Ongoing Research Seeks to Optimize Targeted Therapy Use in mCRC

Aparna Parikh, MD

Targeted therapy has been integrated into later-line settings for patients with metastatic colorectal cancer (mCRC) harboring actionable mutations, and ongoing research could help optimize treatment for select patient populations by bringing these types of treatments to earlier settings, according to Aparna Parikh, MD.

“Molecular testing is now considered to be standard of care at the time of diagnosis for mCRC. It is imperative the patients get tested,” Parikh stated in an interview with OncLive^® following a State of the Science Summit^™, which she chaired.

In the interview, Parikh expanded on novel targeted therapies under investigation in mCRC, and targeted therapy options currently available in the clinical for different patient populations.

Parikh is an associate professor of medicine at Harvard Medical School and an assistant in Medicine, Hematology, and Oncology at Massachusetts General Hospital, both located in Boston, Massachusetts. She also serves as an attending oncologist in the Tucker Gosnell Center for Gastrointestinal Cancers and the Henri and Belinda Termeer Center for Targeted Therapies.

OncLive: As the mCRC treatment paradigm has expanded beyond traditional chemotherapy-based approaches, what is the importance of molecular testing?

Parikh: There are first-line [treatments] options for patients with microsatellite instability-high [disease], with those individuals being eligible for [immune] checkpoint inhibitors.

Several targeted therapies, including BRAF- and HER2[-directed therapies], are available for patients in the second line and beyond. Increasingly, we're seeing clinical trials looking at bringing those targeted therapies up to the first line of therapy. It is imperative that patients get [molecular] testing, and I foresee in the near-term future that those targeted therapies will come up in earlier lines of therapy as well.

Editor’s note: This interview was conducted prior to the December 20, 2024, FDA accelerated approval of first-line encorafenib (Braftovi) plus cetuximab (Erbitux) and mFOLFOX6 for patients with BRAF V600E–mutated mCRC.

What are some of the key molecular targeted treatment options in mCRC, and which trials build on these insights?

For targeted therapy in CRC, I will not include immunotherapy as a part of [that discussion]. Immunotherapy is a molecular-driven option for patients, but it is not considered to be a targeted therapy. Targeted therapy is a different type of therapy than immunotherapy, and targeted therapy approaches that are available for CRC currently fall into a couple different buckets.

It is important to mention RAS status. Patients who are RAS wild-type—especially patients who have left-sided tumors—are eligible for anti-EGFR therapy, which is a targeted therapy that has been well-established for over a decade. In terms of mutations or other alterations, such as amplifications, we have the BRAF V600E mutation, which is [present in] approximately 5% to 10% of [patients with] mCRC. Those patients are eligible for the BEACON regimen [in the second-line setting], which is a combination of the BRAF inhibitor encorafenib and an anti-EGFR inhibitor cetuximab, after progression on first-line chemotherapy. This was evaluated in the phase 3 BEACON CRC trial [NCT02928224] that established the clinical utility of that regimen. That regimen was tested in the first line in combination with chemotherapy in the phase 3 BREAKWATER study [NCT04607421].

Another targeted option is HER2. In CRC, we see more HER2 amplifications rather than mutations. There are a couple of different options for patients with HER2-positive disease. The first option is from the phase 2 MOUNTAINEER trial [NCT03043313] regimen of trastuzumab [Herceptin] plus tucatinib [Tukysa], which is a small molecule HER2 inhibitor. [This regimen is approved by the FDA] in the second line for patients with HER2-positive mCRC.

How have other agents, such as antibody-drug conjugates (ADCs) come into play in the CRC treatment space?

Alongside the MOUNTAINEER data, there are also data around a newer-in-CRC ADC called fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], which has effectiveness in patients with HER2-high disease. The indications for T-DXd, or in terms of how I think about it, are patients who have truly amplified HER2 by fluorescence in situ hybridization or immunohistochemistry, and we will often sequence T-DXd after trastuzumab plus tucatinib. There are data suggesting that T-DXd is effective after prior HER2-directed therapy or if a patient happens to have a KRAS mutation. Those patients [with KRAS mutations] would also be eligible for T-DXd. We could perhaps swap out trastuzumab plus tucatinib for T-DXd if a patient’s [tumor] is HER2 amplified and has a RAS mutation; however, this is not that common.

What are some ongoing studies that might bring options into the earlier lines of therapy in this space?

We're looking at the phase 3 MOUNTAINEER-03 trial [NCT05253651], which is looking at the [addition of] chemotherapy to the MOUNTAINEER regimen in the first-line setting for the HER2-positive patient population.

There is a whole pipeline of new RAS-targeted therapies that are coming, such as pan-KRAS inhibitors and pan-RAS inhibitors. We have an option for KRAS G12C–targeted therapy in patients who have KRAS G12C alterations. KRAS G12D mutations are another target with drugs currently in clinical trials.