In the phase II MOUNTAINEER trial, tucatinib in combination with trastuzumab produced durable responses in patients with previously treated HER2-positive metastatic colorectal cancer. The late-breaking data were presented at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancers by John H. Strickler, MD, Associate Professor of Medicine, Duke University School of Medicine, Durham, North Carolina.¹

John H. Strickler, MD

“MOUNTAINEER is the largest prospective trial to date for patients with previously treated HER2-positive metastatic colorectal cancer. Based on the robust clinical activity and favorable tolerability, the combination of tucatinib and trastuzumab has the potential to become a new standard-of-care option. These results also provide rationale for continued investigation of tucatinib in combination with trastuzumab in earlier lines of therapy,” Dr. Strickler said in an interview with The ASCO Post.

At a median duration of follow-up of 20.7 months, the 86 patients treated with tucatinib and trastuzumab had a 38.1% confirmed objective response rate by blinded independent central review and a disease control rate of 71.4%. The median duration of response was 12.4 months, median progression-free survival was 8.2 months, and median overall survival was 24.1 months.

At 12 months, 34.2% of patients receiving tucatinib/trastuzumab were free of disease progression and 72.7% were alive. At 24 months, 51.3% were alive.

In a smaller cohort of patients who received tucatinib monotherapy, the response rate at 12 weeks was 3.3%, and the disease control rate was 80.0%. Participants who did not respond to tucatinib monotherapy by 12 weeks or had disease progression at any time had the option to receive the combination of tucatinib and trastuzumab.

Tucatinib in combination with trastuzumab was well tolerated, with a low treatment discontinuation rate. Diarrhea, an adverse event of potential concern, was predominantly low-grade and manageable, he added.

Rationale, Study Details

As Dr. Strickler pointed out, up to 3% of patients with metastatic colorectal cancer and approximately 10% with RAS/BRAF wild-type tumors have HER2 amplification or overexpression. Tucatinib is a highly selective tyrosine kinase inhibitor for HER2, with minimal inhibitory effect on the epidermal growth factor receptor. The combination of tucatinib and trastuzumab has shown strong activity in patient-derived xenograft models.

MOUNTAINEER is evaluating the efficacy and safety of this combination in patients with HER2-positive and RAS wild-type metastatic colorectal cancer previously treated for metastatic disease. About three-quarters of patients had received at least two prior lines of therapy.

The U.S. and European multicenter open-label randomized phase II trial enrolled 86 patients into the combination cohorts; 31 were treated with single-agent tucatinib. At study entry, 64.3% of the patients had liver metastases and 70.2% had lung metastases; patients had received a median of three prior lines of therapy. Approximately 85% of patients had tumors in the left side of the colon or rectum.

MOUNTAINEER began as a U.S. investigator–sponsored trial and initially consisted of a single cohort of patients who received tucatinib, 300 mg twice per day, plus trastuzumab (cohort A). The trial was then expanded globally to include patients who were randomly assigned to receive tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint of the trial is confirmed objective response rate by blinded independent central review in patients receiving the combination of tucatinib and trastuzumab (cohorts A and B).

Combination Well Tolerated

The most common treatment-emergent adverse events in patients treated with tucatinib and trastuzumab were diarrhea (60% grade 1/2 and 3% grade 3); fatigue (42% grade 1/2 and 2% grade 3); nausea (35% grade 1/2); and infusion-related reaction (21% grade 1/2). The most common grade ≥ 3 toxicity was hypertension (7%).

Adverse events of special interest for the combination include diarrhea, hepatoxicity, and cardiotoxicity. Grade 3 diarrhea occurred in 3% of patients and did not necessitate treatment discontinuation. Because of diarrhea, tucatinib doses were modified or held for 6% of patients. Antidiarrheal prophylaxis was not mandated, Dr. Strickler said.

Grade ≥ 3 hepatotoxicity included increased alanine aminotransferase in 3%, increased aspartate transaminase in 2%, and hypertransaminasemia in 1%. Approximately 6% of patients had tucatinib doses modified or discontinued because of hepatotoxicity. Approximately 4% of patients had doses reduced or stopped because of asymptomatic left-ventricular function decrease.

The most common tucatinib-related events were diarrhea, fatigue, nausea, and dermatitis acneiform, but grade ≥ 3 toxicities were limited to alanine aminotransferase increase (2%) and diarrhea (2%). Adverse events leading to discontinuation of any treatment occurred in about 6% of patients. No deaths due to toxicity were reported.

Data from this trial will form the basis of a planned supplemental new drug application to the U.S. Food and Drug Administration under the Accelerated Approval Program. The ongoing phase III MOUNTAINEER-03 trial will compare tucatinib plus trastuzumab plus modified FOLFOX6 (mFOLFOX6; fluorouracil, leucovorin, oxaliplatin) vs mFOLFOX6 with or without bevacizumab or cetuximab in 400 patients. 

DISCLOSURE: Dr. Strickler has served as an advisor or consultant to AbbVie, Takeda, AstraZeneca, Bayer, GSK, Inivata, Natera, Pfizer, Seagen, Silverback Therapeutics, and Viatris; and has received research support from Amgen, Bayer, Erasca, Seagen, Daiichi-Sankyo, Gossamer Bio, AStar D3, Sanofi, Roche/Genentech, Curegenix, Nektar, AbbVie, and Silverback Therapeutics.

REFERENCE

1. Strickler JH, Cercek A, Siena S, et al: MOUNTAINEER: Open-label, phase 2 study of tucatinib in combination with trastuzumab for HER2-positive metastatic colorectal cancer. ESMO World Congress on Gastrointestinal Cancers 2022. Abstract LBA-2. Presented July 2, 2022.