Tucatinib/Trastuzumab Combo Elicits Tumor Response in HER2+ mCRC

John H. Strickler, MD

Data from the phase 2 MOUNTAINEER trial (NCT03043313) showed that patients with previously treated metastatic HER2-positive colorectal cancer (mCRC) had a sustained response to treatment with dual-HER2 inhibitors tucatinib (Tukysa) plus trastuzumab (Herceptin).¹

Findings, which were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer, showed that at a median follow-up of 20.7 months the confirmed objective response (ORR) among 84 patients who received the combination was 38.1% (95% CI, 27.7%-49.3%) as assessed by blinded independent central review (BICR) with a median duration of response of 12.4 months (95% CI, 8.5-20.5). Further, the median progression-free survival was 8.2 months (95% CI, 4.2-10.3) and the median overall survival of 24.1 months (95% CI, 20.3-36.7).

“Patients with chemotherapy-refractory HER2-positive metastatic colorectal cancer receive limited clinical benefit with currently available therapies,” lead trial investigator John H. Strickler, MD, an associate professor of medicine at Duke University School of Medicine, said in a news release. “With sustained responses and favorable tolerability in heavily pretreated patients, tucatinib in combination with trastuzumab has the potential to be a new treatment option for previously treated HER2-positive mCRC.”

The pivotal MOUNTAINEER study was originally designed to include 1 cohort of patients to receive tucatinib at 300 mg twice daily and trastuzumab at 8 mg/kg intravenously on day 1 of the cycle 1 followed by 6 mg/kg on day 1 of every 21-week cycle thereafter. Investigators adapted the protocol to enroll an additional 70 patients randomly assigned 4:3 to a new cohort of the experimental regimen or tucatinib monotherapy.^2,3

The primary end point of the study was confirmed ORR in both experimental cohorts per BICR and RECIST 1.1. Secondary outcomes included ORR at 12 weeks, DOR, PFS and OS in the experimental cohorts, safety, dose modifications, and laboratory results.²

The ORR at 12 weeks in a cohort of patients who were randomly assigned to tucatinib monotherapy (n = 30) was 3.3% (95% CI, 0.1-17.2) with a disease control rate of 80%. Of note, those who did not respond at 12 weeks or experienced disease progression were permitted to crossover to the experimental treatment.¹

In terms of safety, commonly reported grade 1/2 treatment-emergent adverse effects (TEAEs) among patients who received tucatinib and trastuzumab (n = 86) were diarrhea (60.5%), fatigue (41.9%), nausea (34.9%) and infusion-related reaction (20.9%). Grade 3 or higher TEAEs included diarrhea (3.5%) and fatigue (2.3%). In terms of overall AEs observed on study, hypertension was the most common grade 3 or higher AE (7.0%).¹

No deaths were reported and 5.3% of patients discontinued treatment due to an AE.

The most common Grade ≥3 AE was hypertension (Grade 3: 7.0%). AEs leading to discontinuation of any treatment occurred in 5.8% of patients. No deaths due to AEs were reported. Please see Important Safety Information at the end of this press release for further safety information regarding tucatinib.

“This study has shown the benefits of dual-HER2 inhibition with tucatinib and trastuzumab in patients with HER2-positive metastatic colorectal cancer, including many whose cancer had spread to the liver or lungs before joining the trial,” Roger Dansey, MD, interim CEO and chief medical officer of Seagen said in the news release. “We believe this chemotherapy-free combination may play an important role in addressing the unmet needs of patients with this disease.”

Data from MOUNTAINEER will support a new drug application for patients with mCRC. In 20202, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced, unresectable, or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 1 prior anti-HER2-based regimens in the metastatic setting.⁴

References

1. Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of Tukysa (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. July 2, 2022. Accessed July 2, 2022. https://bwnews.pr/3yC4xQH
2. Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Updated June 8, 2022. Accessed July 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03043313
3. 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. 2021;39(suppl 3):TPS153. doi:10.1200/JCO.2021.39.3_suppl.TPS153
4. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed July 2, 2022. https://bit.ly/3nBclfs