FOLFOX plus nab-paclitaxel exceeds expected ORR, shows favourable haematotoxicity in gastric/GEJ adenocarcinoma

An open-label single-arm phase II trial of FOLFOX and nab-paclitaxel (FOLFOX-A) reports a target-exceeding objective response rate (ORR) and a more favourable haematologic toxicity profile than triplet regimen historical controls in metastatic/advanced unresectable gastric/gastroesophageal junction (GEJ) adenocarcinoma.

In recent years, there have been major improvements in the treatment of metastatic HER2-negative gastric/GEJ adenocarcinoma with the addition of immune checkpoint inhibitors to chemotherapy in the frontline setting. [Lancet 2021;398:27-40; Lancet 2021;398:759-771] “While these advancements are important, some patients will not be candidates for immunotherapy for a variety of reasons, including autoimmune history, preexisting need for immunosuppression, or immune-related adverse events [AEs]. With a median overall survival [OS] of less than 1 year across current doublet and triplet chemotherapy regimens, more options are needed for patients who are unable to tolerate immunotherapy,” wrote the researchers.

Between 2017 and 2023, 39 chemotherapy-naïve patients with advanced/metastatic HER2-negative unresectable gastric/GEJ adenocarcinoma were enrolled in in the present study to receive FOLFOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 2400 mg/m² over 46–48 hours) plus nab-paclitaxel (150 mg/m²) every 14 days of a 28-day cycle. The primary endpoint was ORR, for which the expected target was set at 20 percent. [Oncologist 2024;29:1044-1050]

ORR in 35 evaluable patients was 42.9 percent. One patient achieved complete response, 14 patients achieved partial response, and 13 patients had stable disease. The median progression-free survival (PFS) was 6.6 months and the median overall survival (OS) was 10.5 months. PFS probability for FOLFOX-A at 6, 12, and 24 months was 51.7, 31.0, and 19.7 percent, respectively. OS probability at 6, 12, and 24 months was 76.3, 44.7, and 24.7 percent, respectively. “There were no differences in ORR, PFS, and OS between gastric and GEJ patients,” noted the researchers.

FOLFOX’s and nab-paclitaxel’s expected toxicities of grade 1–2 peripheral neuropathy, diarrhoea, and fatigue occurred in approximately half of the study participants. The most common grade 3 or 4 adverse events were peripheral sensory neuropathy (18.4 percent), anemia (18.4 percent), neutropenia (15.8 percent), diarrhaea (7.9 percent), and lymphopenia (7.9 percent). Grade 3 or 4 leukopenia occurred in 5.3 percent with the FOLFOX-A regimen. Treatment-related dose adjustments were required in 65.8 percent of patients who started treatment.

The researchers highlighted that the rates of grade 3 or 4 leukopenia and neutropenia with FOLFOX-A were comparable to that in the 5-FU/leucovorin and oxaliplatin regimen (FLO; 6.3 and 11.6 percent, respectively) and more favorable than in the 5-FU/leucovorin, oxaliplatin, and docetaxel (FLOT; 27 and 51 percent, respectively). [J Clin Oncol 2008;26:1435-1442; Lancet 2019;393:1948-1957] “The favourable haematologic toxicity profile of FOLFOX-A vs FLOT means FOLFOX-A is worthy of further study as a first-line therapy for metastatic HER2-negative gastric/GEJ adenocarcinoma,” they commented, adding that future investigations could also consider incorporating FOLFOX-A as the chemotherapy backbone in combination with immunotherapy.