Key US-Based HER2 CRC Clinical Trials

Kanwal Raghav, MD, MBBS, references several HER2 clinical trials, each presenting unique drug combinations to address metastatic colorectal cancer.

Kanwal Raghav, MD, MBBS: Let’s talk a little about some of the clinical trials that form the basis of the NCCN [National Comprehensive Cancer Network] recommendations when it comes to targeting HER2 in colorectal cancer. There are 2 broad categories of these trials that we’ve looked at. The first category is what’s called dual HER2 inhibition—cases where we’ve used 2 agents directed against HER2 because preclinical data and certain clinical data have shown us that single-agent HER2 inhibition doesn’t work very well in colorectal cancer.

Three of these trials have been done across the world. The first one was the HERACLES study [NCT0322593], which was done in Europe. Then there were the MyPathway [NCT02091141] and MOUNTAINEER [NCT03043313] studies. They differ in the type of agents that they use. The HERACLES study used trastuzumab, which is an antibody against HER2, along with lapatinib, which is a small-molecule tyrosine kinase inhibitor. MyPathway used trastuzumab and pertuzumab, which are both IV [intravenous] antibodies. The MOUNTAINEER study used trastuzumab and a next-generation small-molecule tyrosine kinase inhibitor called tucatinib. All 3 of these studies were done in essentially a refractory colorectal cancer population, so these patients have had prior lines of systemic therapies and were heavily pre-treated. They all showed promising activity.

The mode of patient selection was a bit different in each. For example, HERACLES only used a central screening with HER2 IHC [immunohistochemistry] as well as ISH [in situ hybridization]. On the other hand, the MyPathway study used any clear certified test that showed HER2 amplification or overexpression, similar to the MOUNTAINEER study, and they showed response rates of anywhere between 35% and 50%. I don’t think we have enough data to suggest that one of these combinations is better than the other because there’s no randomized comparison and it could be partly due to patient selection. The bottom line is that dual anti-HER2 inhibition works very well in patients who have treatment-refractory metastatic colorectal cancer and HER2 overexpression or amplification. They’re also very well-tolerated treatments overall compared with other options in colorectal cancer.

The second category of HER2 trials is using HER2 as a beacon for targeted chemotherapy, which is the HER2 antibody-drug conjugate [ADC]. As you can see, the story of HER2 targeting in colorectal cancer is very much following the similar paradigms as was done in breast cancer, wherein the antibody small-molecule tyrosine kinase inhibitors came in first followed by ADCs.

The main trial that showed this efficacy was the DESTINY-CRC01 study [ CT03384940]. This is a drug called trastuzumab deruxtecan. This is an ADC of HER2 with a topoisomerase inhibitor payload. This payload is very robust and highly active in colorectal cancer. This study involved patients who were pre-treated with other anti-HER2 therapies, specifically dual anti-HER2 inhibition. They looked at HER2 overexpressed in amplified patients and found a response rate of about 40% to 50%, which was in a highly treatment-refractory population. They found that this activity was even present when patients were pre-treated with anti-HER2 agents. This agent has previously shown activity in both HER2-naive and HER2-treated patients.

There are other ongoing clinical trials. SWOG 1613 is a randomized trial for the MyPathway combination, trastuzumab-pertuzumab, compared with cetuximab-irinotecan, which would be second-line standard of care. There’s a randomized portion of the MOUNTAINEER study that’s comparing trastuzumab-tucatinib with tucatinib alone. There’s the DESTINY-CRC02 study, which is comparing 2 different doses of trastuzumab deruxtecan in HER2-amplified or HER2-overexpressed colorectal cancer.

We haven’t noticed as much discrepancy in the clinical trial population vs real life as far as HER2-amplified or HER2-overexpressed patients are concerned. We have to remember that this is a small subset of patients with colorectal cancer so we often try to enroll as many of these patients in clinical trials as possible. Most of these patients have pretty good PS [performance status] and organ function, hence the need to identify these patients earlier on in their treatment continuum so that we can direct them toward appropriate clinical trials.

Transcript edited for clarity.

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