Welcome to the CCO Site

Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education. 

Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.

Submit

My Take on Tucatinib and Trastuzumab for HER2-Positive Metastatic Colorectal Cancer

John Strickler, MD

Assistant Professor
Division of Medical Oncology
Department of Medicine
Duke University
Durham, North Carolina


John Strickler, MD: consultant/advisor/speaker: AbbVie, AstraZeneca, Bayer, GlaxoSmithKline, Inivata, Mereo BioPharma, Natera, Pfizer, Pionyr Immunotherapeutics, Seagen, Silverback Therapeutics, Takeda, Viatris; researcher (funds paid to institution): AbbVie, Amgen, AStar D3, Bayer, Curegenix, Daiichi Sankyo, Erasca, Gossamer Bio, Nektar, Roche/Genentech, Sanofi, Silverback Therapeutics.


View ClinicalThoughts from this Author

Released: August 10, 2022

Key Takeaways:

  • In the phase II MOUNTAINEER trial, the combination of tucatinib and trastuzumab demonstrated an overall response rate of 38% in heavily pretreated patients with HER2-positive metastatic colorectal cancer.
  • The combination was well tolerated, with diarrhea, fatigue, and nausea as the most frequent treatment-emergent adverse events, and no treatment-related deaths
  • Individuals with metastatic colorectal cancer should have their tumors tested for HER2 overexpression/amplification, particularly those patients with KRAS, NRAS, and BRAF wild-type tumors.

The relevance of ERBB2 (HER2) amplification or overexpression as a therapeutic target in metastatic colorectal cancer (mCRC) is continuing to evolve. I presented findings from the phase II MOUNTAINEER trial evaluating tucatinib and trastuzumab in patients with HER2-positive mCRC at the 2022 European Society for Medical Oncology World Congress on Gastrointestinal Cancers. Below, I discuss the potential clinical implications of the findings.

Study of Tucatinib and Trastuzumab in mCRC
HER2 amplification or overexpression is found in approximately 3% of patients with mCRC, with a higher prevalence in patients with RAS and BRAF wild‑type mCRC. Multiple anti-HER2 treatments have been successfully used in early and advanced breast cancer and other malignancies. Generally, HER2 positivity predicts sensitivity to anti‑HER2 treatment strategies. It is recommended that individuals with mCRC be tested for HER2 amplification or overexpression at diagnosis.

The global, open-label phase II MOUNTAINEER trial evaluated the efficacy and safety of tucatinib in combination with trastuzumab in 84 patients with HER2‑positive, chemotherapy‑refractory, RAS wild‑type mCRC. Trastuzumab is a recombinant monoclonal antibody against HER2 with proven efficacy in various HER2-positive solid tumors. Tucatinib is a highly selective tyrosine kinase inhibitor with minimal EGFR receptor inhibition. It is a potent inhibitor of HER2 and is associated with less rash and diarrhea than expected with other less-selective anti‑HER2 tyrosine kinase inhibitors. The combination of tucatinib and trastuzumab has shown preclinical activity in xenograft models of HER2-positive mCRC.

The MOUNTAINEER trial enrolled patients with RAS wild-type and HER2 positive mCRC with progression on or intolerance to 5-fluorouracil, oxaliplatin, irinotecan, and an anti‑VEGF monoclonal antibody. More than 80% of patients had 2 or more previous lines of therapy. Per blinded independent central review, the overall response rate (ORR; primary endpoint) was 38% in patients who received the tucatinib and trastuzumab combination, and the confirmed ORR by investigator review was 43%. Time to objective response was 2.1 months, with a disease control rate of 71%. The median duration of response was noteworthy at 12.4 months. Median progression-free survival was 8.2 months, and the median overall survival was 24.1 months, with median follow up of 20.7 months. The combination of tucatinib and trastuzumab was well tolerated, with the most common treatment-emergent adverse events (AEs) of any grade including diarrhea (52.3%), fatigue (29.1%), and nausea (18.6%). Eight patients (9%) experienced grade 3 or greater tucatinib‑related AEs, including alanine aminotransferase increase (2.3%) and diarrhea (2.3%). Trastuzumab-related AEs occurred in 7.0% of patients, with 3.5% of patients having an asymptomatic decrease in left ventricular ejection fraction (a known toxicity of trastuzumab), but there did not appear to be an elevated risk of cardiotoxicity on the study. There were no treatment-related deaths.

In addition, a randomized component to this study assessed the clinical activity of tucatinib monotherapy. Patients who received tucatinib monotherapy were allowed to cross over to receive the combination of tucatinib and trastuzumab if they had not responded by 12 weeks of treatment. In this cohort of patients receiving tucatinib monotherapy, 1 of 30 patients had a response by 12 weeks of treatment, and most patients achieved stable disease as best response. Of note, the disease control rate was high at 80%.

Clinical Implications: My Thoughts
MOUNTAINEER is the largest prospective trial, to date, for patients with previously treated HER2‑positive mCRC. We noted a high ORR at 38%, with clinically meaningful and durable responses. Overall, the combination was well tolerated, and there was a low discontinuation rate due to AEs (5.8%). Based on the favorable tolerability and high response rates, this combination has the potential to become a new standard of care in patients with chemotherapy‑refractory, HER2‑positive mCRC. These data support ongoing efforts to explore the tucatinib and trastuzumab combination in earlier lines of therapy, including the ongoing MOUNTAINEER‑03 trial comparing tucatinib/trastuzumab and FOLFOX in the first‑line setting against standard of care.

In clinical practice, these data may be most important to our patients with left‑sided primary tumors with RAS and BRAF wild‑type disease, where HER2 amplification or overexpression tend to be most common. HER2 amplification or overexpression may be associated with resistance to anti‑EGFR therapies, which are the current standard of care for patients with RAS and BRAF wild‑type left‑sided mCRC.

To date, guidelines list several anti‑HER2 regimens as options for patients with chemotherapy‑refractory, HER2‑amplified, RAS/BRAF-wildtype mCRC, but there are currently no FDA-approved HER2-targeted therapies for mCRC. Hopefully, these findings will support potential registration of this combination so it will be become available to all patients and improve accessibility. 

These study findings also reinforce the need to routinely test for HER2 amplification or overexpression at diagnosis of mCRC, particularly in patients with KRAS, NRAS, and BRAF wild‑type left‑sided primary tumors. As we have seen, HER2 is an actionable target with implications for patient management.

Your Thoughts?
What are your biggest challenges when caring for patients with HER2‑positive, previously treated mCRC? We encourage you to answer the polling question and join the conversation in the discussion box below.


Provided by Clinical Care Options, LLC.

Contact Clinical Care Options

For customer support please email: customersupport@cealliance.com

Mailing Address
Clinical Care Options, LLC
12001 Sunrise Valley Drive
Suite 300
Reston, VA 20191

Supported by educational grants from
Bristol-Myers Squibb
Seagen Inc.

Leaving the CCO site

You are now leaving the CCO site. The new destination site may have different terms of use and privacy policy.

Continue

Cookie Settings