FRUTIGA Meets Primary End Point of PFS, Hints at OS Benefit in G/GEJ Cancer

Rui-Hua Xu, MD, PhD

The phase 3 FRUTIGA study (NCT03223376) successfully met its primary end point, demonstrating significantly improved progression-free survival (PFS) among patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma treated with fruquintinib (Elunate) combined with paclitaxel vs those receiving paclitaxel alone.¹

Updated findings were presented by Rui-Hua Xu, MD, PhD, at the American Society of Clinical Oncology (ASCO) Plenary Series: February Session. Among those treated with the fruquintinib/paclitaxel combination vs paclitaxel alone, the median PFS was 5.55 months (95% CI, 4.6-6.4) vs 2.73 months (95% CI, 2.7-3.5) with a HR of 0.569 (P <.0001). While the study did not reach statistical significance for its dual primary end point of overall survival (OS), there was still a positive trend observed with a median OS of 9.63 months (95% CI, 8.9-10.8) with fruquintinib and paclitaxel and 8.41 months (95% CI, 7.8-9.4) with placebo and paclitaxel (HR, 0.956; P = .6064).

Further, there was a nominal statistically significant improvement in OS among patients given the fruquintinib/paclitaxel combination. These findings suggest that fruquintinib with paclitaxel may be a valuable second-line treatment option for these patients.

“Fruquintinib plus paclitaxel significantly improved PFS, [overall response rate (ORR)], and [disease control rate (DCR)], and demonstrated a trend for overall survival benefit. However, this was not statistically significant, possibly due to the imbalance between groups’ subsequent antitumor therapy,” Xu, professor of medical oncology and the president of Sun Yat-Sen University Cancer Center in Guangzhou, China, explained during the presentation. “The sensitivity analysis adjusting for compounding effects support the overall survival benefit of fruquintinib plus paclitaxel.”

Stomach cancer. Cancer attacking cell. Stomach disease concept: © Crystal Light - stock.adobe.com

Fruquintinib is a highly selective and potent oral inhibitor of VEGFR-1, -2, and -3. The agent was designed to improve kinase selectivity to decrease off-target toxicities, improve tolerability, and provide more consistent target coverage. In preclinical studies, fruquintinib has demonstrated good tolerability and a low potential for drug-drug interaction, suggesting that it may be useful in combination with other anticancer therapies.

In the randomized, double-blind, placebo-controlled, phase 3 FRUTIGA trial, investigators evaluated the efficacy and safety of fruquintinib plus paclitaxel vs paclitaxel alone in patients with advanced gastric/GEJ adenocarcinoma who experienced disease progression on fluoropyrimidine- or platinum-containing first-line chemotherapy.²

Enrollment was open to patients with histologically or cytologically confirmed gastric or GEJ adenocarcinoma with metastatic disease or locally advanced, unresectable disease; disease progression during or within 4 months after the last dose of the first-line therapy; at least 1 measurable lesion; an ECOG performance status of 0 to 1; and adequate hepatic, renal, heart, and hematologic functions.

Once enrolled, patients were randomized in a 1:1 ratio to receive fruquintinib at a dose of 4 mg once daily for 3 weeks on/1 week off or matching placebo given orally, plus paclitaxel at a dose of 80 mg/m2 via intravenous infusion on days 1/8/15 per cycle in 4-week cycles until progressive disease or intolerable toxicity. Patients were able to receive paclitaxel for up to 6 cycles. A total of 703 patients were randomized to receive fruquintinib with paclitaxel (n = 351) vs placebo plus paclitaxel (n = 352), and 699 patients received at least 1 dose of fruquintinib (350 vs 349).¹

The dual primary end points of the trial were PFS and OS. Secondary end points included ORR; DCR; duration of response; quality-of-life; and safety and tolerance evaluated by incidence, severity, and outcomes of adverse events.

Additional findings presented at the 2024 ASCO Plenary Session showed that the ORR was significantly higher among patients in the fruquintinib and paclitaxel group at 42.5% (95% CI, 37.2%-47.8%) compared with 22.4% (95% CI, 18.2%-27.2%) in the placebo group (P <.0001). The disease control rates were 77.2% (95% CI, 72.5%-81.5%) in the fruquintinib arm vs 56.3% (95% CI, 50.9%-61.5%) in the placebo arm (P <.0001).

The best responses among patients include complete response in 5 patients in the fruquintinib arm and 5 patients in the placebo arm, partial response in 144 and 74 patients, stable disease in 122 and 119, progressive disease in 55 and 135, and not evaluable in 25 and 19 patients.

An imbalance of patients receiving subsequent antitumor therapies was observed at 52.7% of patients given the combination with fruquintinib vs 72.2% of patients treated with placebo. As a result, post hoc analyses were performed using Cox proportional hazards model adjusting for subsequent antitumor therapies and baseline factors.

Additionally, the median PFS was longer among patients with lymph node metastases (n = 190) and nondiffuse gastric/GEJ adenocarcinoma (n = 208) at 6.08 months vs 2.69 months with the fruquintinib combination vs placebo (HR, 0.454; P <.0001). The OS results also showed a nominal statistically significant improvement in these groups with median OS rates of 9.56 months vs 7.85 months (HR, 0.767; P =.0233).

Looking at safety, the most common treatment-emergent adverse events deemed grade ≥ 3 in the fruquintinib and paclitaxel arm vs placebo and paclitaxel arms included neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with what is seen with fruquintinib and paclitaxel alone, and there were no new safety signals identified.

“Fruquintinib plus paclitaxel was well-tolerated with a safety profile consistent with expectations. Overall, fruquintinib plus paclitaxel could be a promising second-line treatment option for patients with advanced gastric/GEJ adenocarcinoma who have failed a platinum-containing chemotherapy,” added Xu.

Overall, FRUTIGA was a positive study as it reached statistical significance for the primary end point of PFS. Though not statistically significant, there was also an improvement observed for the other primary end point of OS. These positive findings support the potential use of fruquintinib plus paclitaxel as a second-line treatment for patients with advanced gastric/GEJ adenocarcinoma, warranting further research to confirm its OS benefits.

REFERENCES:

1. Xu RH, Wang F, Shen L, et al. Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study. Presented at: 2024 February ASCO Plenary Series. Abstract 438780.

2. A phase III study of fruquintinib in combination with paclitaxel in second line gastric cancer (FRUTIGA) (FRUTIGA). ClinicalTrials.gov. Updated September 2, 2022. Accessed February6, 2024. https://clinicaltrials.gov/ct2/show/study/NCT03223376