FTD/TPI-bevacizumab a glimmer of hope for refractory CRC?

A combination of trifluridine/tipiracil (FTD/TPI) and bevacizumab provided significant survival benefit when used as third-line treatment for refractory metastatic colorectal cancer (CRC) than FTD/TPI alone, findings from the phase III SUNLIGHT study suggest.

“Our study met its primary endpoint,” said lead study author Dr Josep Tabernero from Vall d’Hebron Hospital Campus and Institute of Oncology, Barcelona, Spain, at ASCO GI 2023. “Median overall survival (OS) improved by 3.3 months with FTD/TPI-bevacizumab. The survival benefit was observed across all subgroups, irrespective of age, sex, location of primary disease, number of metastatic sites, and RAS mutation status.”

Patients on FTD/TPI-bevacizumab had a statistically significant and clinically meaningful superior OS than those on FTD/TPI alone (median 10.8 vs 7.5 months; hazard [HR], 0.61; p<0.001). The curves diverged from the early beginning, and this was sustained until the end of follow up, said Tabernero.

FTD/TPI-bevacizumab also significantly extended median progression-free survival (PFS) than FTD/TPI alone (5.6 vs 2.4 months; HR, 0.44; p<0.001). [ASCO GI 2023, abstract 4]

The subgroup analyses for both OS and PFS did not show any subgroup that did not benefit from the addition of bevacizumab to FTD/TPI, noted Tabernero. “Of note, patients who had previously received bevacizumab also gained benefit from the addition of bevacizumab to the combination regimen.”

Among patients evaluable for tumour response, both overall response rate (ORR) and disease control rate (DCR) were higher with the combo regimen vs FTD/TPI alone. The respective absolute gains for ORR and DCR were 5.4 percent (p=0.004) and 29.6 percent (p<0.001).

 

Safety, QoL

The rates of grade ≥3 adverse events (AEs) were similar between the groups receiving FTD/TPI-bevacizumab and FDT/TPI alone (72 percent and 70 percent). No new safety signals were noted. There were no treatment-related deaths in either arm.

Despite the slightly higher percentage of FTD/TPI-bevacizumab-treated patients having dose modifications than those on FTD/TPI alone (16 percent vs 12 percent [dose reductions] and 70 percent vs 53 percent [dose delays]), there were similar fractions of patients who withdrew from the study owing to AEs (13 percent for both arms).

“The safety profile of the combination regimen was manageable and consistent with the individual safety profiles of FTD/TPI and bevacizumab,” said Tabernero.

Regarding quality of life (QoL), FTD/TPI-bevacizumab was superior to FTD/TPI alone in terms of time to deterioration in global health status (median 8.5 vs 4.7 months; HR, 0.5; p<0.001) and time to worsening to ECOG PS ≥2 (median 9.3 vs 6.3 months; HR, 0.5; p<0.001). Again, the curves for both parameters diverged from the early beginning, noted Tabernero. These findings imply that the worsening of both QoL parameters was substantially delayed with the combo regimen than with FTD/TPI alone.

 

Trumps an existing active treatment

The study included 492 patients (median age 63 years, 53 percent male) with histologically confirmed metastatic CRC and ECOG PS* 0/1 who have failed 1–2 prior chemotherapy** regimens in an advanced setting. They were randomized 1:1 to receive FTD/TPI 35 mg/m² BID (days 1–5 and 8–12 of each 28-day cycle) alone or in combination with bevacizumab 5 mg/kg (days 1 and 15).

“This randomized phase III trial in European patients … validates earlier phase II Danish data,” commented ASCO Expert in gastrointestinal cancers Dr Cathy Eng from the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, US, in a press release.

“This is one of the first studies to show improved efficacy over an existing active treatment in patients with refractory metastatic CRC. In addition, the magnitude of benefit observed was greater than that seen in other trials, and in a population that included patients with poor prognostic factors such as RAS mutations,” said Tabernero.

“[Our findings therefore suggest that] the combination of FTD/TPI and bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic CRC who had previously progressed after two lines of therapy,” he concluded.

In a press release, Dr Nadia Caussé-Amellal, Servier Head of Global Development, Gastrointestinal Indications, Oncology and Immuno-Oncology Therapeutic Area, expressed their intent to forward the data for regulatory authorization to bring “this innovation combination to patients as early as possible … We are delighted by [these findings demonstrating that FTD-TPI-bevacizumab] may be an effective and manageable post-progression therapy in metastatic CRC.”