‘Promising second-line treatment’ delays progression of advanced stomach cancers
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Key takeaways:
- Fruquintinib plus paclitaxel conferred significantly longer PFS compared with placebo.
- A lack of OS benefit in the fruquintinib arm raises questions about the impact of subsequent antitumor therapies.
Fruquintinib plus paclitaxel significantly improved PFS in patients with advanced gastric or gastroesophageal junction adenocarcinoma, according to results from a phase 3 trial presented during an ASCO Plenary Series session.
The FRUTIGA study did not meet its secondary endpoint of superior OS, but after adjusting for subsequent antitumor therapies, researchers determined patients had a nominal survival benefit from treatment with fruquintinib (Fruzaqla, Takeda) plus paclitaxel.
“Fruquintinib plus paclitaxel could be a promising second-line treatment option for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have failed fluoropyrimidine- or platinum-containing chemotherapy,” Rui-Hua Xu, MD, PhD, president of Sun Yat-sen University Cancer Center in China, said during his presentation.
Subsequent discussion of the trial raised questions, including why post-progression treatment imbalances existed between the two study arms, why fruquintinib plus paclitaxel did not get compared with ramucirumab (Cyramza, Eli Lilly & Co.) — considered the standard of care for this patient population — and the frequency of treatment-related hematologic and gastrointestinal adverse events.
“We would expect to see an improvement in overall survival before it becomes a new second-line standard,” Florian Lordick, MD, PhD, director of the University Cancer Center at Leipzig Medical Center, said during his analysis. “However, fruquintinib could become another option in the sequential treatment of advanced gastric cancer.”
Background and methodology
Almost half of patients with advanced gastric or gastroesophageal junction adenocarcinoma receive second-line treatments, but those are limited to ramucirumab plus chemotherapy or chemotherapy on its own, according to background information provided by ASCO and the study investigators.
Fruquintinib, like ramucirumab, is a vascular endothelial growth factor receptor inhibitor.
Healio previously reported fruquintinib improved OS in patients with refractory metastatic colorectal cancer, and the FDA approved it as a third-line treatment last year.
To be eligible for the double-blind trial, conducted in China, patients had to have advanced gastric or gastroesophageal junction adenocarcinoma, progressed on fluoropyrimidine- or platinum-containing chemotherapy, and have an ECOG performance status of 0 or 1.
Researchers randomly assigned 703 study participants in a 1:1 ratio to receive either fruquintinib plus paclitaxel (n = 351) or placebo plus paclitaxel. Both study groups had a majority of patients above the age of 65 years, comprised mostly men, and predominately reported Asian ethnicity.
PFS and OS served as the study’s primary endpoints.
Results
TBoth populations had a majority of patients above the age of 65 years, men and of Asian ethnicity.
Patients who received fruquintinib had a median PFS of 5.6 months vs. 2.7 for the placebo group (stratified HR = 0.57; 95% CI, 0.48-0.68).
Treatment with fruquintinib also improved the secondary endpoints of overall response rate (42.5% vs. 22.4%) and disease control rate (77.2% vs. 56.3%) compared with placebo, both of which served as secondary endpoints.
However, the fruquintinib did not confer a statistically significant improvement of OS vs. the placebo (9.6 vs. 8.4 months).
Researchers attributed this lack of OS benefit to a higher portion of patients in the placebo arm (20% more) receiving subsequent antitumor therapies. They recalculated OS for study participants who did not receive additional therapies and found improved OS among those who received fruquintinib (6.9 vs. 4.8 months; stratified HR = 0.72; 95% CI, 0.53-0.99).
Patients in the fruquintinib arm had a higher rate of grade 3 or greater treatment-emergent adverse events (86.9% vs. 63.3%), treatment-related grade 3 or-greater treatment-emergent adverse events (82% vs. 56.7%), treatment-emergent adverse events leading to death (9.7% vs. 4.6%) and treatment-related treatment-emergent adverse events leading to death (5.1% vs. 1.7%) compared with the placebo group.
However, Xu described the safety profile as “well-tolerated” and “consistent with expectations.”
“The positive results of FRUTIGA further enrich the evidence for the effectiveness of the VEGFR signaling pathway acting on advanced gastric/gastroesophageal adenocarcinoma, which had been previously supported by the efficacy of ramucirumab,” Xu said in an ASCO press release.
Discussion and next steps
Lordick praised the PFS and ORR of fruquintinib during his discussion, but he raised questions about the results as well.
His first question revolved around why patients in the placebo arm had more subsequent antitumor therapies.
“It remains unclear why these differences occurred and exactly what subsequent therapies were administered,” Lordick said. “Were patients in the experimental arm of the trial less able to receive subsequent therapies because of side effects and impaired health status?”
Lordick also discussed the increased number of hematologic and gastrointestinal adverse events.
“Decreased appetite, weight loss and palmar-plantar erythrodysesthesia, all of which may (affect) quality of life, unfortunately were not reported,” he said, although he noted “no major difference” in adverse events between fruquintinib compared with ramucirumab.
Nevertheless, when Lordick compared fruquintinib with ramucirumab, he distinguished the statistically significant improvement in OS for ramucirumab vs. placebo.
Xu responded during a question-and-answer session that fruquintinib did not get tested against ramucirumab because it had not been commercially available in China when the trial began in 2017.
The success of fruquintinib in the FRESCO-2 study involving patients with advanced colorectal cancer made Lordick question, “Is the small molecule fruquintinib a more effective drug when tumors have been pretreated with an anti-VGEF monoclonal antibody?”
Lordick believes more studies are needed on fruquintinib, particularly fruquintinib plus chemotherapy after ramucirumab, and fruquintinib after or with immunotherapy.
Of the patients in the fruquintinib arm of the trial, 10% had prior immunotherapy, whereas 13% of the placebo arm had received such treatment, Xu said.
“Maybe the 10% of patients who received prior immunotherapy in the FRUTIGA trial is not enough to have robust results when I think about subgroup analysis,” Lordick said. “The sequence could be quite interesting.”
References:
- ASCO. New treatment alternative for patients with advanced gastric or gastroesophageal junction adenocarcinoma (press release). Available at: https://old-prod.asco.org/about-asco/press-center/news-releases/new-treatment-alternative-patients-advanced-gastric-or. Posted Feb. 5, 2024. Accessed Feb. 8, 2024.
- Xu RH, et al. Abstract 438780. Presented at: ASCO Plenary Series; Feb. 6, 2024.
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Xu RH, et al. Abstract 438780. Presented at: ASCO Plenary Series; Feb. 6, 2024.
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