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Survival Outcomes Affected by Tumor Location in KRAS Wild-Type mCRC

Laura Panjwani
Published: Tuesday, Jul 12, 2016

Alan P. Venook, MD

Alan P. Venook, MD

The debate between the phase III CALGB/SWOG 80405 and FIRE-3 studies has been settled, as findings of a retrospective analysis of 80405 show that tumor location is significant in determining survival outcomes for patients with KRAS wild-type metastatic colorectal cancer (mCRC), according to Alan P. Venook, MD.

In the analysis, which was presented at the 2016 ASCO Annual Meeting, the primary tumor location of all patients enrolled in the 80405 trial was identified either right (293), left (732), transverse (66), or uncertain (46). Across both treatment arms, the median overall survival (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). Progression-free survival (PFS) was 8.9 versus 11.5 months, respectively (HR, 1.26; 95% CI, 1.096-1.453; P = .002).1

Results showed that, among patients who received cetuximab (Erbitux), 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 tumors (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 were similar to a previously reported subgroup analysis from the phase III FIRE-3 trial, which compared FOLFIRI plus either bevacizumab (Avastin) 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).  

Previously, there were contrasting results with the CALGB/SWOG 80405 and FIRE-3 studies—both of which looked at the same patient population with cetuximab and bevacizumab, says Venook, the CALGB/SWOG 80405 lead study author.

In the primary studies, frontline therapy with bevacizumab or cetuximab combined with either FOLFOX or FOLFIRI yielded a comparable survival benefit in CALGB/SWOG 80405 while a survival benefit was seen with cetuximab over bevacizumab in KRAS wild-type patients in the FIRE-3 study.

“Two years ago I was literally in the middle of a mud-slinging fight because people were trying to figure out who was right and wrong; FIRE-3 or 80405,” says Venook, the Madden Family Distinguished professor of Medical Oncology and Translational Research at the University of California in San Francisco. “Now two of these datasets together make a pretty compelling story that patients with right-sided colon cancer shouldn’t be treated with cetuximab, and for patients with left-sided, you could go either way. So we’ve gone from having disparate results where there was a big debate, to realizing that in a number of instances our studies are exactly the same, and I think that’s helped clarify some of these questions.”

In an interview with OncLive, Venook provides a deeper understanding of the impact that tumor location has on patients with mCRC, and the significance of them change the results of the CALGB/SWOG 80405 and FIRE-3 studies.

OncLive: What started the debate regarding the results of the CALGB/SWOG 80405 and FIRE-3 studies?

Venook: FIRE-3 and 80405 are very interesting studies. They were started around the same time, in 2003 or 2004. FIRE-3 is a European study that built on FOLFIRI as a backbone. The 80405 study was built on the choice of either FOLFIRI or FOLFOX, because in the United States FOLFOX is much more popular. FIRE-3 had the same randomizations to cetuximab and bevacizumab as we did.

However, the results of the 2 studies were different. Both studies did not select for KRAS originally and in the 80405 study we realized early on that we should be selecting for KRAS wild-type and made that change. FIRE-3’s results showed that cetuximab was superior to bevacizumab in patients in that study by about 3.5 months.

Then, when they analyzed the ‘All RAS’ population, which essentially meant getting rid of the patients from the mix we thought would not respond because of their RAS, the difference was 7.5 to 8 months between cetuximab and bevacizumab. Our study, 80405, was a cooperative group study where our original goal was to look to see a difference. Again, we amended it. We thought patients would live 22 months when we started. They all lived 30 months. In our study we saw no difference at all between the 2 groups.

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