Tumor Location Linked to Survival Outcomes in Metastatic Colorectal Cancer

Alan P. Venook, MD

Survival outcomes in patients with KRAS wild-type metastatic colorectal cancer (mCRC) were significantly longer among those with tumors originating on the left versus the right side of the colon, according to a retrospective analysis of the phase III 80405 trial.¹

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 cetuximab plus chemotherapy and an over 7-month survival benefit in patients receiving frontline bevacizumab 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 cetuximab inducing a greater benefit in patients with left-sided tumors, and those with tumors on the right-side of the colon benefiting more from bevacizumab.

“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, MD, 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 80405 analysis,² 1137 patients with treatment-naïve KRAS wild-type (codons 12 and 13) mCRC (performance status 0-1) were randomized in a 1:1 ratio to cetuximab (n = 578) or bevacizumab (n = 559) plus physician’s choice of FOLFOX or FOLFIRI. Cetuximab was administered at an induction dose of 400 mg/m² followed by 250 mg/m² weekly, and patients received bevacizumab at 5 mg/kg every 2 weeks. Among all patients, 26.6% were treated with FOLFIRI and 73.4% 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 bevacizumab or cetuximab. At a median follow-up of 24 months, OS was 29 months in the bevacizumab arm and 29.9 months in the cetuximab arm (HR, 0.925; 95% CI, 0.78-1.09; P = .34).

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 (95% CI, 16.7-23.6) among patients with right-sided tumors compared with 33.3 months (95% CI, 31.4-35.7) for patients with left-sided tumors (HR, 1.60; 95% CI, 1.37-1.86; P <.001). PFS was 8.9 versus 11.5 months, respectively (HR, 1.26; 95% CI, 1.096-1.453; P = .002).

Among patients who received cetuximab, the median OS was 16.7 months (95% CI, 13.1-19.4) in patients with right-sided tumors versus 36 months (95% CI, 32.6-40.3) in the left-sided cohort (HR, 1.987; 95% CI, 1.60-2.46; P <.001). PFS was 7.7 months versus 11.9 months, respectively (HR, 1.539; 95% CI, 1.259-1.882; P <.001).

The cetuximab outcomes are similar to a previously reported subgroup analysis from the phase III FIRE-3 trial, which compared FOLFIRI plus either bevacizumab or cetuximab 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 (n = 137) versus 16.1 months in patients with right-sided (n = 30) tumors (P <.0001).

Patients in study 80405 with right-sided tumors fared far better with bevacizumab compared with cetuximab. Among the bevacizumab cohort, OS was 24.2 months (95% CI, 17.9-30.3) in the right-sided population versus 31.4 months (95% CI, 28.3-33.6) in patients with left-sided tumors (HR, 1.297; 95% CI, 1.05-1.60; P = .017). PFS was 9.6 versus 11.1 months, respectively (HR, 1.035; 95% CI, 0.848-1.263; P = .73).

“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,” ASCO President Julie M. Vose, MD, 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.”

References:

1. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016 (suppl; abstr 3504).
2. Venook AP, Niedzwiecki D, Lenz H-J, 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 32:5s, 2014 (suppl; abstr LBA3).

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“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 cetuximab,” said Venook.