Dr Muslimani on Unanswered Questions to be Addressed in HER2+ mCRC

Alaa Muslimani, MD, oncologist and hematologist, Hematology and Medical Oncology, Atrium Health Levine Cancer Institute, discusses unanswered questions in the treatment of patients with metastatic colorectal cancer (mCRC), highlighting how these unmet needs may be addressed through continued research.

When discussing future avenues for research in HER2-positive mCRC, it is important to note that not all HER2-positive solid tumors exhibit the same response to a given therapeutic agent. An example of this can be seen in the phase 2 DESTINY-CRC01 trial (NCT03384940) investigatingfam-trastuzumab deruxtecan-nxki (Enhertu), Muslimani begins.

Final analysis from the phase 2 trial showed that the agent produced durable responses and had a safety profile consistent with what has been previously been seen within the space. In cohort A, patients with HER2-positive disease had an overall response rate (ORR) of 45.3%. The disease control rate was 83%, and the median duration of response was 7 months. However, patients who had borderline HER2-positive mCRC, or had an IHC of 2+ and negative ISH, did not experience significant responses with T-DXd, Muslimani reports. The lack of response in this population is noticeably different from typical response rates in patients with breast cancer who display the same profile, Muslimani adds.

Additionally, no first-line therapies have been FDA approved for use in HER2-positive mCRC, and there is a lack of trials providing strong evidence for novel therapeutic options in this space, Muslimani states. To address this unmet need, the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) is currently evaluating the use of tucatinib (Tukysa) and trastuzumab (Herceptin) plus mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin) vs mFOLFOX with and without bevacizumab (Avastin) or cetuximab (Erbitux) in the frontline setting.

Patients with HER2-positive mCRC also appear to have poorer prognosis compared with those who have other HER2-positive solid tumors, Muslimani continues. For example, patients with HER2-positive mCRC are known to have a high risk of developing brain metastases, which can negatively affect their treatment outcomes, he states.

Lastly, clinical trials in HER2-positive mCRC typically enroll a limited number of patients compared with study populations for other HER2-positive solid tumors, Muslimani says. Ultimately, more trials with a larger patient population should be conducted to better understand the disease biology of HER2-positive mCRC, Muslimani concludes.

Disclosures: Dr Muslimani reports serving in an advisory role for Seagen.