HER2 Doublet Induces Durable Responses in HER2+ mCRC

John H. Strickler, MD

Tucatinib (Tukysa) in combination with trastuzumab (Herceptin) led to significant responses and survival outcomes among patients with previously treated HER2-positive metastatic colorectal cancer (mCRC) treated in the phase 2 MOUNTAINEER trial (NCT03043313), according to findings presented at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer 2022.^1,2

At a median follow-up of 20.7 months, the confirmed objective response rate (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 (DOR) of 12.4 months (95% CI, 8.5-20.5). The disease control rate (DCR) by BICR was 71.4% (TABLE¹). Reduction in tumor burden was observed in 65.0% of patients.

Further, the median progression-free survival (PFS) was 8.2 months (95% CI, 4.2-10.3), the rate of PFS at 6 months was 59.0% and 34.2% at 12 months. The median overall survival (OS) was 24.1 months (95% CI, 20.3-36.7) with a 12-month OS rate of 72.7% and a 24-month OS rate of 51.3%.

“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 in Durham, North Carolina, said in a news release.² “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 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.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.³

The ORR at 12 weeks in a cohort of patients randomly assigned to tucatinib monotherapy (n = 30) was 3.3% (95% CI, 0.1%-17.2%) with a DCR of 80%. Those who did not respond at 12 weeks or who experienced disease progression were permitted to cross over 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

Serious AEs were observed in 22.1% of patients but no deaths were reported. A total of 5.8% of patients discontinued treatment due to an AE and 25.6% of patients required a dose modification for tucatinib treatment.

The most common grade 3 or higher 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.

“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.2 “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 2020, 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 regimen in the metastatic setting.⁴

_REFERENCES:

_{1. Strickler J. MOUNTAINEER: open-label, phase 2 study of tucatinib in combination with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017). Presented at ESMO World Congress on Gastrointestinal Cancer 2022; June 29-July 2, 2022; Barcelona, Spain. Abstract LBA-2.}

_{2. 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. July 2, 2022. Accessed July 2, 2022. https://bwnews.pr/3yC4xQH}

_{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. April 20, 2020. Accessed July 2, 2022. https:// bit.ly/3nBclfs}