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Nivolumab in gastric cancer: Efficacy update and the role of gut microbiome

Presented by
Dr Kohei Shitara, National Cancer Center Hospital East, Japan; Dr Yu Sunakawa, St. Marianna University School of Medicine, Japan
ASCO GI 2022
Phase 3, CheckMate 649, DELIVER
Nivolumab added to chemotherapy displayed ongoing increased efficacy over chemotherapy alone in treatment-naïve patients with advanced gastric cancer (GC), gastroesophageal junction cancer (GEJC), or oesophageal adenocarcinoma (OAC). The long-term follow-up data of the CheckMate 649 trial also did not show new safety issues for this combination regimen [1]. In addition, the observational DELIVER study revealed that host-related biomarkers in the gut microbiome could predict toxic events related to nivolumab therapy in patients with advanced GC [2].

The phase 3 CheckMate 649 trial (NCT02872116) previously showed that, after 12 months of follow-up, treatment with nivolumab plus chemotherapy was superior to chemotherapy alone in patients with advanced GC, GEJC, or OAC [3]. These results led to the approval of this regimen in the US and Europe. The CheckMate 649 trial randomised patients to nivolumab plus standard chemotherapy (n=789), chemotherapy alone (n=833), or nivolumab plus ipilimumab (n=409). The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 combined positive score (CPS) ≥5. Dr Kohei Shitara (National Cancer Center Hospital East, Japan) presented the results after 24 months of follow-up of the nivolumab plus chemotherapy arm and the chemotherapy alone arm.

At 2 years, a clinically meaningful improvement in median OS was observed in the nivolumab plus chemotherapy arm (13.8 months) compared with the chemotherapy alone arm (11.6 months; HR 0.79). Similarly, long-term follow-up showed maintained PFS benefits for the combination arm (7.7 months vs 6.9 months; HR 0.79).

The safety analysis did not identify new safety issues. Grade 3 or 4 adverse events (AEs) were more common in the combination arm (60%) than in the monotherapy arm (45%). The most frequently reported grade 3 or 4 AEs in the combination arm were neutropenia (15%), decreased neutrophil count (11%), and anaemia (6%). Immune-related AEs of grade 3 or 4 occurred in ≤5% of patients in the combination group across organ categories. All in all, the safety profile of nivolumab plus chemotherapy was acceptable.

The OS benefit of nivolumab plus chemotherapy was consistent across key subgroups in patients with PD-L1 CPS ≥5. “Although patients with higher PD-L1 CPS cut-offs benefitted more from the combination regimen, a numerical benefit was also seen in patients with lower PD-L1 CPS,” said Dr Shitara. In addition, the overall response rate and median duration of response in patients with PD-L1 CPS ≥5 were 60% and 9.7 months in the combination arm versus 45% and 7.0 months in the chemotherapy alone arm. The corresponding results for patients with PD-L1 CPS <5 were 55% and 7.7 months in the nivolumab plus chemotherapy group and 46% and 6.9 months for the chemotherapy group.

Prof. Stefano Cascinu (Università Vita-Salute San Raffaele, Italy) mentioned that next to PD-L1 CPS, the subgroup analysis revealed other factors that may influence patient selection for this novel combination therapy. “For example, patients with malnutrition or peritoneal involvement may benefit less from the nivolumab plus chemotherapy regimen. Furthermore, we need to establish the efficacy of this regimen in patients with ECOG PS scores of 2, a relevant subgroup in clinical practice.”
Gut microbiome

Dr Yu Sunakawa (St. Marianna University School of Medicine, Japan) said that several studies indicated that the composition of the gut microbiome is associated with AEs of PD-1 inhibitor therapy. In GC, this association is not well investigated. Dr Sunakawa and colleagues designed the DELIVER trial (UMIN000030850) to assess whether host-related factors, including information in the gut microbiome, are associated with the efficacy of nivolumab and AEs evoked by nivolumab therapy in patients with advanced GC. The research team collected blood samples and faecal samples from 501 patients with GC who were treated with nivolumab. The secondary outcomes of this study, relationships between markers of the gut microbiome and clinical outcomes, were presented by Dr Sunakawa.

The data displayed a significant association of the genus of Arthrobacter and nivolumab-induced skin toxicities in both the training cohort (n=200; P=0.02) and the validation cohort (n=301; P=0.01). Moreover, the fatty acid metabolism pathway was related to skin toxicities in both cohorts (P=0.02 and P=0.01, respectively). Furthermore, certain genetic polymorphisms were related to toxicities. Single nucleotide polymorphisms (SNPs) of SEMA4D and NOTCH1 were associated with diarrhoea, and SNPs of IL6R and NLRC5 were related to skin toxicities. According to Dr Sunakawa, these SNPs may become biomarkers for nivolumab-induced diarrhoea and skin toxicities and could help in toxicity management.

  1. Shitara K, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: expanded analyses from 24-months follow-up of CheckMate 649. Abstract 240, ASCO GI 2022, 20–22 January.
  2. Sunakawa Y, et al. Host-related biomarkers including gut microbiome to predict toxicities of nivolumab in advanced gastric cancer: DELIVER trial (JACCRO GC-08). Abstract 308, ASCO-GI 2022, 20–22 January.
  3. Janjigian YY, et al. Lancet. 2021;398(10294):27–40.


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