Second-Line Fruquintinib Plus Paclitaxel Significantly Improves PFS But Not OS in Advanced Gastric or GEJ Adenocarcinoma

Rui-Hua Xu, MD, PhD

The addition of fruquintinib (Fruzaqla) to paclitaxel led to significant improvements in progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) but did not significantly improve overall survival (OS) vs paclitaxel alone when used as second-line treatment in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to data from the phase 3 FRUTIGA study (NCT03223376).¹

The findings, which were presented as part of the February 2024 ASCO Plenary Series, showed that the fruquintinib regimen (n = 351) led to a median PFS of 5.6 months (95% CI, 4.6-6.4) vs 2.7 months (95% CI, 2.7-3.5) with paclitaxel alone (n = 352), translating to a 43% reduction in the risk of disease progression or death (HR, 0.57; 95% CI, 0.48-0.68; P < .0001), meeting one of the co-primary end points.

At a median follow-up of 31.7 months, fruquintinib plus paclitaxel resulted in a numerical but not statistically significant improvement in median OS vs paclitaxel, at 9.6 months (95% CI, 8.9-10.8) vs 8.4 months (95% CI, 7.8-9.4), respectively (HR, 0.96; 95% CI, 0.81-1.13; P = .6064). It was noted that this could potentially be explained by an imbalance in receipt of subsequent antitumor therapy between the fruquintinib and placebo arms, at 52.7% and 72.2%, respectively.

However, after correcting for confounding effects, fruquintinib plus paclitaxel showcased a trend for OS benefit over paclitaxel alone, irrespective of receipt of subsequent antitumor therapy. Those in the fruquintinib arm who did not receive subsequent treatment (n = 166) experienced a median OS of 6.9 months vs 4.8 months for those in the placebo arm who did not receive subsequent treatment (n = 98; HR, 0.72; 95% CI, 0.53-0.99; P = .0422). Those in the fruquintinib (n = 185) and placebo (n = 254) arms who did receive subsequent treatment experienced median OS of 12.2 months vs 10.0 months, respectively (HR, 0.90; 95% CI, 0.73-1.11; P = .3262).

“Fruquintinib plus paclitaxel could be a promising second-line treatment option for patients with advanced gastric or GEJ adenocarcinoma who have [experienced failure with] fluoropyrimidine- or platinum-containing chemotherapy,” Rui-Hua Xu, MD, PhD, professor of medical oncology and president of the Sun Yat-Sen University Cancer Center in Guangzhou, China, said in a presentation of the data.

Patients with gastric cancer who progress on their first line of treatment are limited to receiving ramucirumab (Cymraza) plus chemotherapy or chemotherapy alone. Alternative options in this setting are needed, Xu said. Fruquintinib—an agent that inhibits VEGFRs 1, 2, and 3—has received regulatory approval in China for use in the third-line treatment of patients with metastatic colorectal cancer (mCRC). More recently, in November 2023, the FDA approved fruquintinib for use in adult patients with mCRC who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy, if they had RAS wild-type disease and was medically appropriate.²

The double-blind, placebo-controlled, randomized FRUTIGA study enrolled patients with advanced gastric or GEJ adenocarcinoma who had progressed on fluoropyrimidine- or platinum-containing chemotherapy and who had an ECOG performance status of 0 or 1.1

Participants (n = 703) were randomly assigned 1:1 to receive 4 mg of fruquintinib daily for 3-weeks-on/1-week-off plus 80 mg/m2 of paclitaxel on days 1, 8, and 15 of each cycle or placebo plus paclitaxel at the same dose and schedule. Treatment continued until disease progression by RECIST v1.1 criteria or unacceptable toxicity. Stratification factors comprised primary tumor location (GEJ vs stomach), presence of peritoneal metastasis (yes vs no), and performance status (0 vs 1).

In addition to the dual primary end points of PFS and OS, secondary end points included ORR, DCR, duration of response, safety, and quality of life (QOL).

“It was prespecified in the statistical analysis plan that the study results could be declared positive if OS or PFS was statistically significant at [the] predefined alpha level,” Xu said. “To control overall type I error as 2-sided 0.049 in the final analysis, 0.01 was allocated to PFS, and 0.039 was allocated to OS. If PFS was declared positive, OS analysis was performed at a recycled level of significance at 0.049. If OS was declared positive, PFS analysis was performed at a recycled level of significance at 0.049. The final analysis for OS was planned at approximately 525 events.”

Across the fruquintinib and placebo arms, the median patient age was 58 years (range, 24-75), with most patients younger than 65 years (75.2% vs 70.2%). Most patients were male (70.9% vs 68.2%), Asian (99.7% vs 100.0%), had an ECOG performance status of 1 (85.2% vs 85.2%), a primary tumor location of the stomach (82.9% vs 83.0%), had multiple metastatic sites (74.1% vs 74.7%), but did not have peritoneal metastases (68.7% vs 70.5%). Slightly more than half of patients had stage IV disease (57.5% vs 57.7%) and had not undergone prior gastrectomy (58.1% vs 58.0%). The majority of patients previously received chemotherapy (99.7% vs 100.0%) in the form of a doublet regimen (98.0% vs 98.6%). Prior treatments also included targeted therapy (3.4% vs 4.5%) and immunotherapy (10.0% vs 13.4%).

