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Regorafenib (Stivarga) plus nivolumab (Opdivo) displayed noninferior survival and a numerically higher response rate and disease control rate (DCR) compared with chemotherapy for patients with previously treated, refractory, advanced gastric or gastroesophageal junction (GEJ) cancer, according to findings from the phase 3 INTEGRATE IIb (NCT04879368) presented at the European Society for Medical Oncology (ESMO) Congress 2025.

Among patients in the intent-to-treatment population in the regorafenib arm (n = 309) vs the chemotherapy arm (n = 153), the median overall survival (OS) was 5.9 months vs 6.3 months (HR, 0.88; 95% CI, 0.71-1.09; P = .23). Additionally, the median progression-free survival (PFS) in the respective arms was 1.9 months (95% CI, 1.8-2.0) vs 1.9 months (95% CI, 1.8-2.0; HR, 0.85; 95% CI, 0.69-1.05).

Furthermore, a numerically higher objective response rate (ORR) was observed among patients treated with regorafenib plus nivolumab vs chemotherapy, with respective rates of 7.4% vs 2.6% (OR, 2.99; 95% CI, 1.00-12.11). The DCR in the regorafenib and chemotherapy arms was 39% vs 26% (OR, 1.84; 95% CI, 1.18-2.90), with 12-month DCR rates of 14% (95% CI, 8.5%-21%) vs 0% (95% CI, not estimable [NE]), respectively.

Global quality of life (QOL) was numerically improved with regorafenib, with 12-month deterioration-free rates of 3.9% (95% CI, 2.1%-6.5%) vs 0.7% (95% CI, <0.1%-3.5%) with chemotherapy (HR, 0.74; 95% CI, 0.60-0.91). Additionally, the physical functioning QOL scores exhibited similar values, with event-free rates of 3.9% (95% CI, 2.1%-6.5%) and 0.7% (95% CI, <0.1%-3.5%), respectively (HR, 0.86; 95% CI, 0.70-1.05).

“[Regorafenib plus nivolumab] was not superior to investigator’s choice of chemotherapy in third- or later-line treatment,” presenting investigator, David Goldstein, MBBS, FRACP, PRCP, conjoint clinical professor and senior staff specialist in the Department of Medical Oncology at Prince of Wales Hospital in Syndey, Australia, stated in the presentation. “We note that secondary end points of ORR and DCR were numerically higher in the [experimental] arm, without any adverse impact on global QOL and a prolonged 12-month time to deterioration in the regorafenib/nivolumab arm.”

In the phase 3 AGITG intergroup study, patients with unresectable locally advanced, metastatic, or recurrent gastric or GEJ adenocarcinoma who previously received at least 2 prior lines of chemotherapy—including a platinum-containing agent and fluoropyrimidine —were randomly assigned 2:1 to receive the regorafenib/nivolumab regimen or chemotherapy. Those eligible for enrollment also must have had an ECOG performance status of 0 or 1, and those with HER2-positive disease must have received trastuzumab (Herceptin).

Treatment in the investigational arm consisted of 90 mg of daily oral regorafenib on days 1 to 21 of each 28-day cycle and intravenous nivolumab at 240 mg on day 1 of each 14-day cycle for 2 months of treatment, followed by 480 mg of intravenous nivolumab on day 1 of 28-day cycles. The chemotherapy regimen used was determined by the investigator’s choice and consisted of taxane-based chemotherapy (25%), irinotecan (25%), or trifluridine/tipiracil (Lonsurf; 49%). In both arms, treatment continued in the absence of disease progression or unacceptable toxicity.

In the investigational and control arms, 48% in each arm were treated in Asia, 73% vs 75% were male, and the median age was 63 years (range, 22-85) vs 63 years (range, 24-83). Most patients were previously treated with VEGF inhibitors (61% vs 59%), had an ECOG performance status of 1 (57% vs 55%), and had gastric disease (63% vs 59%). A total of 33% vs 33% received prior immunotherapy, 44% vs 44% received more than 2 prior lines of therapy, and 50% vs 48% had more than 2 metastatic sites of disease.

The primary end point of the study was OS. Secondary end points included PFS, ORR, DCR, QOL, and safety.

Any-grade adverse effects (AEs) were observed in 98% of the regorafenib/nivolumab arm vs 92% of the chemotherapy arm; 58% vs 38%, 8% vs 10%, and 4% vs 1% experienced grade 3, 4, and 5 AEs, respectively. The frequency of serious AEs (SAEs) in either arm was 41% vs 25%. However, Goldstein noted that an expedited reporting for SAEs was not required in the chemotherapy arm, and an imbalance in the reporting of these events was expected.

The most common grade 3 or higher AEs in the investigational and control arms included neutrophil count decreases (3% vs 18%), anemia (6% vs 9%), fatigue (6% vs 4%), nausea (1% vs 7%), aspartate aminotransferase increases (5% vs 3%), and platelet count decreases (6% vs 2%).

Reference

Goldstein D, Sjoquist K, Espinosa D, et al. Regorafenib plus nivolumab vs investigator’s choice of chemotherapy in previously treated gastric or gastroesophageal cancer: INTEGRATE IIb, a randomized phase 3 AGITG Intergroup [NHMRC-CTC/IKF/AIO, ACCRU, TCOG/NHRI] study. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA80.