Doublet Immunotherapy Disappoints in Gastric Cancer Study

BARCELONA — The combination of standard FOLFOX chemotherapy with doublet immunotherapy did not improve progression-free survival compared with chemotherapy alone in patients with HER2-negative gastric or gastroesophageal junction adenocarcinoma, a new study shows.
Results of the phase 2 AIO-STO-0417 (MOONLIGHT) trial were disappointing, given that the combination of FOLFOX and nivolumab monotherapy “has improved overall survival in metastatic esophagogastric cancer and has become standard of care,” lead investigator Sylvie Lorenzen, MD, from the Technical University of Munich in Germany, said during a presentation at the European Society of Medical Oncology (ESMO) 2024 Congress. 
Still, the prognosis in this patient population remains poor.
The study sought to explore whether doublet immunotherapy delivered either in parallel or sequentially with FOLFOX might add further benefit to chemotherapy. The study also explored the potential of combining triplet chemotherapy (FLOT – fluorouracil, leucovorin, oxaliplatin, docetaxel) with nivolumab. 
A total of 262 patients with unresectable locally advanced or metastatic disease were recruited irrespective of PDL1 expression status. 
The patients were randomly assigned into a complex sequence of study arms that compared modified FOLFOX (mFOLFOX) alone (Arm B, n = 60) with mFOLFOX plus doublet ipilimumab and nivolumab (Arm A), delivered either in a parallel (Arm A/A1, n = 90) or sequential regimen (Arm A2, n = 60). The study also compared Arm B to an experimental Arm C (n = 52) that looked at triplet chemotherapy (FLOT) plus nivolumab.
Depending on the treatment arm, age varied from 58 to 63 years, 65% to 68% of patients were male, between 21% and 37% of patients had undergone primary resection, and 48% to 65% of tumors were located in the stomach. Overall, 38% (Arm B) to 65% (Arm C) of patients had PD-L1 expression of at least 1%.
For the primary endpoint of progression-free survival, there was no difference between the doublet immunotherapy parallel arm (Arm A/A1) and mFOLFOX alone (Arm B) based on the intent-to-treat (ITT) population — median progression-free survival of 5.8 vs 6.6 months, respectively — or based on PD-L1 expression — median progression-free survival of 5.4 vs 6.1 months, respectively. The addition of doublet immunotherapy even appeared to result in a slightly detrimental effect compared with chemotherapy alone. 
Overall survival results were similar between the two groups as well: 10.1 months for doublet immunotherapy plus chemotherapy vs 12.5 months for chemotherapy alone in the ITT population, and 9.2 versus 12.5 months, respectively, in the PD-L1 expression group.
When comparing parallel vs sequential FOLFOX and immunotherapy, the median progression-free survival at 6 months was inferior in the sequential approach (4.0 months vs 5.8 months) as was overall survival (7.6 vs 10.1 months), Lorenzen reported.
Arm C, which examined treatment with FLOT and nivolumab, showed the highest median progression-free survival compared with chemotherapy alone — 7 months vs 6.6 months, respectively — and a higher overall survival of 14.6 months compared with 12.5 months, respectively.
More than 40% of patients in the parallel doublet immunotherapy arm (A1) experienced serious treatment-related adverse events of grade 3 or higher. In the FLOT/nivolumab arm, 23% of patients experienced grade 3 or higher serious treatment-related adverse events. Rates of serious treatment-related adverse events were similar in Arm B (18%) and Arm 2 (17%).
The most common any-grade treatment-related adverse events across all arms were diarrhea, fatigue, nausea, decreased neutrophil count, and peripheral sensory neuropathy.
Overall, “our study doesn’t support the concept of chemotherapy induction followed by [doublet] immunotherapy,” Lorenzen concluded. 
“The combination of the triplet FLOT plus nivolumab is feasible and seems to be associated with improved efficacy,” she added. “However, results must be interpreted with caution due to the small number of patients and low PD-L1 expression rates in all treatment arms.”
Tania Fleitas Kanonnikoff, MD, PhD, invited discussant for the study, said a serious limitation of the study was the fact there was no stratification of patients based on PDL1 status.
“We need to plan immunotherapy trials with PD-L1 stratification in all trials,” Kanonnikoff, a medical oncologist at the University Hospital of Valencia in Spain, told Medscape Medical News. “It is not a perfect marker but it matters.”
It’s already a standard biomarker test, and for those with PD-L1 positivity, phase 3 clinical trials with a long-term follow-up — the CheckMate 649 and Keynote-859 trials, for example — show that adding the checkpoint inhibitors nivolumab or pembrolizumab to standard doublet chemo is beneficial.
The study was funded by Bristol Myers Squibb. Lorenzen reported being an invited speaker with Servier, Lilly, MSD, BMS, and AstraZeneca; and being on the advisory board for Astellas.
Kanonnikoff reported consultant or advisory roles with Amgen, AstraZeneca, MSD, and BeiGene; research funding from Gilead; speaking engagements with Amgen, Servier, Bayer, BMS, MSD, Lilly, and Roche; and institutional funding from Genentech, Adaptimmune, Roche, BeiGene, Bayer, Servier, Astellas, BMS, and Daiichi Sankyo. 
 
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