Evolving Treatment Landscape in Metastatic Colorectal Cancer

Transcript:

Tanios S. Bekaii-Saab, MD:It’s becoming quite a complicated landscape, which is great, that’s what we want. I want my life to be complicated because that means I’m going to do better for my patients; I have more options in hand. You know, 20-plus years ago, I didn’t have that many options. Ten years ago, I only had one target, KRAS [Kirsten rat sarcoma viral oncogene homolog] exon 2 [mutations], which told me I cannot use an EGFR [epidermal growth factor receptor] inhibitor. So, it was a negative predictive biomarker. Today, we have a number of targets, including even targeting KRAS, which is pretty amazing by itself. We never thought we would be able to target what we call the undruggable. Now we do that, we look at way more targets from the beginning to decide how we want to best optimize the treatment of our patients. The targets of relevance are KRAS, HER2 [human epidermal growth factor 2], MSI [microsatellite instability]-high tumors, and NTRK [neurotrophic tyrosine kinase receptor] fusions, red fusions. Now there’s a BRAF V600E [gene] and HER2 amplifications, and a lot of others. We really need to have all these targets or identify those targets because we have so many agents now that can turn around even the smallest subset of patients into more favorable biology and getting extension of survival for our patients.

When we think about first line, you have at least 4 elements that we need: HER2 amplifications, MSI-high [status], BRAF V600E, and KRAS. Just as a broad stroke, if you have a left-sided tumor that is RAS wild type, BRAF wild type, and HER2 nonamplified, those patients would do best with an EGFR inhibitor added to a doublet. Although one can argue that you can still do a triplet with bevacizumab [Avastin]. So, for FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan], FOLFIRINOX with bevacizumab, that would be a viable option. For those patients with right-sided tumors, regardless of the mutational status, for BRAF V600E or for RAS, those patients tend not to respond well to EGFR inhibitors, so those would receive primarily bevacizumab. I prefer also the triplet because they tend to be a little bit more aggressive. Then we have a number of in between, so the gray. But most of the gray’s right in the middle.

Now, the importance of having HER2 amplifications tested early, in addition to excluding patients from receiving EGFR inhibitors and planning what comes next beyond the first line, we have now a study called MOUNTAINEER III [NCT05253651] that’s assessing the role of tucatinib [Tukysa] and trastuzumab [Herceptin] in addition to FOLFOX versus FOLFOX and standard-of-care biologic. And it’s important to be able to identify those patients early, as we’ve seen those benefits in later lines of therapy, which we’ll be talking briefly about, as well. So, it’s very important to have all these elements tested early. Now, what do the data show us? At least from the clinical practice standpoint today and how to use these HER2-targeted strategies in patients with metastatic colorectal cancer that overexpress HER2. This is about 2% to 4% percent of the patients, so it’s not uncommon, but it’s not rare to see a HER2-amplified tumor. If we look consistently for them, we’re going to find those patients at the same rate we’ll find MSI high, a little bit less than BRAF V600E, more than KRAS G12C, just to put that in perspective. It’s not an impossible target. It’s actually an uncommon, but not rare, target.

We have multiple studies over the last 10-plus years that looked at different ways to target HER2. There are multiple ways for us to target HER2. So, the backbone of all this is an agent called trastuzumab, which targets HER2 directly, established in both breast cancer and gastric cancer. [Trastuzumab] didn’t show as much activity on its own in colorectal cancer. It seemed like it needed some help for biologic reasons. Either the addition of an agent called pertuzumab, which essentially targets the dimerization site, which is needed for activation of the pathway. Or what we call vertical inhibition, which is a little bit more effective way to do that, that’s by adding a tyrosine kinase inhibitor, hitting the target intracellularly and extracellularly with trastuzumab. That was the first rationale for the study with trastuzumab lapatinib, which is an older TKI that’s a little bit less clean, less potent than tucatinib, which showed interesting results. Then the HERACLES study [NCT03225937], which looked at trastuzumab and pertuzumab, which also showed consistently interesting results. Before we ultimately got to trastuzumab-tucatinib, tucatinib is an oral tyrosine kinase inhibitor that is essentially a more potent cleaner because it doesn’t have that EGFR background noise, etc., which improves its toxicity profile. But at the same time, you also get a significantly, at least theoretically, more potent, higher level of activity at the clinical proposed dose.

So, the first study with trastuzumab and tucatinib, called MOUNTAINEER [NCT03043313], was conducted over the last few years. And then [the study] ultimately showed a very promising response rate of 38.1% duration of response of 12.4 month and median overall survival of 24 months in a very refractory patient population. This study essentially started as cohort A, a single-arm study, which was an investigator-initiated trial going through the ACCRU [Academic & Community Cancer Research United] research consortium under the auspices of Mayo Clinic. And then ultimately it moved on into a phase 2 randomized study with trastuzumab tucatinib vs tucatinib alone, just to understand what is trastuzumab adding to tucatinib, with a crossover design. The gist of it, the study met its primary end point and was approved by the FDA on an accelerated basis January 19, 2023. Now it has become available for patients in actual practice and also was attached to MOUNTAINEER III, which is the registration trial in the first line looking at tucatinib-trastuzumab.

Transcript edited for clarity.