FDA Grants Priority Review to Fruquintinib for Previously Treated mCRC

FDA

The FDA has granted priority review to the new drug application (NDA) seeking the approval of fruquintinib (HMPL-013) for use in the treatment of adult patients with previously treated metastatic colorectal cancer (mCRC).¹

The application was supported by findings from the phase 3 FRESCO-2 trial (NCT04322539)—conducted in the United States, Europe, Japan, and Australia—and the phase 3 FRESCO trial (NCT02314819), which was conducted in China.

In FRESCO-2 trial, fruquintinib plus best supportive care (BSC; n = 461) resulted in a significant improvement in overall survival (OS) compared with placebo plus BSC, at a median of 7.4 months (95% CI, 6.7-8.2) and 4.8 months (95% CI, 4.0-5.8), respectively (HR, 0.662; 95% CI, 0.549-0.800; P < .001).² The addition of fruquintinib also improved progression-free survival (PFS) over the control regimen, at a median of 3.7 months (95% CI, 3.5-3.8) and 1.8 months (95% CI, 1.8-1.9), respectively (HR, 0.321; 95% CI, 0.267-0.386; P < .001).

In FRESCO, fruquintinib plus BSC (n = 278) significantly also extended median OS over placebo plus BSC (n = 138), at 9.3 months (95% CI, 8.2-10.5) and 6.6 months (95% CI, 5.9-8.1), respectively (HR, 0.65; 95% CI, 0.51-0.83; P < .001).³ The agent also improved PFS over placebo, with a median 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).

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the NDA by November 30, 2023.¹

“We are confident that fruquintinib has the potential to transform the treatment landscape for those living with previously treated mCRC, as demonstrated by its strong clinical profile,” Awny Farajallah, MD, head of Global Medical Affairs Oncology at Takeda, stated in a press release. “There are significant needs for patients with this disease in the United States, and we believe fruquintinib has the potential to address these needs regardless of patients’ biomarker status. We look forward to continuing conversations with the FDA with the goal to make this therapy available to patients as soon as possible.”

FRESCO-2

The pivotal trial enrolled patients who had mCRC who received prior chemotherapy comprised of fluoropyrimidine, oxaliplatin, or irinotecan; a VEGF inhibitor; and an EGFR inhibitor if they had RAS wild-type disease.2 To be eligible, they were required to have experienced disease progression on or been intolerant to trifluridine/tipiracil (TAS-102; Lonsurf) and/or regorafenib (Stivarga). Notably, the number of regorafenib-pretreated patients was limited to 344 to ensure the trial population was reflective of clinical practice.

Patients were randomly assigned 2:1 to receive fruquintinib at 5 mg daily in a 3-weeks-on/1-week-off schedule paired with BSC or placebo plus BSC. Treatment was continued until progressive disease or unacceptable toxicity, and stratification factors included prior treatment (TAS-102 vs regorafenib vs both), RAS mutational status (wild-type vs mutant), and duration of metastatic disease (≤18 months vs >18 months).

The primary end point of the trial was OS, and key secondary end point was PFS. Other important end points included objective response rate (ORR), disease control rate (DCR), and safety.

Data from FRESCO-2 were shared at the 2022 ESMO Congress and had a data cutoff date of June 24, 2022. Across the arms, the median age was 64 years (range, 25-86). More than 50% of patients were male and approximately 70% were from Europe.

In the fruquintinib arm, patients had received a median number of 5 prior lines of treatment, with a range of 2 to 16. Specifically, 27.1% of patients had received up to 3 previous lines of therapy, and 72.9% of patients received more than 3 lines. Those in the placebo arm received a median of 5 prior lines of therapy, with a range of 2 to 12 lines. Here, 27.8% and 72.2% of patients received up to 3 prior lines and more than 3 lines, respectively.

Previous treatment in the investigative arm included VEGF inhibition (96.5%), EGFR inhibition (39.0%), TAS-102 (52.1%), regorafenib (8.7%), and TAS-102 plus regorafenib (39.3%); in the control arm, these rates were 96.1%, 38.3%, 52.6%, 7.8%, and 39.6%, respectively.

Fruquintinib elicited a confirmed ORR of 1.5% vs 0% with placebo (adjusted difference, 1.5; 95% CI, 0.4%-2.7%; 2-sided, P = .059). The DCR achieved with fruquintinib was 55.5% compared with 16.1% with placebo (adjusted difference, 39.4; 95% CI, 32.8%-46.0%; P < .001).

