Numerous Frontline CRC Options Allow Individualized Approach

Given the numerous available treatment options, the most important issue in frontline colorectal cancer care is clarifying the goals of therapy.

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.

Chemotherapy Regimen With Highest Response

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.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.

VEGF Versus EGFR Inhibitors

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.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.

Looking Forward

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

Another key topic Messersmith repeatedly mentioned was tumor location. He said prognosis and outcomes for patients may be impacted by whether they have left- or right-sided tumors. Studies of this phenomenon are ongoing, and data on this topic will be presented at the upcoming 2016 ASCO Annual Meeting, according to Messersmith.


  1. Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (BEV) versus FOLFIRI plus BEV as first-line treatment of metastatic colorectal cancer: updated survival results of the phase III TRIBE trial by the GONO Group. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 657.
  2. Bendell JC, Tan BR, Reeves JA, et al. Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 34, 2016 (suppl 4S; abstr 492).
  3. Heinemann V, von Weikersthal LF, Decker T, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol. 2013;(suppl; abstr LBA3506).
  4. Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s (suppl; abstr LBA3).

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