SUMMARY: The FDA on August 2, 2023, approved LONSURF® (Trifluridine and Tipiracil with Bevacizumab, for metastatic ColoRectal Cancer (mCRC) previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, 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 colorectal cancer 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).
LONSURF® is a combination of two agents – a novel thymidine-based nucleoside analogue, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil. Trifluridine incorporates into DNA resulting in DNA damage and cell death. Trifluridine however is rapidly metabolized when taken orally and this is prevented by Tipiracil, which increases the bioavailability of Trifluridine. Single agent LONSURF® was approved by the FDA in 2015 for the treatment of patients with metastatic CRC, who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. This approval was based on the RECOURSE study, which is a pivotal, global, Phase III trial in which LONSURF® significantly improved Overall Survival as well as Progression Free Survival, when compared to placebo in this patient population.
Bevacizumab is a humanized monoclonal antibody that targets VEGF, a cytokine secreted by tumor cells and tumor-associated macrophages. VEGF is responsible for neoangiogenesis, proliferation, and metastasis, through its effects on endothelial cells. Bevacizumab was approved for the treatment of CRC in 2004. Maintenance of VEGF inhibition with Bevacizumab beyond disease progression has shown clinical activity in patients with metastatic CRC. A combination of LONSURF® in combination with Bevacizumab improved Overall Survival in several single-group and randomized Phase II trials.
The present FDA approval was based on SUNLIGHT trial, which is a multinational, multicenter, randomized Phase III study, designed to assess the efficacy and safety of LONSURF® in combination with Bevacizumab, as compared with LONSURF® alone, in patients with refractory metastatic CRC. In this study, a total of 492 patients with refractory metastatic CRC were randomly assigned in a 1:1 ratio to receive LONSURF® along with Bevacizumab (N=246) or LONSURF® alone (N=246). Patients received LONSURF® 35 mg/m2 orally, twice daily, on days 1-5 and on days 8-12 every 28 days. Bevacizumab was administered at a dose of 5 mg/kg IV on days 1 and 15. The 28-day treatment cycle was continued until disease progression or unacceptable toxicities. Bevacizumab monotherapy was not allowed. The two treatment groups were well balanced. Most patients (92%) had received two previous treatment regimens for metastatic disease, all patients had received previous Fluoropyrimidine-based therapy, 72% had received previous anti-VEGF therapy, 94% of the patients with RAS wild-type disease had received previous anti-EGFR therapy, and 30% had RAS wild-type disease. The Primary end point was Overall Survival. Secondary end points included Progression Free Survival, Objective Response and Disease Control Rate, Quality of Life and Safety. The median follow up was 14.2 months in the LONSURF® combination group and 13.6 months in the LONSURF® alone group.
The median Overall Survival was 10.8 months in the combination group and 7.5 months in the LONSURF® alone group (HR=0.61; P<0.001), suggesting a 39% reduction in the risk of death with the combination regimen. The median Progression Free Survival was 5.6 months in the combination group and 2.4 months in the LONSURF® alone group (HR=0.44; P<0.001). These benefits of LONSURF® plus Bevacizumab with respect to Overall Survival and Progression Free Survival were observed in all subgroups examined, including patients with poor prognostic factors. Survival benefits with the combination regimen were observed regardless of age, sex, location of primary disease, number of metastatic sites, RAS mutation status and previous treatment with Bevacizumab. The Objective Response Rate was 6.1% in the combination group versus 1.2% in the LONSURF® alone group. The median time to worsening of the ECOG PS from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the LONSURF® alone group (HR=0.54). The addition of Bevacizumab to LONSURF® did not increase the risk of serious adverse events or treatment discontinuation. The most common adverse events in both groups were neutropenia, nausea, and anemia.
It was concluded from this study that among patients with refractory metastatic colorectal cancer, treatment with LONSURF® plus Bevacizumab resulted in longer Overall Survival and Progression Free Survival, compared to LONSURF® alone, and this benefit was noted in all subgroups of patients.
Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. Prager GW, Taieb J, Fakih M, et al., for the SUNLIGHT Investigators. N Engl J Med 2023; 388:1657-1667
