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The addition of fruquintinib to best supportive care improved overall survival compared with BSC alone in patients with metastatic colorectal cancer who progressed on standard chemotherapy and relevant biologic agents, and who had progressed on or were intolerant to trifluridine/tipiracil and/or regorafenib.
The addition of fruquintinib (HMPL-013) to best supportive care (BSC) improved overall survival (OS) compared with BSC alone in patients with metastatic colorectal cancer (mCRC) who progressed on standard chemotherapy and relevant biologic agents, and who had progressed on or were intolerant to trifluridine/tipiracil (TAS-102; Lonsurf) and/or regorafenib (Stivarga), meeting the primary end point of the phase 3 FRESCO-2 trial (NCT04322539).1
The highly selective and potent oral inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 in combination with BSC also resulted in a statistically significant improvement in progression-free survival over BSC alone in this population, which was a key secondary end point of the research.
Moreover, the safety of the agent proved to be consistent with what has previously been reported.
The full findings from the trial will be submitted for presentation at a future medical conference, according to HUTCHMED Limited.
“We are very happy to see the positive outcomes of the FRESCO-2 study which offers a potential new treatment for patients with advanced mCRC, where the unmet need is very high and patients have limited treatment options,” Marek Kania, MD, MBA, executive vice president, managing director, and chief medical officer of HUTCHMED International, stated in a press release. “Results from the global FRESCO-2 study supplement findings from the original FRESCO study that led to the marketing approval and commercialization of fruquintinib in China.”
Fruquintinib was designed to improve kinase selectivity to minimize off-target adverse effects (AEs), improve tolerability, and offer more constant target coverage. Preclinical evaluation of the agent has shown that it has low potential for drug-drug interactions, which suggests that it could be amenable for combinations with other therapeutic agents.
The global, randomized, double-blind, placebo-controlled, multicenter FRESCO-2 trial enrolled patients who were at least 18 years of age, and who had histologically and/or cytologically documented mCRC with documented RAS, BRAF, microsatellite instability, or mismatch repair status.2 Patients were also required to have an ECOG performance status of 0 or 1 and an expected survival of longer than 12 weeks.
They could not have a neutrophil count of less than 1.5 × 109/L, a platelet count of less than 100 × 109/L, and a hemoglobin of less than 9.0 g/dL. Patients were also not allowed to have received a blood transfusion within 1 week of study enrollment. Other exclusion criteria included having uncontrolled hypertension, a history of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhaging of an unresected gastrointestinal tumor, and a history of perforation or fistulas, among others.
“By meeting the primary end point of OS with a secondary end point of PFS, fruquintinib provides a significant potential new option for our refractory CRC patients,” Cathy Eng, MD, FACP, FASCO, David H. Johnson Endowed Chair in Surgical and Medical Oncology, and co-leader of the Gastrointestinal Cancer Research Program at the Vanderbilt-Ingram Cancer Center, added in the press release. “As an oral agent, fruquintinib also provides added convenience for our patients.”
In September 2018, the China National Medical Products Administration approved fruquintinib (Elunate) for use in patients with mCRC who previously received fluoropyrimidine, oxaliplatin, and irinotecan, as well as those who received prior anti-VEGF therapy and/or anti-EGFR therapy.3 The decision was based on data from the phase 3 FRESCO trial (NCT02314819).4
Patients enrolled to FRESCO were between the ages of 18 years and 75 years, weighed at least 40 kg, and had histologically and/or cytologically confirmed mCRC that had progressed after at least 2 standard chemotherapy regimens.
To be eligible, patients were required to have disease progression during or within 3 months of their last standard treatment or have stopped treatment due to intolerable toxicity. They were also required to have an ECOG performance status of 0 or 1, left ventricular ejection fraction of at least 50%, measurable disease per RECIST V1.1 criteria, and acceptable bone marrow, liver, and renal function. Prior VEGF or EGFR inhibition was permitted.
A total of 416 participants were randomly assigned 2:1 to oral fruquintinib at a daily dose of 5 mg (n = 278) or matching placebo (n = 138), both in combination with BSC. Treatment was given until progressive disease, unacceptable toxicity, withdrawn content, discontinuation by physician, or death.
Patients were stratified based on prior VEGF inhibition (yes vs no) and KRAS mutational status (wild-type vs mutated). No crossover from the control arm to the investigative arm was permitted.
The primary efficacy end point was OS, and key secondary end points comprised PFS, objective response rate, and disease control rate. Investigators also examined duration of response and safety.
Most of the baseline demographics, disease characteristics, and previous treatments received were comparable between the treatment arms. However, more men were enrolled to the control arm than the investigative arm, at 70.3% vs 56.8%, respectively. Notably, most patients had several metastases, with liver metastases present in 66.5% and 73.9% of those in the fruquintinib and placebo arms, respectively.
Moreover, 30.2% of those in the fruquintinib arm previously received VEGF inhibitors vs 29.7% of those in the placebo arm; 14.4% and 13.8%, respectively, had prior EGFR inhibitors, and 4.7% and 3.6%, respectively, had prior chemotherapy with VEGF and EGFR inhibitors. In the investigative and control arms, 56.5% and 53.6% of patients, respectively, had KRAS wild-type disease.
The median follow-up in the fruquintinib arm was 13.2 months vs 13.2 months in the placebo arm. Data published in JAMA showed that fruquintinib significantly prolonged the median OS over placebo, at 9.3 months (95% CI, 8.2-10.5) vs 6.6 months (95% CI, 5.9-8.1), respectively (HR, 0.65; 95% CI, 0.51-0.83; P < .001). Fruquintinib also significantly prolonged median PFS over placebo, at 3.7 months (95% CI, 3.7-4.6) and 1.8 months (95% CI, 1.8-1.8), respectively (HR, 0.26; 95% CI, 0.21-0.34; P < .001).
Treatment-emergent AEs that were grade 3 and 4 in severity were experienced by 61.2% of those in the fruquintinib arm vs 19.7% of those in the placebo arm. Serious AEs were reported in 15.5% and 5.8% of patients in the investigative and control arms, respectively. Moreover, 14.4% and 5.1% of patients, respectively, required hospitalization.