Regorafenib Provides Modest Survival Benefit in Refractory Advanced Gastric/GEJ Cancer

Treatment with regorafenib (Stivarga) led to an improvement in overall survival (OS) compared with placebo in patients with refractory advanced gastric or gastroesophageal junction (GEJ) cancer, according to data from the phase 3 INTEGRATE IIa trial (NCT02773524) published in the Journal of Clinical Oncology.

Findings showed that at a median follow-up of 48 months, patients treated with regorafenib (n = 169) experienced a median OS of 4.5 months (95% CI, 4.0-5.5) compared with 4.0 months (95% CI, 3.1-4.6) for those given placebo (n = 82; HR, 0.68; 95% CI, 0.52-0.90; P = .006)

Pooled data from INTEGRATE IIa and the phase 2 INTEGRATE I trial (ACTRN12612000239864) showed that there was also a statistically significant improvement in OS for those treated with regorafenib (INTEGRATE I, n = 100; INTEGRATE IIA, n = 169) vs those given placebo (INTEGRATE I, n = 52; INTEGRATE IIa, n = 82; HR, 0.70; 95% CI, 0.56-0.87; P = .001)

“The results of INTEGRATE IIa confirmed clinical benefit of regorafenib in patients with refractory advanced gastric/GEJ cancer by delaying disease progression and quality-of-life [QOL] deterioration, leading to prolonged survival,” lead study author Nick Pavlakis, PhD, MBBS, FRACP, of Royal North Shore Hospital and the University of Sydney in Australia, and colleagues wrote in the publication of the data. “Moreover, the results support regorafenib as a platform for combination studies, as in the recently reported first-line phase 2 study [NCT04757363] of regorafenib combined with nivolumab [Opdivo] and chemotherapy and the ongoing [phase 3] INTEGRATE IIb study [NCT04879368].”

INTEGRATE II was initially designed to evaluate regorafenib vs placebo; however, due to shifts in clinical practice, the study was amended and divided into 2 parts: INTEGRATE IIa and INTEGRATE IIb. Those enrolled in INTEGRATE IIa are receiving regorafenib vs placebo and patients with pretreated advanced gastric/GEJ enrolled in INTEGRATE IIb are receiving regorafenib vs investigator’s choice of standard chemotherapy.

INTEGRATE IIa was a randomized, double-blind, international, placebo-controlled trial that enrolled patients at least 18 years of age with metastatic or locally recurrent, confirmed adenocarcinoma or undifferentiated carcinoma of the GEJ or stomach. At least 2 prior lines of therapy for recurrent or metastatic disease were required, including at least 1 platinum agent and a fluoropyrimidine analog. Patients with HER2-positive disease were required to have prior treatment with trastuzumab (Herceptin). Other key inclusion criteria consisted of evaluable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and acceptable organ function. Patients were excluded if they received prior treatment with a small molecule VEGF TKI, such as rivoceranib; however, prior treatment with an anti-VEGF monoclonal antibody was permitted.

Investigators randomly assigned patients 2:1 to receive 160 mg of oral regorafenib or placebo once per day on days 1 to 21 of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. Regorafenib was permitted to be given at 120 mg or 80 mg once per day if dose-level modifications were required due to adverse effects (AEs). Dose re-escalation was not permitted except for in patients who required modifications due to reversible Palmar-plantar erythrodysesthesia, hypertension, or deranged levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST).

OS served as the trial’s primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), health-related QOL, safety, and tolerability.

Among patients enrolled in INTERGRATE IIa, the median age was 63 years (interquartile range [IQR], 56-70) in the regorafenib arm vs 64 years (IQR, 59-73) in the placebo arm. The majority of patients were male (regorafenib arm, 72%; placebo arm, 84%), from Asia (63%; 62%), had stomach as the primary disease site (72%; 73%), and had negative or unknown HER2 status (84%; 93%).

The median time since diagnosis was 24 months (IQR, 13-38) in the regorafenib arm vs 21 months (IQR, 14-29) in the placebo arm; this information was unknown for 1 patient in the experimental arm. Fifty-one percent of patients in both arms underwent prior surgery to the primary cancer site. Forty-one percent of patients in the regorafenib arm received prior VEGF inhibitors vs 43% of those in the placebo arm. The rates of patients who received prior immunotherapy were 26% and 27%, respectively. The median time from the cessation of last immunotherapy to baseline was 7.2 months (IQR, 2.5-9.8) in the regorafenib arm vs 8.0 months (IQR, 1.7-11.9) in the placebo arm.

At the data cutoff date of August 1, 2022, all patients in the regorafenib and placebo arms had discontinued treatment. In the experimental arm (n = 169), reasons for discontinuation included disease progression per RECIST 1.1 criteria (n = 110), clinical progression (n = 19), patient preference (n = 19), toxicity (n = 13), death (n = 3), compliance issue (n = 1), other (n = 1), and did not receive any treatment (n = 3). In the placebo arm (n = 82), discontinuation reasons comprised disease progression per RECIST 1.1 criteria (n = 55), clinical progression (n = 16), clinician preference (n = 3), patient preference (n = 3), toxicity (n = 1), other (n = 1), and did not receive treatment (n = 3).

Additional data showed that there were no statistically significant differences in treatment effects in subgroups based on region or other prespecified subgroups. The OS benefit with regorafenib was consistent across prespecified subgroups.

The median PFS was 1.8 months (95% CI, 1.8-2.1) in the regorafenib arm vs 1.6 months (95% CI, 1.3-1.7) in the placebo arm (HR, 0.53; 95% CI, 0.40-0.70; P < .0001). The ORR was 2.4% in the regorafenib group vs 0% in the placebo group. The respective disease control rates were 21.3% and 4.9%.

QOL data demonstrated that the median time to deterioration in global QOL (was significantly prolonged in patients treated with regorafenib vs those given placebo (HR, 0.68; 95% CI, 0.52-0.89; P = .0043).

Regarding safety, any-grade AEs occurred in 96% of patients in the regorafenib arm (n = 166) vs 87% of patients in the placebo arm (n = 79). In the experimental arm, the rates of grade 1/2, grade 3, grade 4, and grade 5 AEs were 31%, 55%, 7%, and 2%, respectively; these respective rates were 47%, 37%, 4%, and 0% in the placebo arm. The rates of any-grade serious AEs were 26% for regorafenib vs 16% for placebo.

The three grade 5 AEs reported in the regorafenib arm included hepatic failure deemed related to study treatment (n = 1) and sepsis deemed unrelated to treatment (n = 2).

The most common differentiating AEs reported in the regorafenib arm included palmar-plantar erythrodysesthesia (grade 1/2, 31%; grade 3, 9%; grade 4, 0%), oral mucositis (20%; 1%; 0%), diarrhea (18%; 4%; 0%), hypertension (14%; 8%; 0%), increased ALT levels (12%; 5%; 0%), increased AST levels (14%; 4%; 1%), and constipation (12%; 1%; 0%).

Reference

Pavlakis N, Shitara K, Sjoquist K, et al. INTEGRATE IIa phase III study: regorafenib for refractory advanced gastric cancer. J Clin Oncol. Published online October 4, 2024. doi:10.1200/JCO.24.00055