“The Cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors showed nominal statistically significant OS benefit of fruquintinib plus paclitaxel, with a HR in the range of 0.79 to 0.83 and a P value in the range of 0.0105 to 0.0350, with different subsequent antitumor therapy factors,” Xu said. “To correct the confounding effect introduced by subsequent antitumor therapies, statistical models including the IPCW model, modified 2-stage method, and RPSFT, as well as a simulation with Bootstrap, were performed to estimate the OS treatment effect, and the corrected HR range was 0.73 to 0.91.”

He added that in those with lymph node metastases (n = 190) and non-diffuse disease (n = 208), fruquintinib plus paclitaxel led to a nominal statistically significant improvement in OS vs paclitaxel alone, at 9.6 months and 7.9 months, respectively (HR, 0.77; P = .0233).

Additional efficacy data showed that fruquintinib plus paclitaxel elicited an ORR of 42.5% (95% CI, 37.2%-47.8%) vs 22.4% (95% CI, 18.2%-27.2%) with paclitaxel alone (P < .0001). Among those who responded to the fruquintinib regimen, the complete response rate was 1.4% and the partial response rate was 41.0%; 34.8% of patients achieved stable disease, 15.7% experienced disease progression, and 7.1% were not evaluable for response.

The DCRs reported in the fruquintinib and placebo arms were 77.2% (95% CI, 72.5%-81.5%) and 56.3% (95% CI, 50.9%-61.5%), respectively (P < .0001). The median DOR with the doublet was 5.5 months (95% CI, 4.6-6.4) vs 3.7 months (95% CI, 3.7-4.6) with paclitaxel alone.

The median treatment duration with fruquintinib was 4.5 months (range, 0.26-41.40) vs 2.6 months (range, 0.43-40.05) with placebo. The median relative dose intensity with fruquintinib was 97.6% (range, 47.60%-104.76%) vs 100.0% (range, 25.00%-103.57%) with placebo. The median treatment duration with paclitaxel in the doublet arm was 3.9 months (range, 0.26-7.62) vs 2.6 months (range, 0.49-7.56) in the paclitaxel-alone arm. The median relative dose intensity with paclitaxel in these respective arms was 83.3% (range, 20.00%-100.00%) and 100.0% (range, 20.00%-100.00%).

The combination of fruquintinib and paclitaxel was well tolerated with a toxicity profile that proved to be consistent with expectations. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.4% of those in the fruquintinib arm vs 99.4% of those in the placebo arm; these effects were grade 3 or greater for 86.9% and 63.3% of patients, respectively. Treatment-related AEs that were grade 3 or higher occurred in 82.0% of those in the fruquintinib arm vs 56.7% of those in the placebo arm. Serious TEAEs occurred in 38.6% of those given the fruquintinib regimen vs 19.2% of those given paclitaxel alone.

In the fruquintinib/paclitaxel arm, TEAEs resulted in dose interruptions, reductions, and discontinuations for 70.3%, 47.4%, and 16.9% of patients, respectively; in the paclitaxel-alone arm, these respective rates were 45.3%, 21.8%, and 9.2%, respectively. TEAEs led to death for 9.7% and 4.6% of patients in the fruquintinib and placebo arms, respectively; treatment-related TEAEs resulted in death for 5.1% and 1.7% of patients.

The most common any-grade TEAEs to occur in at least 20% of patients in the fruquintinib/paclitaxel and paclitaxel-alone arms included leukopenia (86.3% vs 73.6%), neutropenia (84.0% vs 72.8%), anemia (60.3% vs 59.9%), alopecia (40.6% vs 43.6%), thrombocytopenia (34.3% vs 17.5%), reduced appetite (29.7% vs 18.6%), diarrhea (28.0% vs 16.6%), proteinuria (27.1% vs 15.2%), constipation (26.0% vs 18.6%), hypoalbuminemia (25.1% vs 13.2%), occult blood positivity (24.6% vs 22.9%), Palmar-plantar erythrodysesthesia syndrome (24.0% vs 4.9%), weight decrease (24.0% vs 12.9%), increased aspartate aminotransferase (22.3% vs 17.8%), and increased blood bilirubin (21.1% vs 12.3%).

The most common grade 3 or higher TEAEs experienced in the fruquintinib and placebo arms were leukopenia (42.9% vs 23.5%), neutropenia (60.0% vs 36.4%), and anemia (11.7% vs 10.6%).

Florian Lordick, MD, of the University of Leipzig Medical Center, in Germany, outlined the strengths and weaknesses of FRUTIGA in the discussant portion of ASCO Plenary Series. He said that the strengths of the trial were that it was a well-powered study for PFS/OS analysis, that the baseline patient characteristics were balanced, there was a promising effect size for PFS, and there was an interesting increase in response rate. He added that the weaknesses of the trial include imbalances in post-progression treatment, no subgroup analyses were performed, there was a negative co-primary end point in terms of OS, and no data on QOL or symptom control.

When asking the question of whether fruquintinib plus paclitaxel will be the next standard of care for the second-line treatment of patients with advanced gastric cancer, Lordick said, “We would expect to see an improvement in OS before it becomes a new second-line standard. However, fruquintinib could become another option in the sequential treatment of advanced gastric cancer.” He concluded by saying that more studies are needed to understand the outlook for fruquintinib in this disease.

Editor’s Note: Dr Xu disclosed serving in a consulting or advisory role for HenRui, BeiGene, AstraZeneca, Junshi Biosciences, Bristol Myers Squibb, Merck Serono, Roche, Astellas Pharma, and KYM Biosciences.

References

1. Xu R-H, 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. J Clin Oncol. 2024;42(suppl 36):438780. doi:10.1200/JCO.2024.42.36_suppl.43878
2. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed February 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer