Nivolumab plus chemotherapy as a potential new standard first-line treatment option for patients with advanced gastric and oesophageal cancers
At ESMO 2020, Prof. Moehler presented the first results of the randomized, phase III CheckMate 649 trial evaluating nivolumab plus chemotherapy as a first-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer or oesophageal adenocarcinoma. These results revealed that the addition of nivolumab to chemotherapy results in a significant improvement in the overall and progression free survival in patients with a PD-L1 combined positive score (CPS) of 5 or more. In addition, significant improvements were also observed in patients with PD-L1 CPS ≥1 tumours and in the overall patient population.
Patients with advanced or metastatic, HER2-negative gastric or gastro-oesophageal junction cancers (GC/GEJC) face a poor prognosis with the current standard of care, resulting in a median overall survival (OS) of less than one year. Previously, nivolumab provided superior OS compared to placebo in heavily pre-treated advanced/recurrent GC/GEJC (ATTRACTION-2 trial), while the combination of nivolumab and chemotherapy showed promising antitumour activity in the first-line setting (phase II part of ATTRACTIO-4). PD-L1 expression by a combined positive score (CPS) at a cut-off of at least 5 has shown better enrichment for efficacy of checkpoint inhibitors than tumour cell PD-L1 expression in GC, GEJC and oesophageal adenocarcinoma (EAC). CheckMate 649 is the largest randomised, global phase III study of a PD-1 inhibitor-based therapy in the first line treatment of patients with advanced GC, GEJC or EAC.
In CheckMate 649, a total number of 1,581 adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of PD-L1 expression. Patients with known HER2-positive status were excluded. Patients were randomised to receive nivolumab (360 mg Q3W) plus chemotherapy (XELOX), or nivolumab (240 mg Q2W) plus FOLFOX), or nivolumab plus ipilimumab, or XELOX or FOLFOX alone. The two co-primary endpoints of the trial consist of overall (OS) and progression-free survival (PFS) in patients with a PD-L1 CPS of ≥ 5 (i.e. 955 [60%] of the enrolled patients). At ESMO 2020, Prof. Moehler reported the first results of the comparison between nivolumab + chemotherapy (NIVO + chemo) versus chemotherapy alone.
The median age of PD-L1 CPS ≥ 5 patients was 63 years, approximately 70% was male and three quarters of patients were of non-Asian origin. Seventy percent of the PD-L1 CPS ≥ 5 cohort consisted of GC patients, while 18% and 12% of patients had GEJC or EAC, respectively. At the time of the analysis, the median treatment duration was 6.8 months for patients treated with NIVO + chemo, as compared to 4.9 months with chemotherapy alone. In total, respectively 89% and 95% discontinued treatment, mostly because of disease progression (66% and 69%, respectively). Overall, 39% of all randomised patients received subsequent treatment.
With a minimum follow-up of 12.1 months (data cut-off May 27th, 2020) , NIVO + chemo showed a statistically significant superior OS compared to chemotherapy alone in PD-L1 CPS ≥ 5 patients, with a 29% reduction in the risk of death (median OS of 14.4 vs. 11.1 months, HR [98.4%CI]: 0.71 [0.59–0.86], p<0.0001). At one year, 57% of patients in the NIVO + chemo arm and 46% of patients in the chemo arm were still alive. The OS consistently favoured NIVO + chemo versus chemotherapy alone across multiple pre-specified subgroups, including age, sex, race, region, ECOG performance status, primary tumour location and the presence of baseline liver metastases. Interestingly, a statistically significant OS benefit was also observed in patients with PD-L1 CPS ≥ 1 (14.0 vs. 11.3 months, HR [99.3%CI]: 0.77 [0.64-0.92], p=0.0001) and in the overall patient population (13.8 vs. 11.6 months, HR [99.3%CI]: 0.80 [0.68-0.94], p=0.0002).
For patients with a PD-L1 CPS ≥ 5, the PFS was significantly prolonged from 6.0 months with chemotherapy alone to 7.7 months upon the addition of nivolumab (HR [98%CI]: 0.68 [0.56–0.81], p<0.0001]). As such, the combination of NIVO + chemo was associated with a 32% reduction in the risk of disease progression or death compared to chemotherapy alone. Comparable results were observed in the PD-L1 CPS ≥1 (HR [95%CI]: 0.74 [0.65-0.85]) and overall patient population (HR [95%CI]: 0.77 [0.68-0.87]). Finally, also the objective response rate for patients with PD-L1 CPS ≥ 5 was higher with NIVO + chemo (60%) compared to chemotherapy alone (45%) and the responses also proved to be more durable in the immunotherapy-based treatment arm (duration of response of respectively 9.5 and 7.0 months).
No new safety signals were observed. Adverse events of grade 3 and 4 were more common in the combination arm (59%) as compared to the chemotherapy arm (44%), leading to treatment discontinuation in 17% and 9% of patients, respectively. The most common any-grade TRAEs across both arms were nausea, diarrhoea and peripheral neuropathy. In the NIVO + chemo arm, twelve treatment-related deaths (2%) were reported, as compared to four deaths (<1%) in the chemotherapy arm.
Nivolumab is the first PD-1 inhibitor to demonstrate superior OS and PFS in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced GC/GEJC/EAC, with a manageable safety profile. This benefit was most pronounced in patients with a PD-L1 CPS ≥5 but was also significant in PD-L1 CPS ≥1 patients and in the overall study population. As such, nivolumab plus chemotherapy represents a potential new standard first-line treatment option for these patients.
Moehler M, Shitara K, Garrido 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. Presented at ESMO 2020; Abstract LBA6.