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Numerous Frontline CRC Options Allow Individualized Approach

Jason M. Broderick @jasoncology
Published: Saturday, Apr 23, 2016

Wells Messersmith, MD

Wells Messersmith, MD

Given the numerous available treatment options, the most important issue in frontline colorectal cancer (CRC) care is clarifying the goals of therapy, according to Wells Messersmith, MD.

“If the patient might be cured…then I would go ‘all-in’ with cytotoxics [FOLFOXIRI], because we’re going to try and shrink [the tumor] and we’re going to get really high response rates [with that regimen],” Messersmith, director of the Gastrointestinal Medical Oncology Program at the University of Colorado Cancer Center, said in a presentation at the 1st Annual School of Gastrointestinal Oncology meeting.

Messersmith said he would also focus on achieving a high response with an “all-in” cytoxic backbone (FOLFOXIRI) combined with a targeted agent in highly symptomatic patients, because the high response might improve the patient’s quality of life by providing symptom relief.

In other patients—elderly patients, or asymptomatic/unresectable individuals—frontline “response is irrelevant,” said Messersmith, because “you’re not going to cure the patient, you’re just trying to keep things at bay.” With these patients, he said he uses a 5-FU plus bevacizumab (Avastin) approach.

At the meeting, Messersmith discussed several topics in frontline CRC care, including responses with FOLFOXIRI, comparing EGFR and VEGFR targeted therapies, and emerging treatment approaches.

Chemotherapy Regimen With Highest Response

The chemotherapy backbone with the highest demonstrated response rate in frontline CRC has been FOLFOXIRI in the phase III TRIBE trial.1 The study randomized 508 patients with metastatic CRC to receive either FOLFOXIRI plus bevacizumab (n = 252) or FOLFIRI plus bevacizumab (n = 256) for up to 12 cycles over 6 months.

The response rate was 65% with FOLFOXIRI plus bevacizumab versus 53% with FOLFIRI (P = .006). The FOLFOXIRI combination had a median overall survival (OS) rate of 29.8 months compared with 25.8 months for the FOLFIRI arm (HR, 0.80; CI, 0.65-0.98; P = .030). The median progression-free survival (PFS) was 12.3 months versus 9.7 months, respectively (HR, 0.77; CI, 0.65-0.93; P = .006).

In the study, the FOLFOXIRI regimen increased the incidence of grade 3/4 diarrhea, stomatitis, febrile neutropenia, and neutropenia compared with the FOLFIRI regimen.

Messersmith said the phase II STEAM trial2 “basically confirmed the response rate in the TRIBE study.” The STEAM trial randomized patients to FOLFOXIRI and concurrent bevacizumab (cFOLFOXIRI), FOLFOXIRI and sequential bevacizumab (sFOLFOXIRI), or FOLFOX plus bevacizumab. Overall response rate for the 3 arms was 60.2%, 62%, and 47%, respectively. The median PFS was 11.7 months with cFOLFOXIRI, 10.7 months with sFOLFOXIRI, and 9.3 months with FOLFOX.

VEGF Versus EGFR Inhibitors

Messersmith described the inconsistent results between the FIRE-3 and CALGB/SWOG 80405 trials, which compared VEGF and EGFR inhibitors in the frontline setting for patients with KRAS wild-type CRC.

In the European FIRE-3 study,3 frontline cetuximab (Erbitux) plus FOLFIRI improved OS by 3.7 months versus bevacizumab plus FOLFIRI in patients with KRAS wild-type metastatic CRC. However, no advantage was observed with either the primary endpoint of objective response rate or the secondary endpoint of PFS. Based on these data, many European physicians will use an EGFR inhibitor in the frontline setting for KRAS wild-type CRC, Messersmith noted.

In the larger, US-based 80405 trial,4 frontline therapy with bevacizumab or cetuximab combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit of approximately 29 months in patients with KRAS wild-type metastatic CRC.

Messersmith said, in his view, both drugs remain valid options in the first-line setting.

Looking Forward

Messersmith described key emerging issues in CRC treatment, including immunotherapy, that may eventually impact the frontline-line paradigm. As with most solid tumors, PD-1 inhibitors are being explored in CRC. In November 2015, the FDA granted a breakthrough therapy designation to the anti–PD-1 agent pembrolizumab (Keytruda) as a potential therapy for patients with microsatellite instability-high (MSI-H) metastatic CRC.

The designation was based on findings from an ongoing phase II study, which demonstrated high response rates with pembrolizumab in patients with heavily pretreated CRC with mismatch repair deficiency, a condition that causes MSI. Given this emerging potential for immunotherapy, Messersmith stressed the importance of MSI testing in patients with CRC.


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