Tanios S. Bekaii-Saab, MD, Reflects on How Targeted Therapy Regimens Will Push Precision Approaches in CRC

At the 2022 American Society of Clinical Oncology Annual Meeting, Tanios S. Bekaii-Saab, MD, Gastrointestinal Cancer Program lead at the Mayo Clinic Cancer Center and medical director of the Cancer Clinical Research Office as well as vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona, spoke with CancerNetwork^® about the ongoing phase 2 MOUNTAINEER trial (NCT03043313) of tucatinib (Tukysa) plus trastuzumab (Herceptin) for patients with metastatic colorectal cancer (CRC) and other similar combination being explored in this patient population.¹ Going forward, he foresees the treatment landscape evolving to rely more heavily on tumor genotyping to select therapy for patients with metastatic tumors.

Transcript:

Here’s the good news. There is a follow-up study called the MOUNTAINEER-03 trial [NCT05253651] that is looking at moving this to the first line. [The MOUNTAINEER] trial was in the refractory setting, and we have never looked at first-line strategies with HER2-positive metastatic [CRC. MOUNTAINEER-03 is looking at] moving it to the first line in combination with chemotherapy. The hope is that whatever advantages we’re going to see in the refractory setting will translate to an even bigger scale in the first line.

That becomes exciting because we know BRAF-directed strategies have moved to being researched in the first line after being approved in later lines, with or without combinations of chemotherapy. What we’re going to be looking at is essentially the number of first line options, including biologics, getting diversified in colon cancer. The way we foresee this is if you have MSI [microsatellite instability]–high disease, you get pembrolizumab [Keytruda] or another PD-1 inhibitor. If the BREAKWATER [study; NCT04607421] shows that adding the BRAF inhibitor encorafenib [Braftovi] to cetuximab [Erbitux] and chemotherapy is positive, then patients with BRAF V600E–mutated tumors will receive this regimen.

If MOUNTAINEER-03 ends up being positive in the first line, that could create an opportunity for HER2-amplified tumors. We have seen that left-sided, KRAS wild-type tumors from the PARADIGM trial [NCT02394795] preferentially seem to respond better to panitumumab [Vectibix] plus chemotherapy [vs bevacizumab (Avastin)/chemotherapy], so that’s an option.² We’ve moved a lot of the strategies that were initially tested in the later lines into the first line, and that will continue to move [CRC] to where we want it to be. Then we have the [targeting of] KRAS G12C moving to the second line in the phase 2 KRYSTAL-10 trial [NCT04793958] with adagrasib plus cetuximab vs chemotherapy, and that [accounts for] a small subset of KRAS mutations—about 2%. That will continue to expand, and there’s KRAS G12D targeted agents and others that are in development that are exciting as well.

You can imagine a few years from now that we’re going to genotype [CRC] tumors from day one and be able to assign them to the correct targeted strategy at some point in the next few years. That’s exciting. This is coming from 10 to 12 years prior when we only had RAS [as a therapeutic indicator]. We’re going to move the world of [CRC] from a binary world to small subgroups that we can very specifically target.

References

1. Strickler JH, Ng K, Cercek A, et al. MOUNTAINEER: open-label, phase II study of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017, trial in progress). J Clin Oncol. 2022;40(suppl 3):TPS153. doi:10.1200/JCO.2022.40.4_suppl.TPS153
2. Yoshino T, Watanabe J, Shitara K, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): results from the phase 3 PARADIGM trial. J Clin Oncol. 2022;40(suppl 17):LBA1. doi:10.1200/JCO.2022.40.17_suppl.LBA1