Moving Into a New Era in Colorectal Cancer

Manuel Hidalgo, M.D., Ph.D.

We’re moving into a new era of understanding with genetic abnormalities in colorectal cancer (CRC) as researchers continue to investigate tumor sidedness and the role of microsatellite instability (MSI) testing.

MSI has become an influential biomarker, with two immunotherapy agents — Keytruda (pembrolizumab) and Opdivo (nivolumab) — being approved in the past four months for the treatment of patients with MSI-high (MSI-H) or deficient mismatch repair (dMMR) CRC.

In August 2017, the FDA granted an accelerated approval to Opdivo for the treatment of adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan based on findings from the phase 2 CheckMate-142 trial, in which the overall response rate (ORR) was 28 percent in these patients who received Opdivo, including one complete response (CR) and 14 partial responses (PRs).

Keytruda was granted FDA approval for the same indication in May 2017, based on data from 149 patients with MSI-H or dMMR cancers enrolled across five single-arm clinical trials. Ninety patients had CRC and the remaining 59 patients had 1 of 14 other tumor types. The overall ORR with Keytruda was 39.6 percent, including 11 (7.4 percent) CRs and 48 (32.2 percent) PRs. The ORR was 36 percent in patients with CRC.

How are mutations in CRC being considered in treatment decisions?

Could you comment on the current guidelines regarding mutation testing?

These successes have pushed clinicians to further explore genetic testing and its clinical utility in CRC. In an interview with CURE, Manuel Hidalgo, M.D., director of the Rosenberg Clinical Cancer Center and chief of the Division of Hematology Oncology at Beth Israel Deaconess Medical Center, shared his insight on the growth of genetic testing in CRC.We now have the extended RAS panel, which is utilized to determine whether a patient should or should not receive EGFR inhibitors. That is being further determined in cell-free DNA. We have MSI as a determinate for treatment with Keytruda. Soon, we hope that BRAF mutations will also be used to decide treatment with regorafenib in combination. In CRC, these are the three "must-have" mutations of the moment to decide treatment. They change constantly. The latest addition is the MSI testing in cancer in general—but with a particular emphasis in colorectal cancer.

We are moving toward detecting more mutations. One simple reason is that it takes the same amount of work and the same cost to detect one mutation versus detecting several. Therefore, why not detect several? The clinical implications of many are still to be defined. On one end, the diagnostics are becoming cheaper and, for that reason, broader. Progressively, what we will be learning is how to use those new pieces of information.

In CRC, the interplay of tumor sidedness is discussed a lot. Are there any recent studies shedding light on this?

However, we are not ready to use them. To me, it is a parallel track. We will sequence more and have more information, but if you ask what is really needed today, it is [more information on] extended RAS mutations and MSI.There are studies that suggest that depending on the side of the primary tumor, either the left or the right colon, [it] may have more or less KRAS, RAS or BRAF mutations, and for that reason, respond differently to different treatments.

Could you discuss Zelboraf (vemurafenib) in this space?

Aside from CRC, are there any trends in targeted treatments for gastrointestinal cancers?

That’s interesting, I think—it may point out the etiology of that particular cancer. However, the reality is that, from a clinical perspective, it doesn’t have a significant implication. Yes, a tumor in the right side of the colon will be higher MSI and more BRAF mutations as compared with tumors in the left, but you don’t exclude a tumor from MSI testing because it is coming from the left side.[Zelboraf] showed that, in BRAF-mutant CRC, the combination of it with Erbitux (cetuximab) and irinotecan resulted in a very impressive improvement in progression-free survival, with a hazard ratio of 0.48. This clearly demonstrated activity of the triplet versus Erbitux and irinotecan alone in that subset of patients, which is about 7 percent [of CRC patients]. That is clinical confirmation of some prior preclinical studies that have been conducted. Altogether, it’s a nice story. There is a lot going on. In CRC, we have talked about a few. Cholangiocarcinoma is a disease in which a significant number of mutations have been discovered — HER2, IDH1 and FGFR — and there is a lot of interest in developing drugs against those mutations.

In pancreatic cancer, [we are looking at] the homologous recombination deficiency field with mutations in genes that confer DNA damage-repair deficiency. It is very active these days. In gastroesophageal cancer, we know HER2 [exists], and there is a lot of interest now in learning what other coexisting mutations occurred together with HER2. It is a very rich area and a very high area of research.

Is there anything else occurring in the landscape that you would like to share?

Now, if you ask me which of these mutations will be the next to be clinically useful, that will probably be RAF mutations in CRC. Another interesting target is the role of HER2 in CRC. If you are to look at the future, there may be phase 2 data that may be tested and result in actionable strategy.

The other gene that is very relevant is MET, which there are drugs in development for. Additionally, FGFR in both cholangiocarcinoma and in gastric cancers is also very interesting.