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Mixed Results in Advanced Gastric/GEJ Cancer With Add-On Fruquintinib

— Significant improvement in PFS, but not OS, versus chemo alone in the second-line setting

MedpageToday
A computer rendering of advanced gastric cancer

Adding a targeted agent to second-line chemotherapy significantly improved progression-free survival (PFS) but not overall survival (OS) in advanced gastric cancer, a large randomized trial showed.

Pairing the angiogenesis inhibitor fruquintinib (Fruzaqla) with paclitaxel led to a median PFS of 5.6 months, more than double the 2.7 months with paclitaxel plus placebo. The difference represented a significant 43% reduction in the hazard for disease progression or death.

However, the trial failed to meet the second primary endpoint of OS, as the addition of fruquintinib increased the median by 1.2 months (9.6 vs 8.4), a difference that did not reach statistical significance.

The lack of a survival benefit might have resulted from an imbalance in the proportion of patients who received additional therapy at progression, which was substantially greater in the placebo arm, suggested Rui-Hua Xu, MD, PhD, of Sun Yat-Sen University Cancer Center in Guangzhou, China, during a presentation at an .

"Fruquintinib plus paclitaxel demonstrated a trend for overall survival benefit after correcting for confounding effects," said Xu. "Fruquintinib plus paclitaxel was well-tolerated, with a safety profile consistent with expectations. This combination could be a promising second-line treatment option for patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma who have failed fluoropyrimidine- or platinum-containing chemotherapy."

The trial raised as many questions as it answered, according to invited discussant Florian Lordick, MD, PhD, of University Cancer Center Leipzig in Germany. Beyond the lack of OS benefit, the reason for the imbalance in subsequent treatment remained unclear, the investigators performed no subgroup analyses to identify patients who might benefit from the combination, and data on quality of life and symptom control are lacking.

Moreover, the results differ from previous trials evaluating antiangiogenics in gastric/GEJ and colorectal cancer, he continued.

The randomized with fruquintinib compares favorably with the RAINBOW trial with ramucirumab (Cyramza) with respect to PFS and overall response rate (ORR), but unlike FRUTIGA, the RAINBOW trial also showed an OS benefit. A previous trial of fruquintinib and best supportive care in advanced colorectal cancer (CRC) also produced a significant survival benefit, which supported FDA approval of the agent for metastatic CRC.

"Will fruquintinib and paclitaxel be the next standard of care in second-line advanced gastric cancer?" Lordick asked. "We would expect to see an improvement in overall survival before it becomes a new second-line standard. However, fruquintinib could become another option in the sequential treatment of advanced gastric cancer."

Conducted at sites throughout China, FRUTIGA included 703 patients with previously treated gastric/GEJ adenocarcinoma. All patients received paclitaxel and were randomized to add-on fruquintinib or placebo. The trial had dual primary endpoints of PFS and OS.

The study population had a median age of 58, and men accounted for 70% of the patients. Tumors were localized in the stomach in 83% of cases, about 30% had visceral metastases, and 42% of the patients had prior gastrectomy.

The PFS curves separated early and remained in favor of the fruquintinib arm throughout the study, said Xu. Data analysis showed a significant difference favoring the addition of the anti-angiogenic agent (HR 0.57, 95% CI 0.48-0.68).

After a median follow-up of 31.7 months, the OS analysis showed an early advantage for fruquintinib, but the survival curves crossed with continued follow-up (HR 0.96, 95% CI 0.81-1.13).

Xu presented results of a separate OS analysis stratified by subsequent antitumor therapy. Patients who did not receive additional therapy (n=166 for fruquintinib vs 98 for placebo) had a statistically significant 2.1-month improvement in median OS (6.9 vs 4.8 months; HR 0.72, 95% CI 0.53-0.99). In the larger subgroup of patients who did receive additional therapy (n=185 for fruquintinib vs 254 for placebo), the addition of fruquintinib to paclitaxel produced a trend toward better survival (12.2 vs 10.0 months; HR 0.90, 95% CI 0.73-1.11).

To account for the confounding effect of subsequent antitumor therapies, investigators developed statistical models that showed a corrected estimated hazard range of 0.73-0.91. Patients with lymph node metastases and non-diffuse disease also showed statistically better OS (9.6 vs 7.9 months; HR 0.77, P=0.0233).

The fruquintinib-paclitaxel combination produced an ORR of 42.4%, including five complete responses (CRs). That compared with an ORR of 22.4% (with five CRs) in the placebo-paclitaxel arm (P<0.0001). The disease control rate was 77.2% with fruquintinib versus 56.3% with placebo (P<0.0001).

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred more often with fruquintinib (86.9% vs 63.3%), as did grade ≥3 treatment-related adverse events (TRAEs; 82% vs 56.7%). Rates of fatal TEAEs were 9.7% with fruquintinib and 4.6% with placebo. Fatal TRAEs occurred in 5.1% of the fruquintinib group versus 1.7% of the placebo group. The most common TEAEs in both groups were hematologic in nature, said Xu.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The study was supported by Hutchmed.

Xu disclosed relationships with HenRiu, BeiGene, AstraZeneca, Junshi Biosciences, Bristol-Myers Squibb, Merck Serono, Roche, and KYM Biosciences.

Lordick disclosed relationships with Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, BioNTech, Servier, Merck KGaA, Roche, Medscape, Incyte, Art Tempi, Mediupdate, Streatedup!, Daiichi Sankyo, Novartis, Falk Foundation, Astellas, PAGE, Boehringer Ingelheim, and Gilead.

Primary Source

ASCO Plenary Series

Xu RH, 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 III study" ASCO Plenary Series. 2024; Abstract 438780.