Treatment Strategies for HER2-Amplified mCRC

Transcript: Richard Kim, MD: HER2 amplification in colon cancers occurs about 2% to 3% of the time. It more commonly occurs in left-sided tumors, mostly in rectal tumors, and most commonly in MSS [microsatellite stable] type. And MSS type is about 5%. This is important because now there are drugs targeting the HER2 pathways. So, for example, there is a combination of trastuzumab plus pertuzumab or trastuzumab plus lapatinib showing in the refractory setting a response rate up to 30%. Therefore, in anybody with HER2 amplifications, these are the patients who we try to put on a study or possibly try to get the combination off label to use, knowing that these are the HER2-dependent tumors.

Recently at the AACR [American Association for Cancer Research annual meeting] last year, there was a case report series of patients who are HER2 amplified where they used trastuzumab as a single agent in the first-line setting. And it shows that those patients who got trastuzumab as a single agent for HER2 amplified disease had a durable response, even with a single agent. Now having said that, I think it’s too early to say that we should be using this kind of medication in the first line. I would say still in the first line in patients who are HER2-amplified, I would still go with standard chemotherapy. However, if they do progress on first-line therapy, in the second-line setting, this is where I would definitely try to bring in the HER2-targeted drugs, either on a trial basis or off-label basis based on the similar data that have been presented.

Scott Kopetz, MD, PhD: For HER2-targeted therapy, there’s a number of different options. The data that have been generated in the United States looked at trastuzumab and pertuzumab on the MyPathway study. And this showed a promising response rate above 30%, with a progression-free survival above 4 months for that population. And the thought is that this is an active regimen in this setting. There is a randomized study ongoing to confirm that benefit in the second line. And while this is on the guidelines, this is not something that’s FDA approved yet for metastatic colorectal cancer.

Similarly, there are data about trastuzumab and a tyrosine kinase inhibitor, lapatinib. This regimen has been reported in the HERACLES study. This was done predominantly in Europe, and similarly had a higher response rate and progression-free survival in a range similar to the MyPathway study. This remains an option for treatment as well. Both of these are on the NCCN [National Comprehensive Cancer Network] guidelines.

There are some really compelling recent data that have come out of the MOUNTAINEER study with tucatinib, another tyrosine kinase inhibitor, with trastuzumab. And I think there’s a lot of interest in trying to evaluate that option for patients as well. It is important to note that the data suggest that the patients with a KRAS mutation do not derive as much benefit. Whether we can say no benefit remains to be seen. But if you have a HER2 amplification and a KRAS mutation, that’s a subgroup that does not do as well with these types of targeted therapies.

It is important to note, because this is a common question that comes up, that HER2 mutations in colorectal cancer are a very different entity, and there are not good data that these are responding to HER2-directed treatment. It appears that many of those mutations are passenger mutations and may not be driver mutations in colorectal cancer like they are in at least some breast cancers.

Transcript Edited for Clarity