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Combo Improves Survival in Refractory Colorectal Cancer

Patients with chemorefractory metastatic colorectal cancer (CRC) had significant improvement in progression-free survival (PFS) with the addition of bevacizumab (Avastin) to trifluridine/tipiracil (FTD/TPC, Lonsurf), according to a randomized trial.

Median PFS increased from 2.6 months with FTD/TPC monotherapy to 4.6 months with FTD/TPC plus bevacizumab. Median overall survival (OS, a secondary endpoint) also improved with the addition of bevacizumab (9.4 vs 6.7 months), reported Per Pfeiffer, PhD, of the University of Southern Denmark in Odense, and colleagues.

The combination led to more grade 3 neutropenia, but serious adverse events (SAEs) occurred in a similar proportion of patients treated with monotherapy or the combination, they reported in The Lancet Oncology.

“The combination of TAS-102 (FTD/TPC) plus bevacizumab is an encouraging new potential treatment option for patients with refractory metastatic colorectal cancer and could be practice changing,” the authors stated. “Ongoing clinical trials are investigating this combination in earlier treatment lines for patients with metastatic colorectal cancer.”

The trial clearly addressed an unmet clinical need, and the results with the combination appear promising, wrote the author of an invited commentary. Even so, “notable limitations” need to be taken into account when evaluating the results.

“The trial is a small phase II study of less than 100 patients from four centers in Denmark,” said Cathy Eng, MD, of Vanderbilt-Ingram Cancer Center in Nashville. “Surprisingly, a larger number of participants (~40% in both groups) required at least one hospitalization. The exact reasons for hospitalization are not well defined; presumably they are attributed to neutropenia.”

“The cause of the higher prevalence of neutropenia [with the addition of bevacizumab] remains unclear, given the small number of neutropenia cases with single-agent bevacizumab,” Eng continued. “Given that the average age a patient is diagnosed with colorectal cancer is 67 years, similar to the median age of patients in both groups from this trial, it is likely we will see greater incidences of neutropenia in a real-world setting, potentially placing patients at increased risk of morbidity and mortality.”

Despite the promising results of the study, additional data are needed before considering a change in current treatment guidelines for metastatic CRC, she concluded.

About half of patients with metastatic CRC have objective responses to first-line systemic therapy, decreasing to 10%-20% in the second-line setting. No therapy has demonstrated efficacy in third line, and tumor regression rarely occurs, Pfeiffer and colleagues noted.

The goal of therapy for chemorefractory metastatic CRC is to prevent tumor progression and prolong survival without compromising quality of life. Both FTD/TPC and regorafenib (Stivarga) have been shown to prolong PFS and OS versus best supportive care for patients who received all available standard therapies, the authors continued.

The favorable safety profile of FTD/TPC has led to investigation of potential combination regimens for patients with metastatic CRC. The angiogenesis inhibitor bevacizumab improves PFS and OS as add-on therapy in both first- and second-line management of metastatic CRC.

A small, nonrandomized evaluation of FTD/TPC plus bevacizumab yielded encouraging PFS and OS, and provided the basis for the randomized, phase II trial reported by Pfeiffer and colleagues. The open-label trial included 93 randomized patients, who had a median age of 65. A majority of patients in both groups had prior exposure to bevacizumab.

The primary endpoint was investigator-assessed PFS. After a median follow-up of 10 months, a 2-month absolute difference in median PFS had emerged in favor of the bevacizumab arm, representing a 55% reduction in the hazard for disease progression or death (95% CI 0.29-0.72, P=0.0010). Statistical adjustment for RAS mutation status and participating institution continued to show a significant advantage for the addition of bevacizumab (HR 0.47, 95% CI 0.29-0.74, P=0.0015).

The difference in median OS also proved to be statistically significant in favor of the combination therapy (HR 0.55, 95% CI 0.32-0.94, P=0.028). The adjusted analysis yielded similar results (HR 0.58, 95% CI 0.34-0.99, P=0.048).

The disease control rate (response plus stable disease) favored the combination arm, but the difference did not achieve statistical significance (67% vs 51%, P=0.14). The only objective response (partial) occurred in a patient who received the combination.

Grade ≥3 neutropenia occurred in 38% of patients who received only FTD/TPC as compared with 67% of those randomized to the combination. SAEs occurred in 45% of the monotherapy group and 41% of the combination arm. Treatment-related SAEs occurred in four patients on monotherapy (one case each of vomiting, obstipation, febrile neutropenia, and vomiting) and four in the combination arm (three cases of febrile neutropenia and one of diarrhea). No treatment-related deaths occurred in either arm.

The study was supported by Servier.

Pfeiffer disclosed a relevant relationship with Servier. One co-author disclosed relevant relationships with Servier, Roche, and Merck.

Eng disclosed no relevant relationships with industry.

2020-01-28T18:00:00-0500

Source: MedicalNewsToday.com