Regorafenib Combo Yields Promising Activity in Advanced Gastric Cancer

"Our findings suggest that regorafenib with nivolumab and chemotherapy is safe and showed promising anti-tumor activity in patients with advanced esophagogastric cancer," according to the authors of a phase 2 trial (NCT04757363).

Regorafenib (Stivarga) demonstrated promising clinical activity and safety when combined with nivolumab (Opdivo) and chemotherapy in patients with HER2-negative metastatic esophagogastric adenocarcinoma, according to findings from a phase 2 trial (NCT04757363) published in Lancet Oncology.

Investigators reported that the median progression-free survival (PFS) was 13.0 months (95% CI, 7.6-not reached [NR]). Additionally, treatment yielded a PFS rate of 71% (95% CI, 58%-88%) at 6 months and 51% (95% CI, 37%-71%) at 12 months. The median overall survival (OS) was NR, and 6-month and 12-month rates, respectively, were 97% (95% CI, 92%-100%) and 85% (95% CI, 74%-98%).

The objective response rate (ORR) was 76% among 29 patients with measurable disease at baseline, which included complete responses (CRs) in 10% and partial responses (PRs) in 66%. According to findings from a post hoc analysis, the median duration of response (DOR) was 17.0 months (95% CI, 5.7-NR), and patients had a median time to response of 2.1 months (95% CI, 1.78-3.71).

The ORR was 75% (n = 12/16; 95% CI, 48%-93%) in patients with PD-L1–negative, measurable disease and 77% (n = 10/13; 95% CI, 46%-95%) in those with PD-L1–positive, measurable disease (P >.99). Additionally, the 6-month PFS rate in each respective subgroup was 75% (95% CI, 51%-91%) and 67% (95% CI, 38%-88%).

“We believe that the activity observed in this study support the development of regorafenib-based combinations in future clinical trials,” the study authors wrote. “Our findings suggest that regorafenib with nivolumab and chemotherapy is safe and showed promising anti-tumor activity in patients with advanced esophagogastric cancer. Additional biomarker work is underway to dissect the associations among neoantigen immunogenicity, immune suppression, and response to immune checkpoint blockade.”

In this single-arm phase 2 study, patients received 400 mg/m² of fluorouracil followed by 2400 mg/m² over 48 hours plus 400 mg/m² of leucovorin, 85 mg/m² of oxaliplatin, 240 mg of nivolumab intravenously on days 1 and 15, and 80 mg of regorafenib orally on days 1 to 21 as part of 28-day treatment cycles.

The study’s primary end point was PFS. Secondary end points included ORR per RECIST v1.1 criteria, OS, and safety.

Patients 18 years and older with previously untreated advanced esophagogastric, gastric, or gastroesophageal junction (GEJ) carcinoma and any kind of PD-L1 expression were able to enroll on the study. Additional eligibility criteria included having measurable or non-measurable disease based on RECIST v1.1 guidelines, adequate organ function, and an ECOG performance status of 0 or 1.

Among 35 patients enrolled on the study, the median age was 57 years (interquartile range [IQR], 52-66). Overall, 74% of patients were male, 80% were White, and 46% had gastric tumors. Additionally, 69% had an ECOG performance status of 0, 83% had metastatic disease, 86% had 2 or more organs with metastases, and 57% had PD-L1–negative disease with a combined positive score of less than 1.

Investigators observed no significant reduction in all-cause mortality with respect to clearance of circulating tumor DNA (ctDNA) at any time (HR, 0.26; 95% CI, 0.05-1.40; P = .12). Additionally, durable ctDNA responses were reported in 48% (n = 15/31), with the remainder (52%) experiencing an increase in ctDNA following clearance or nadir. Disease progression succeeded elevated ctDNA levels by a median of 7.6 weeks (IQR, 0-16).

Among the safety population, 97% of patients experienced any-grade adverse effects, which mostly included fatigue (92%), paresthesia or peripheral neuropathy (77%), and palmar-plantar erythrodysesthesia syndrome (67%). Investigators also reported grade 3 or higher toxicities in 79% of patients, including decreased neutrophil count (46%), hypertension (15%), and anemia (10%). There was 1 fatal instance of respiratory failure that was not related to study treatment or disease.

Discontinuation of regorafenib occurred in 18% of patients, and investigators implemented dose reductions from 80 mg to 40 mg for 26%. The most common reasons for requiring dose reductions included rash (13%), palmar-plantar erythrodysesthesia syndrome (10%), and fatigue (8%).

Reference

Cytryn SL, Moy RH, Cowzer D, et al. First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. Lancet Oncol. Published online September 1, 2023. doi:10.1016/S1470-2045(23)00358-3