FDA Grants Priority Review to Tucatinib/Trastuzumab Combo for Previously Treated HER2+ mCRC

The FDA has granted a priority review to a supplemental new drug application (sNDA) seeking the approval of tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) in adult patients with HER2-positive colorectal cancer (CRC) who have received at least 1 prior treatment regimen for unresectable or metastatic disease.¹

The application is supported by findings from the phase 2 MOUNTAINEER trial (NCT03043313). At a median follow-up of 20.7 months, the doublet induced a confirmed objective response rate (ORR) of 38.1% (95% CI, 27.7%-49.3%) per blinded independent central review (BICR) in this population (n = 84), with a median duration of response (DOR) of 12.4 months (95% CI, 8.5-20.5).² Additionally, the median progression-free survival (PFS) achieved with tucatinib plus trastuzumab was 8.2 months (95% CI, 4.2-10.3), and the median overall survival (OS) was 24.1 months (95% CI, 20.3-36.7).

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the sNDA by January 19, 2023.

“There are currently no FDA-approved therapies for metastatic CRC [mCRC] that specifically target HER2,” Marjorie Green, MD, senior vice president and head of Late-Stage Development at Seagen, stated in a press release. “The FDA’s prioritization of our application for tucatinib in combination with trastuzumab supports our belief in its significant potential to benefit people with previously treated HER2-positive mCRC.”

The original design of the MOUNTAINEER study was to include 1 cohort of patients, who would receive tucatinib at a twice-daily dose of 300 mg in combination with trastuzumab at a dose of 8 mg/kg on day 1 of the first cycle followed by 6 mg/kg on day 1 of every 21-week cycle thereafter. The protocol was adapted to enroll an additional 70 patients, who were randomly assigned in a 4:3 fashion to a new cohort, where they received the doublet or single-agent tucatinib.^3,4

ORR in both investigative cohorts by BICR and RECIST v1.1 criteria served as the primary end point of the research. Secondary end points comprised 12-week ORR, DOR, PFS, and OS in the investigative cohorts, as well as safety, dose modifications, and laboratory data.³

Additional findings presented during the 2022 ESMO World Congress on Gastrointestinal Cancer indicated that at 12 weeks, the ORR was 3.3% (95% CI, 0.1%-17.2%) in the cohort of participants who received tucatinib monotherapy (n = 30); the disease control rate in these patients was 80%. Those who did not respond at this time point or who experienced progressive disease were allowed to crossover to receive the doublet.²

The most common grade 1 or 2 treatment-emergent adverse effects (TEAEs) in those who received tucatinib plus trastuzumab (n = 86) included diarrhea (60.5%), fatigue (41.9%), nausea (34.9%), and infusion-related reactions (20.9%). TEAEs that were grade 3 or higher in severity comprised diarrhea and fatigue, which occurred in 3.5% and 2.3% of patients, respectively. Overall, hypertension was the most frequently experienced grade 3 or higher AE (7.0%).²

Moreover, 5.8% of patients experienced an AE that resulted in treatment discontinuation. Notably, no deaths occurred.

The phase 3 MOUNTAINEER-03 trial (NCT05253651), which is examining the combination of tucatinib/trastuzumab and mFOLFOX6 (oxaliplatin, leucovorin, levoleucovorin, and fluorouracil) compared with standard-of-care therapy in the frontline treatment of patients with HER2-positive mCRC, was initiated in February 2022.⁵

The trial is enrolling those with histologically and/or cytologically confirmed, metastatic and/or unresectable adenocarcinoma of the colon or rectum. Participants must have HER2 positivity per a tissue-based assay performed at a central laboratory, radiographically measurable disease by RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.⁵ Patients should have no evidence of brain metastases or previously treated brain metastases that are asymptomatic.

The primary outcome measure for the research is PFS by RECIST v1.1 criteria and BICR. Secondary outcome measures included OS as well as confirmed ORR and DOR per RECIST v1.1 criteria and BICR. Other outcome measures included PFS, confirmed ORR, and DOR per RECIST v1.1 criteria and investigator assessment. Time to second progression or death, incidence of AEs, incidence of dose alterations, and patient-related outcome measures will also be evaluated.

This trial is intended to serve as a confirmatory trial in the United States and to support global filings, according to a press release issued by Seagen.

References

1. Seagen announces Tukysa (tucatinib) in combination with trastuzumab granted priority review by FDA for previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. September 19, 2022. Accessed September 19, 2022. https://bit.ly/3DyydRB
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 Inc. July 2, 2022. Accessed September 19, 2022. https://bwnews.pr/3yC4xQH
3. Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Updated June 8, 2022. Accessed September 19, 2022. https://clinicaltrials.gov/ct2/show/NCT03043313
4. 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
5. A study of tucatinib with trastuzumab and mFOLFOX6 versus standard of care treatment in first-line HER2+ metastatic colorectal cancer (MOUNTAINEER-03). Clinicaltrials.gov. Updated September 6, 2022. Accessed September 19, 2022. https://clinicaltrials.gov/ct2/show/NCT05253651