Cetuximab Benefit, Tumor Sidedness Impact Still Unclear in mCRC

Alan P. Venook, MD

There are several significant questions that still remain to be answered regarding the treatment of patients with metastatic colorectal cancer (mCRC), says Alan P. Venook, MD.

One key challenge facing physicians, according to Venook, is the inconsistent data regarding the role of cetuximab (Erbitux).

The FIRE-3 study, which was conducted at 150 centers across Europe, compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab (Avastin) in 592 patients with KRAS exon 2 wild-type mCRC. An extended RAS analysis was carried out in KRAS and NRAS exon 2, 3, and 4.¹

Independent evaluation in the KRAS exon 2 wild-type population showed an overall response rate (ORR) of 66.5% in the cetuximab arm and 55.6% in the bevacizumab arm (P = .016). In the final RAS wild-type population, the ORR was 72% in the cetuximab arm versus 56.1% in the bevacizumab arm (P =.003).

Overall survival (OS) also favored the cetuximab arm, with 28.7 months versus 25 months seen in those who received bevacizumab (HR, 0.77; P = .017).

However, the phase III CALGB/SWOG 80405 trial, for which Venook was an investigator, showed conflicting results.

In 80405, 1137 patients with treatment-naïve KRAS wild-type mCRC were randomized to cetuximab or bevacizumab plus physician’s choice of FOLFOX or FOLFIRI.² The study found no OS or progression-free survival differences between the bevacizumab or cetuximab arms. 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).

This study also opened up questions regarding the significance of tumor location.

A retrospective analysis of the 80405 trial found that the median 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 a more than 7-month survival benefit in patients receiving frontline bevacizumab plus chemotherapy.³

In an interview with OncLive, Venook discussed several of the big queries that remain in mCRC and the possible explanations for survival differences between left- and right-sided tumors. He also explained how answering these questions could pave the way for more novel treatment approaches.

OncLive: What questions would you like to see addressed in mCRC?

Venook: We don’t think that chemotherapy is particularly critical one way or the other; however, 1 question is the choice of the biologic to use with combination chemotherapy. Patients who have combination chemotherapy with biologic agents do a little better than those who don’t, but there are some disparities in data between studies. One study suggests that there is a benefit with cetuximab in patients with RAS wild-type mCRC when used with chemotherapy. Our study, CALGB/SWOG 80405, suggests that bevacizumab and cetuximab are the same in that population.

With biomarkers, we will soon be making decisions based less on the RAS status, and more so on other factors. The most disappointing thing about the all-RAS data is that—at least in our study—patients didn’t do better with cetuximab, even if they had all-RAS wild-type disease. What we saw, and what others have now replicated, is that patients with tumors on the right side of the colon had no benefit from cetuximab. That is really a new observation that we’ve demonstrated, and numerous other groups have shown the same thing.

Hopefully, we will soon have the data to explain what is going on. It is not a function of right versus left side; it’s molecular features that appear to be non-randomly distributed across the colon. I am hoping that we will have the opportunity in the next year or 2 to explain not only why patients do better on the left versus right with certain drugs, but also to prospectively understand why that is and how we should be treating patients. Right now, we do very little in terms of biomarker decision-making; we decide what not to use instead of what to use. Hopefully, we will do the opposite in the future.

What factors are currently being taken into consideration for first-line mCRC treatment?

The main issue is whether the patient is potentially curable or not. As opposed to in most solid tumors, some patients with mCRC are curable. Patients with liver metastases have the best chance of being cured. The first decision is based on the goals of therapy and how aggressively the patient can be treated. Then, we need to square away the ramifications of different treatments. Part of the problem is that there is enough uncertainty and confusion in the literature that it is not a clear path.

For example, we have the FIRE-3 study, which looked at frontline cetuximab plus chemotherapy versus [bevacizumab] plus chemotherapy and showed a benefit with cetuximab. We have 80405—the study that we did—that shows no difference between [cetuximab] and bevacizumab. Then, we have the EPIC study, in which patients with potentially resectable colorectal cancer and liver metastases did worse if they received cetuximab—even if they had RAS wild-type disease. These things don’t square, and there has to be some other way to figure this out.

What we are hoping we will see—and hope to have this fully defined at the 2017 ASCO Annual Meeting—is that there are molecular subtypes of colon cancer. We think there are 4, and some of them are overrepresented on the right side or the left side. We think that, in fact, could explain much of the biological difference between right and left.

The mystery we have to settle is why would all RAS tumors of the right side not benefit from cetuximab? It does not make sense initiatively or, otherwise, and we have to try and figure that out.

What role does immunotherapy play in all of this?

One of the subtypes, which we are calling subtype 4 and was defined in a Nature paper a few years ago, may tend to have tumors with heavy lymphocytic infiltrate. Those may be patients who will benefit. Right now, the only thing we know is that microsatellite instability (MSI)­—high patients with metastatic disease may benefit from the checkpoint inhibitors, but that is only 3% to 4% of patients with metastatic disease.

There is some data now that suggest that it may be possible to sort of “fake” cancers out, and make them behave as if they are MSI-high, even if they are not. There is a randomized study looking at the combination of a MEK inhibitor plus a checkpoint inhibitor, to see whether that can flip the cancer to be more like MSI-high. It remains to be seen if that is possible.

There are a variety of strategies similar to that we are working on to try and expand the number of patients who can benefit from checkpoint inhibitors.

References

1. Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase III trial. Lancet Oncol. 2014;15(10):1065-1075.
2. 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 (suppl; abstr LBA3).
3. 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;34 (suppl; abstr 3504).