Regarding safety, more than half (68.4%) of patients who received fruquintinib experienced dose interruptions vs 47.8% of those who received placebo. Dose interruptions were required in 26.5% of those in the investigative arm and 4.3% of those in the control arm.

Any-grade treatment-emergent adverse effects (TEAEs) were experienced by 98.9% vs 92.6% with placebo, with grade 3 or higher toxicities reported in 62.7% and 50.4% of patients, respectively. Grade 3 or higher treatment-related toxicities were observed in 36.0% of those who received fruquintinib vs 11.3% of those given placebo.

Serious TEAEs were reported in 37.5% of those in the investigative arm and 38.3% of those in the control arm; grade 3 or higher serious TEAEs were observed in 35.5% and 37.0% of patients, respectively. AEs led to death in 10.5% of those in the fruquintinib arm and 19.6% of those in the control arm.

The most frequent TEAEs that were grade 3 or higher in severity and occurred in at least 15% of participants in the investigative and control arms were hypertension (13.6% vs 0.9%), asthenia (7.7% vs 3.9%), reduced appetite (2.4% vs 1.3%), diarrhea (3.5% vs 0%), hypothyroidism (0.4% vs 0%), fatigue (3.9% vs 0.9%), hand-foot syndrome (6.4% vs 0%), abdominal pain (3.1% vs 3.0%), nausea (0.7% vs 0.9%), proteinuria (1.8% vs 0.9%), and constipation (0.4% vs 0%).

FRESCO

The randomized, double-blind, placebo-controlled, multicenter trial enrolled patients with China who had histologically or cytologically confirmed mCRC that progressed after at least 2 standard chemotherapy regimens that included fluoropyrimidine, oxaliplatin, and irinotecan.³

They were required to be between the ages of 18 years and 75 years, weigh 40 kg or more, an ECOG performance status of 0 or 1, left ventricular ejection fraction of at least 50%, measurable disease by RECIST v1.1 criteria, a life expectancy of at least 12 weeks, and acceptable bone marrow, liver, and renal function. Patients were allowed to have received prior VEGF inhibition or EGFR inhibition.

Study participants were randomly assigned 2:1 to fruquintinib at 5 mg daily plus BSC or placebo plus BSC. Stratification factors included prior VEGF inhibitor use (yes vs no) and KRAS mutational status (wild-type vs mutated).

OS served as the primary end point, and key secondary end points comprised PFS, ORR, and DCR. Investigators also evaluated duration of response and safety.

Most demographics, disease characteristics, and previous treatments at baseline were comparable between the 2 treatment arms. However, more men were enrolled to the placebo arm than the investigative arm. Notably, most patients had several metastases; liver metastases were observed in 66.5% of those in the fruquintinib arm and 73.9% of those in the placebo arm.

Fruquintinib induced a significantly higher ORR than placebo, at 4.7% and 0%, respectively (P = .01, difference, 4.7%; 95% CI, 2.1%-7.2%). The DCR was also higher in the investigative arm vs the control arm, at 62.2% and 12.3%, respectively (P < .001; difference, 49.9%; 95% CI, 42.0%-57.8%).

In terms of safety, 98.6% of those who received fruquintinib and 88.3% of those who were given placebo experienced at least 1 treatment-emergent toxicity. Grade 3 or higher TEAEs were observed in 61.2% of those in the investigative arm and 19.7% of those in the control arm. Serious toxicities were experienced by 15.5% and 5.8% of patients, respectively; 14.4% and 5.1% of patients, respectively, needed hospitalization.

References

1. Takeda and HUTCHMED announce new drug application (NDA) for fruquintinib for treatment of previously treated metastatic colorectal cancer granted priority review. News release. Takeda and HUTCHMED Limited. May 25, 2023. Accessed May 25, 2023. https://www.takeda.com/newsroom/press-releases/takeda-and-hutchmed-announce-new-drug-application-for-fruquintinib-for-treatment-of-previously-treated-metastatic-colorectal-cancer-granted-priority-review/
2. Dasari NA, Lonardi S, Garcia-Carbonero R, et al. LBA25 FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022;33(suppl 7):S1391-S1392. doi:10.1016/j.annonc.2022.08.021
3. Li J, Qin S, Xu R-H, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855