI]: 0.74[0.65-0.85]). Finally, a 20% reduction in the risk of death (median OS: 13.8 months vs. 11.6 months; HR[95%CI]: 0.80[0.68-0.94], P= 0.0001), and a similar trend in median PFS (7.7 months vs. 6.9 months; HR[95%CI]: 0.77[0.68-0.87]) was observed for patients in the overall population who were treated with NIVO + chemo. In the primary population, 60% had an objective response with NIVO + chemo, compared to 45% in patients who received chemo-alone. Complete responses (CRs) were 12% and 7%, respectively, and the median duration of response was 9.5 months with the combination, and 7.0 months with chemo only. Consistent results were observed in all randomly assigned patients.
Grade 3/4 treatment-related adverse events (TRAEs) occurred in 59% of patients treated with NIVO + chemo, and 44% of those treated with chemo only. The most common grade 3/4 TRAEs were neutropenia (15% vs. 12%), anaemia (6% vs. 3%), diarrhoea (4% vs. 3%) and peripheral neuropathy (4% vs. 3%). Sixteen (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. Finally, there was a trend towards improved HRQoL with nivolumab plus chemotherapy, although this change was not clinically meaningful per the predefined threshold. However, patients treated with NIVO + chemo had a decreased risk of symptom deterioration, compared to chemo-alone in both the PD-L1 CPS ≥5 population (HR[95%CI]: 0.64[0.49-0.83]) and the overall population (HR[95%CI]: 0.77[0.63-0.95]).
This phase III study demonstrates superior OS and a PFS benefit when nivolumab is added to chemotherapy as a first-line treatment for previously untreated patients with advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma, especially in patients with a PD-L1 CPS ≥5. As the combination also has an acceptable safety profile, nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.
Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40.