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Adding regorafenib (Stivarga) to a standard first-line chemoimmunotherapy regimen for HER2-negative metastatic esophagogastric cancer demonstrated "promising" activity in a single-arm phase II study, according to researchers.

Among 35 evaluable patients treated with the tyrosine kinase inhibitor (TKI) plus nivolumab (Opdivo) and FOLFOX chemotherapy, 25 (71%, 95% CI 54-85) remained progression free at 6 months, thus meeting the study's primary endpoint, reported Yelena Janjigian, MD, of the Memorial Sloan Kettering Cancer Center in New York City, and colleagues in .

With a median follow-up of 18 months, the median progression-free survival (PFS) reached 13.0 months (95% CI 7.6-not reached), and the 12-month PFS rate was 51% (95% CI 37-71). Median overall survival (OS) was not reached, with 6- and 12-month rates of 97% (95% CI 92-100) and 85% (95% CI 74-98), respectively.

"To our knowledge, this is the first study to evaluate the activity of regorafenib, nivolumab, and chemotherapy in patients with previously untreated metastatic esophagogastric cancer," Janjigian's group said. "We believe that the activity observed in this study supports the development of regorafenib-based combinations in future clinical trials."

Janjigian and colleagues noted that the median PFS, 12-month PFS, and OS rates in the trial were higher than the median PFS of 7.7 months, 12-month PFS of 33%, and 12-month OS of 55% reported previously for the existing of chemotherapy plus nivolumab in this setting.

A randomized, phase III trial is planned, according to the researchers.

In explaining the rationale behind the study, the authors noted that while nivolumab plus chemotherapy improves survival in patients with esophagogastric (esophageal, gastric, or gastroesophageal junction) adenocarcinoma, outcomes remain poor.

Among 29 patients with measurable disease at baseline in the current study, 22 (76%) had an objective response -- three complete and 19 partial responses. Median duration of response was 17.0 months, with a median time to response of 2.1 months. An additional six patients (21%) had stable disease as their best response.

An exploratory analysis showed no significant difference in 6-month PFS or response rates between PD-L1-positive and PD-L1-negative subgroups.

Janjigian and colleagues noted that 11 patients were started on regorafenib and nivolumab without concurrent chemotherapy as induction therapy, with six of those patients experiencing tumor shrinkage after 3 weeks.

"This observation underscores the potential for positive outcomes in advanced gastric cancer through the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors, even in the absence of chemotherapy," said Ken Kato, MD, PhD, of the National Cancer Center Hospital in Tokyo, and colleagues, in an . "Given the high toxicities associated with combination therapy, the viability of a regimen without chemotherapy is of paramount importance."

However, they noted that while some patients may be able to omit chemotherapy, further research is needed to determine the characteristics of these patients.

The current was a single-center, single-arm trial that enrolled 39 patients. The 35 patients evaluable for 6-month PFS assessment had a median age of 57 years, 74% were male, 80% were white, and 20% were Asian.

Patients received FOLFOX chemotherapy (fluorouracil, leucovorin and oxaliplatin) and nivolumab IV on days 1 and 15, and oral regorafenib on days 1-21 of a 28-day cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

As for the regimen's safety, adverse events (AEs) occurred in all but one of the 39 patients enrolled in the study, with fatigue (92%) being most common.

The most common grade 3/4 AEs were decreased neutrophil count (46%); hypertension (15%); dry skin, pruritus, or rash (13%); and anemia (10%). Serious treatment-related AEs occurred in 10 patients (26%), and included acute kidney injury, hepatotoxicity, sepsis, dry skin, pruritus or rash, nausea, and gastric perforation. There were no treatment-related deaths.

One patient (3%) discontinued fluorouracil and 31 (79%) discontinued oxaliplatin due to AEs. Five patients (13%) discontinued nivolumab, while seven patients (18%) discontinued regorafenib and 10 (26%) required a dose reduction.

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