In SUNLIGHT, a phase III, international, prospective, randomised, active-controlled study that involved patients with refractory metastatic colorectal cancer (mCRC), treatment with trifluridine-tipiracil plus bevacizumab resulted in significantly longer overall survival (OS) and progression-free survival (PFS) and better disease control than treatment with trifluridine-tipiracil alone. This study was predominantly a third-line study with >90% of patients who had received two previous lines of treatment. The safety profile of trifluridine-tipiracil plus bevacizumab was as expected, and patients who received the combination had longer preservation of performance status than patients who received trifluridine-tipiracil alone.
The data from this study confirm that trifluridine-tipiracil plus bevacizumab is an effective treatment option for patients with refractory mCRC, irrespective of mutational status, which side the tumour is on, and whether patients have previously been treated with bevacizumab. The findings are published by Dr. Josep Tabernero of the Vall d’Hebron Barcelona Hospital Campus in Barcelona, Spain, and colleagues on 4 May 2023 in The New England Journal of Medicine.
Patients with mCRC generally receive first- and second-line treatment with fluorouracil-based chemotherapy with oxaliplatin and irinotecan, VEGF-based treatment (mainly bevacizumab), and EGFR-targeted treatment in case of patients with RAS wild-type tumours. Patients who have disease progression after receiving these treatments are considered to have refractory disease; however, many of these patients have a good performance status and may be considered for further treatment.
Third- and fourth-line treatment options for refractory disease include reintroduction of chemotherapeutic agents such as oxaliplatin, rechallenge with EGFR treatment in patients with RAS wild-type disease, and targeted treatments for patients with clinically actionable tumour alterations. However, most patients receive regorafenib, an oral multikinase inhibitor with antiangiogenic activity, or trifluridine-tipiracil.
Trifluridine-tipiracil is an orally administered combination of trifluridine, a cytotoxic nucleic acid analogue, and tipiracil, a thymidine phosphorylase inhibitor that prevents enzymatic breakdown of trifluridine. Trifluridine-tipiracil was approved as monotherapy for third-line treatment of refractory mCRC based on the results of the phase III RECOURSE study, which showed that OS was significantly longer with trifluridine-tipiracil than with placebo, irrespective of RAS mutational status, and that trifluridine-tipiracil had a favourable safety profile. Adverse events were mostly related to myelosuppression.
The authors wrote in the background that continuous inhibition of angiogenesis beyond progression may be an effective strategy in the management of mCRC. Maintenance of VEGF inhibition with bevacizumab beyond disease progression has shown clinical activity in patients with mCRC. Furthermore, the results of a randomised, phase III study of regorafenib and a randomised, phase III study of fruquintinib, an inhibitor of VEGF receptors, both of which involved patients with relapsed or refractory disease, showed that OS was longer with each of these agents than with best supportive care. Therefore, combining bevacizumab with trifluridine-tipiracil may result in meaningful clinical benefit. The combination regimen improved OS in several single-group and randomised, phase II clinical studies.
The phase III SUNLIGHT study was designed to assess the efficacy and safety of trifluridine-tipiracil in combination with bevacizumab as compared with trifluridine-tipiracil alone in patients with refractory mCRC. The investigators randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced CRC to receive trifluridine-tipiracil plus bevacizumab (combination group) or trifluridine-tipiracil alone. The primary endpoint was OS. Secondary endpoints were PFS and safety, including the time to worsening of the ECOG performance status score from 0 or 1 to 2 or more.
A total of 246 patients were assigned to each group. The median OS was 10.8 months in the combination group and 7.5 months in the trifluridine-tipiracil group (hazard ratio [HR] for death 0.61, 95% confidence interval [CI] 0.49 to 0.77; p < 0.001).
The median PFS was 5.6 months in the combination group and 2.4 months in the trifluridine-tipiracil group (HR for disease progression or death 0.44, 95% CI 0.36 to 0.54; p < 0.001).
The most common adverse events in both groups were neutropenia, nausea, and anaemia. No treatment-related deaths were reported.
The median time to worsening of the ECOG performance status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the trifluridine-tipiracil group (HR 0.54, 95% CI 0.43 to 0.67).
The survival benefits of trifluridine-tipiracil plus bevacizumab were observed in all subgroups, including the subgroup of patients with factors indicative of a poor prognosis. Survival benefits of the combination were observed irrespective of age, sex, location of primary disease, number of metastatic sites, or RAS mutation status, a finding that indicates trifluridine-tipiracil plus bevacizumab is an option for all clinically relevant subgroups.
Clinical benefit was also observed regardless of whether patients had received previous treatment with bevacizumab, a finding that adds to the body of evidence supporting a role for continued inhibition of angiogenesis beyond progression and suggesting that the addition of bevacizumab to third-line or later-line treatment may prolong survival in heavily pretreated patients.
The authors commented that the results of this study are noteworthy for several reasons. The study showed superior efficacy of a regimen to an existing proven treatment. Bevacizumab has not previously shown substantial efficacy beyond second-line treatment in mCRC studies. Nearly 70% of the patients in this study had tumours with a RAS mutation, a percentage that is higher than that generally reported in the population of patients with mCRC. This is notable because in randomised studies, bevacizumab plus chemotherapy has been reported to provide only marginal OS benefits in patients with RAS-mutated CRC. The OS benefit observed in this study is larger than the magnitude of benefit observed in other bevacizumab-based combination studies with active controls, even as first-line treatment.
In an accompanied article, Drs. Oladapo O. Yeku and Dan L. Longo of the Massachusetts General Hospital in Boston, MA, US wrote that this study sets the stage for prospective clinical studies testing biomarkers such as RAS mutational status in refractory CRC. For patients with non-mutated RAS, some studies have evaluated a trifluridine-tipiracil backbone in combination with anti-EGFR antibodies, with mixed results. Other studies are evaluating whether EGFR blockade alone or in combination with VEGF blockade will yield better results in this population. With the emergence of RAS-inhibiting drugs, approaches that include such drugs in combination with trifluridine-tipiracil and bevacizumab could be explored. Although toxicity and costs would be compounded with triplet combinations, such an approach would be justified based on non-overlapping mechanisms of action and non-overlapping toxicities. Other combinations that target microsatellite instability and immune checkpoints could be explored.
The study was supported by Servier and Taiho Oncology.
References
- Prager GW, Taieb J, Fakih M, et al. for the SUNLIGHT Investigators. Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 2023;388:1657-1667.
- Yeku OO, Longo DL. Combination Therapy, Including Bevacizumab, for Advanced Colorectal Cancer. N Engl J Med 2023;388:1711-1714.