SUMMARY: The FDA on November 8, 2023, approved Fruquintinib (FRUZAQLA®) for adult patients with metastatic Colorectal Cancer (mCRC) who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.
Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). Regorafenib has limited efficacy and its adverse effects, particularly hepatotoxicity and fatigue, may be difficult to manage. Treatment options are limited for those who progress on these therapies and there is therefore a strong unmet clinical need.
The VEGF pathway plays a very important role in the neoangiogenesis associated with tumor proliferation. Antiangiogenic agents targeting the VEGF pathway inhibit new blood vessel growth and lead to vascular regression, tumor vessel normalization and constriction, in addition to offsetting the ability of chemotherapy to induce VEGF. This benefit was noted in the SUNLIGHT trial which demonstrated longer Overall Survival and Progression Free Survival among patients with refractory metastatic CRC, treated with LONSURF® plus Bevacizumab, compared to LONSURF® alone (N Engl J Med 2023; 388:1657-1667).
Fruquintinib is a highly selective and potent, oral small molecule inhibitor of VEGFR1/2/3. Fruquintinib was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for the potential use as part of combination therapy.
The present FDA approved was based on two Phase III trials, FRESCO and FRESCO-2. FRESCO is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial conducted in China to evaluate the efficacy and safety of oral Fruquintinib, as third-line or later therapy in patients with metastatic CRC. It should be noted that unlike treatment patterns in North America and Europe, VEGF inhibitors such as Bevacizumab and Aflibercept are not routinely integrated into first- or second-line therapy in China. In this study 416 eligible patients (N=416) who had tumor progression following treatment regimens that included Fluoropyrimidine, Oxaliplatin, and Irinotecan were randomly assigned to receive Fruquintinib 5 mg (N=278) or placebo (N=138), both in combination with best supportive care, given orally once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression or intolerable toxicity. Randomization was stratified by prior use of VEGF inhibitor treatment (yes versus no) and K-ras mutational status (wild type versus mutated). The mean age was 55 years and most baseline demographics, disease characteristics, and prior treatments were similar between the treatment groups. Over 65% of patients had liver metastases. The Primary end point was Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate, Duration of Response and Safety.
The median Overall Survival was significantly prolonged with Fruquintinib compared with placebo (9.3 months versus 6.6 months; HR for death=0.65; P<0.001). The median PFS was also significantly increased with Fruquintinib (3.7 months versus 1.8 months; HR for progression or death=0.26; P<0.001).
The FRESCO-2 study is a global, multi-regional, randomized, placebo-controlled, Phase III trial conducted separately in the U.S., Europe, Japan and Australia among patients with heavily pretreated metastatic colorectal cancer. The reason for this trial was that practice patterns are different in these countries compared to China, with VEGF inhibitors such as Bevacizumab routinely integrated into first- or second-line therapy in these countries. In this study, 691 eligible patients (N=691) were randomly assigned (2:1) to receive Fruquintinib 5 mg (N=461) or matched placebo (N=230) orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Patients received therapy until disease progression or unacceptable toxicity. This study included histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to LONSURF® or Regorafenib, or both. Patients had received a median of 4 lines of previous systemic therapy for metastatic disease, and 73% of the eligible patients had received more than 3 lines of therapy for metastatic disease. Patients were stratified based on previous therapy with LONSURF® or Regorafenib, or both, RAS mutation status, and duration of metastatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Duration of Response.
This study met its Primary endpoint and the median OS was 7.4 months in the Fruquintinib group versus 4.8 months in the placebo group (HR=0.66; P<0.0001). This represented a 34% reduction in the risk of death in the Fruquintinib group. The median PFS in the Fruquintinib group was 3.7 months which was also statistically significant. The median Duration of Response was 10.7 months, the Disease Control Rate was 56%, and 41% of patients were alive at 9 months. The most common Grade 3 or worse adverse events in the Fruquintinib group included hypertension (14%)), asthenia (8%), and hand-foot syndrome (6%).
Both FRESCO and FRESCO-2 trials demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, and Progression Free Survival in patients with refractory metastatic colorectal cancer, when treated with Fruquintinib. This innovative therapy fulfills an unmet need and provides a new treatment option for this heavily pretreated group of patients.
Effect of Fruquintinib vs Placebo on Overall Survival in Patients with Previously Treated Metastatic Colorectal Cancer-The FRESCO Randomized Clinical Trial. Li J, Qin S, Xu R_H, et al. JAMA. 2018;319:2486-2496.
Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Lancet. 2023;402:41-53. doi:10.1016/S0140-6736(23)00772-9.
