Patients With Left-Sided Metastatic Colorectal Cancer Live Longer

Patients with KRAS wild-type metastatic colorectal cancer (mCRC) who had tumors originating on the left side of the colon showed longer survival outcomes than those who had their tumor originate on the right, according to a retrospective analysis of the phase 3 80405 trial.

The median overall survival (OS) was nearly 14 months longer in patients with left-sided tumors, including a nearly 20-month survival advantage in patients receiving frontline Erbitux (cetuximab) plus chemotherapy and an over seven-month survival benefit in patients receiving frontline Avastin plus chemotherapy.

The findings, which were presented on a presscast held in advance of the 2016 ASCO Annual Meeting, also indicated that tumor location may inform frontline targeted therapy selection in mCRC, with Erbitux inducing a greater benefit in patients with left-sided tumors, and those with tumors on the right-side of the colon benefiting more from Avastin.

“The 14-month improved survival in left- vs right-sided primary tumors is really striking for patients who present with metastatic disease,” lead study author Alan P. Venook, said when presenting the results on the presscast.

“Molecular analysis of these tissues is underway—certainly we believe that the side is a surrogate marker for a biologic explanation, and we’re hoping to tease that out over the next few months. Until we have sorted that out, colon cancer originating on the right side should be treated differently than colon cancer originating on the left side,” said Venook, who is a professor of Medicine at the University of California, San Francisco.

In the primary 80450 analysis, 1,137 patients with treatment-naïve KRAS wild-type (codons 12 and 13) mCRC (performance status 0-1) were randomized in a one-to-one ratio to Erbitux (578 patients) or Avastin (bevacizumab) (559 patients) plus physician’s choice of FOLFOX or FOLFIRI. Erbitux was administered at an induction dose of 400 mg/m2 followed by 250 mg/m2 weekly, and patients received Avastin at five mg/kg every two weeks. Among all patients, 26.6 percent were treated with FOLFIRI and 73.4 percent received FOLFOX. Treatment was continued until curative surgery, disease progression, or unacceptable toxicity.

The results of the primary analysis presented at the 2014 ASCO Annual Meeting showed that there was no OS or progression-free survival (PFS) difference with Avastin or Erbitux. At a median follow-up of 24 months, OS was 29 months in the Avastin arm and 29.9 months in the Erbitux arm.

For the retrospective analysis, Venook et al identified the primary tumor location of all patients enrolled in the 80405 trial: right (293), left (732), transverse (66), and uncertain (46). The left-side of the colon was defined as the descending colon, sigmoid colon and rectum, and the right side included the cecum and ascending colon. The analysis Venook discussed on the presscast compared only the left and right populations, and excluded the transverse.

Across both treatment arms, the median OS was 19.4 months among patients with right-sided tumors compared with 33.3 months for patients with left-sided tumors. PFS was 8.9 versus 11.5 months, respectively.

Among patients who received Erbitux, the median OS was 16.7 months in patients with right-sided tumors versus 36 months in the left-sided cohort. PFS was 7.7 months versus 11.9 months, respectively.

The Erbitux outcomes are similar to a previously reported subgroup analysis from the phase 3 FIRE-3 trial, which compared FOLFIRI plus either b Avastin or Erbitux in the frontline setting for KRAS wild-type mCRC. In a subgroup of 167 patients from FIRE-3, the median OS was 38.7 months in patients with left-sided tumors (137 patients) versus 16.1 months in patients with right-sided (30 patients) tumors.

“The [80405] data and other findings, both presented at ASCO meetings and in press, suggest that patients with right-sided primary metastatic colon cancer get little to no benefit from Erbitux,” said Venook.

Patients in study 80405 with right-sided tumors faired far better with Avastin compared with Erbitux. Among the Avastin cohort, OS was 24.2 months in the right-sided population versus 31.4 months in patients with left-sided tumors. PFS was 9.6 versus 11.1 months, respectively.

“This is the largest study to date of tumor location in colorectal cancer, and it strongly suggests that this unexpected factor could answer some long-standing questions about why certain patients do better than others,” said ASCO President Julie M. Vose, said in a statement. “It is also an important reminder, in this exciting era of precision medicine, that genomics is not the only source of insight into how cancers should be studied and treated.”