Bevacizumab plus trifluridine/tipiracil demonstrated improved overall survival and progression-free survival vs TAS-102 alone as third-line treatment for patients with refractory metastatic colorectal cancer.
Bevacizumab (Avastin) plus trifluridine/tipiracil (TAS-102; Lonsurf) demonstrated improved overall survival (OS) and progression-free survival (PFS) vs TAS-102 alone as third-line treatment for patients with refractory metastatic colorectal cancer (mCRC), according to data from the phase 3 SUNLIGHT trial (NCT04737187) presented at the 2023 Gastrointestinal Cancers Symposium.1
Patients treated with bevacizumab plus TAS-102 (n = 246) achieved a median OS of 10.8 months vs 7.5 months in patients treated with TAS-102 alone (HR, 0.61; 95% CI, 0.49-0.77; P < .001). The 6- and 12-month OS rates in the bevacizumab arm were 77% and 43%, respectively. In the TAS-102 alone arm, those rates were 61% and 30%, respectively.
“All of the efficacy parameters such as PFS, time to deterioration in global health status, and time to deterioration to an ECOG performance status of 2 or more were favorable for the combination arm [and were] statistically significant,” lead study author, Josep Tabernero, MD, PhD, said in an interview with OncLive®. “[Bevacizumab plus TAS-102] also led to an increase in overall response rate [ORR] and disease control rate [DCR]. [Moreover], the safety profile was very manageable.”
Tabernero is the head of the Medical Oncology Department at the Vall d'Hebron University Hospital and the director the Vall d'Hebron Institute of Oncology (VHIO) in Barcelona, Spain.
Previous data from the phase 3 RECOURSE trial (NCT01607957) found that the use of third-line TAS-102 plus best supportive care (BSC) improved OS and had a tolerable safety profile vs BSC alone in patients with relapsed/refractory mCRC.2 Furthermore, prior data from other phase 2 randomized and single-arm studies showed that adding bevacizumab to TAS-102 demonstrated survival improvements with manageable safety.1
“It’s very important to develop new combination therapies that can prolong survival [and maintain] quality of life [QOL] and global health status during their treatment. This is the reason why we considered combining bevacizumab and [TAS-102],” Tabernero explained.
The SUNLIGHT trial was designed to confirm the efficacy and safety of the combination vs TAS-102 alone as an active comparator. Investigators enrolled patients with histologically confirmed mCRC who received 2 prior treatment regimens. Patients were also required to have known disease progression or intolerance, a known RAS status, and an ECOG performance status of 0 or 1.
Upon enrollment, patients were randomly assigned in a 1:1 fashion to receive 35 mg/m2 of TAS-102 twice daily on days 1 to 5 and days 8 to 12 plus 5 mg/kg of intravenous bevacizumab on days 1 and 15 of every 28-day cycle or TAS-102 alone. Stratification factors included geographic region (North America, European Union, or the rest of the world), time since diagnosis of first metastasis (<18 months or ≥18 months), and RAS status (wild-type or mutant). Follow-up occurred every 8 weeks for radiologic progression and/or survival status.
The primary end point was OS in the full analysis set, and secondary end points included PFS, DCR, ORR, safety, and QOL.
The median age of patients in the bevacizumab/TAS-102 group was 62 years (range, 20-84). Fifty-nine percent of patients were younger than 65 years of age, and half of patients were male. Sixty-four percent of patients were from the European Union, 3% from North America, and 33% from the rest of the world. Primary tumor localization was left side for 75% of patients. Seventy percent of patients had the RAS-mutated disease. Fifty-eight percent of patients had a time from diagnosis of first metastasis to randomization of at least 18 months.
Additionally, 76% of patients had prior treatment with anti-VEGF and 72% had prior bevacizumab. Forty-eight percent of patients had an ECOG performance status of 0.
In the control arm, the median age was 64 years (range, 24-90). Fifty-two percent were younger than age 65, and 55% were male. Sixty-four percent of patients in this group were from the European Union, 3% from North America, and 33% from the rest of the world. Sixty-nine percent of patients had left-sided tumor localization, and 69% had RAS-mutant disease. Fifty-seven percent of patients had a time from diagnosis of first metastasis to randomization of at least 18 months.
Moreover, 76% of patients had prior treatment with anti-VEGF, and 72% had prior bevacizumab. Forty-three percent of patients had an ECOG performance status of 0.
Additional data showed that patients in the bevacizumab arm experienced a median PFS of 5.6 months vs 2.4 months with TAS-102 alone (HR, 0.44; 95% CI, 0.36-0.54; P < .001). The 6- and 12- month PFS rates in the bevacizumab arm were 43% and 16%, respectively, compared with 16% and 1% in the control arm, respectively.
The ORR of patients treated with bevacizumab plus TAS-102 was 6.3% (n = 222) vs 0.9% for TAS-102 alone (n=215; 5.4% difference; P = .004). Additionally, the DCR was 76.6% for bevacizumab plus TAS-102 and 47% for TAS-102 alone (29.6% difference; P < .001).
Patients in the bevacizumab/TAS-102 arm experienced a median time to deterioration of global health status of 8.5 months (range, 0.1-17.6), compared with 4.7 months (range, 0.03-14.3) for those in the control arm (HR, 0.50; 95% CI, 0.38-0.65; P < .001). Additionally, the median time to worsening of ECOG performance status to 2 or higher was 9.3 months (range, 0.03-18.0) and 6.3 months (range, 0.03-16.1) for the experimental and control arms, respectively (HR, 0.54; 95% CI, 0.43-0.67; P < .001).
Regarding safety, any-grade adverse effects (AEs) occurred in 98% of patients in both groups.
AEs related to TAS-102 occurred in 90% of patients in the combination arm vs 81% in the TAS-102 alone arm. In the experimental arm, 48% of patients had bevacizumab-related AEs. The rates of severe (grade 3 or higher) AEs were 72% and 70% in the combination vs control groups, respectively, and the rates of serious AEs were 25% and 31%, respectively.
In both arms, 13% of patients experienced AEs that led to study withdrawal. In the combination arm, AEs led to dose reductions in 16% of patients and dose delays in 70% of patients. In the control group, the rates of dose reductions and delays were 12% and 53%, respectively.
The most common any-grade treatment-related AEs reported in at least 20% of patients included neutropenia (62% and 51% in the experimental and control arms, respectively), nausea (37% and 27%), anemia (29% and 32%), asthenia (24% and 22%), fatigue (22% and 16%), diarrhea (21% and 19%), and decreased appetite (20% and 15%). Forty-three percent of patients in the bevacizumab arm experienced grade 3/4 neutropenia compared with 32% in the TAS-102 alone arm. Six percent of those in the experimental arm had grade 3/4 anemia vs 11% in the control arm. One patient in the bevacizumab arm experienced febrile neutropenia, compared with 6 patients in the TAS-102 alone arm.
“All of characteristics on OS, PFS, and all the other QOL-related aspects and the safety profile favor that [bevacizumab plus TAS-102] becomes a standard-of-care option in the treatment of patients in the third-line setting of mCRC,” Tabernero concluded.