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SAN FRANCISCO -- Survival in treatment-refractory metastatic colorectal cancer (mCRC) improved by more than 3 months in patients who received bevacizumab (Avastin) in addition to chemotherapy, a randomized trial showed.

Median overall survival (OS) increased from 7.5 months with thymidine-targeted trifluridine/tipiracil (FTD/TPI; TAS-102; Lonsurf) to 10.8 months with the addition of the angiogenesis inhibitor. Median progression-free survival (PFS) more than doubled from 2.4 to 5.6 months with bevacizumab.

Adding bevacizumab did not appreciably increase toxicity, and deterioration of health and performance status slowed, reported Josep Tabernero, MD, of Vall d'Hebron Hospital in Barcelona, at the ASCO Gastrointestinal Cancers Symposium.

"The study is the first phase III study in the setting of refractory metastatic colorectal cancer to demonstrate an improvement in overall survival versus an active control," said Tabernero. "In looking at parameters related to the quality of life, most worsening of baseline global health status and performance status from 0 or 1 to 2 or more was significantly delayed in patients that received trifluridine/tipiracil plus bevacizumab compared to those that received FTD/TPI alone."

"The combination of trifluridine/tipiracil plus bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic colorectal cancer who had previously progressed after two lines of therapy," he added.

The SUNLIGHT study solidified the role of FTD/TPI plus bevacizumab in the refractory mCRC setting, as the regimen was previously added to National Comprehensive Cancer Network guidelines on the basis of earlier results, said invited discussant Dustin Deming, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

"There are very exciting advantages to this combination in terms of PFS and OS," said Deming.

Nonetheless, the trial had some limitations: only 3% of patients were from North America; 76% had prior exposure to anti-VEGF therapy, which was less than in previous studies; some patients were treated in an earlier-line setting than the third or fourth line specified in the protocol; and the combination produced a modest response rate of 6.3%.

"Does this study change standard practice?" Deming continued. "Yes. TAS-102 and bevacizumab should be considered the preferred nontargeted or nonbiomarker-driven regimen in the treatment-refractory setting for metastatic colorectal cancer. This combination is seen with only modest increases in toxicity and financial cost with significant improvements in progression-free and overall survival."

"This study also has implications as it relates to future clinical trials. Now if treatments are going to be studied in the third- or fourth-line setting, TAS-102 and bevacizumab needs to be, at a minimum, an option for patients on those trials."

The stage was set for the SUNLIGHT trial by the phase III study, which showed significant improvement in OS with FTD/TPI in the setting of refractory mCRC. Additionally, several phase II randomized and single-arm studies showed improvement in OS and PFS and manageable toxicity with the addition of bevacizumab, Tabernero stated.

Investigators in the multinational trial enrolled patients with mCRC and progression or intolerance on two or more prior regimens. Patients were randomized to FTD/TPI with or without bevacizumab, and treatment continued until disease progression, unacceptable toxicity, or death. The primary endpoint was OS; PFS, disease control rate (DCR), and objective response rate (ORR) were key secondary endpoints.

Data analysis included 494 patients who had a median age of 62-64. About 70% had RAS mutations, 76% had received prior anti-VEGF therapy, and 72% had prior exposure to bevacizumab.

The primary analysis showed a 39% reduction in the survival hazard in favor of the bevacizumab regimen (95% CI 0.49-0.77, P<0.001). Landmark analyses showed survival advantages for the regimen at 6 months (77% vs 61%) and 12 months (43% vs 30%).

The addition of bevacizumab was associated with a 56% reduction in the hazard for disease progression or death (95% CI 0.36-0.54, P<0.001). The regimen achieved a small but statistically significant advantage for ORR (6.3% vs 0.9%, P=0.004) and a large advantage for DCR (76.6% vs 47.0%, P<0.001).

The time to deterioration of global health status was reduced by 50% (8.5 vs 4.7 months, HR 0.50, P<0.001) and the time to worsening of ECOG performance status by 46% (9.3 vs 6.3 months, 95% CI 0.43-0.67, P<0.001).

With regard to safety, the two treatment groups had similar rates of all-grade adverse events (AEs, 98% in both groups), grade ≥3 AEs (72% vs 70%), serious AEs (25% vs 31%), and AEs leading to withdrawal (13% each). Hypertension (10% vs 2%), nausea (37% vs 27%), and neutropenia (62% vs 51%) occurred more often with FTD/TPI-bevacizumab.

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