MOUNTAINEER Data Confirm Clinical Benefit of Tucatinib Plus Trastuzumab in HER2+ mCRC

John H. Strickler, MD

Additional analyses of the phase 2 MOUNTAINEER trial (NCT04262466) further support the early administration of tucatinib (Tukysa) in combination with trastuzumab (Herceptin) as an optimal treatment strategy for patients with previously treated HER2-positive metastatic colorectal cancer (mCRC), according to John H. Strickler, MD.

Updated findings from cohort C of the trial, which were presented at the 2022 ESMO Congress, showed that patients who received tucatinib monotherapy (n = 30) had an overall response rate (ORR) of 3.3% (95% CI, 0.1%-17.2%), with 1 patient experiencing a partial response. Stable disease was reported in 76.7% of patients for a disease control rate (DCR) of 80%. Protocol allowed for crossover and among the 28 patients who went on to receive the combination, the ORR was 17.9% (95% CI, 6.1%-36.9%), with 5 partial responses and 18 patients with stable disease for a DCR of 82.1%.

Safety data showed that both tucatinib monotherapy and the combination regimen were well tolerated by patients, and findings were consistent with the safety profile of tucatinib.In cohort C, 26.7% of patients experienced an AE grade 3 or higher. Post crossover, newly onset or worsened adverse effects (AEs) of grade 3 or higher were reported among 21.4% of patients.

[Although] the ORR was low for tucatinib [alone], the DCR was surprisingly high [at] 80%,” said Strickler, an associate professor of medicine at Duke University School of Medicine and a medical oncologist at Duke Cancer Center. “We also saw that we can convert nonresponders to responders by adding trastuzumab to tucatinib. [This indicates] that the optimal [treatment] strategy [for an individual] with HER2-positive mCRC is to combine tucatinib and trastuzumab at the very beginning [of treatment]. That [combination] generates the highest response rates, shows excellent disease control, and [leads to] a median duration of response exceeding a year.”

In an interview with OncLive^®, Strickler discussed key safety and efficacy data from MOUNTAINEER, continuing investigations engendered by these findings, and the potential benefits of anti-HER2 therapy in this patient population.

OncLive^®: What was the rationale for evaluating a dual HER2-targeted therapy for patients with RAS wild-type mCRC in theMOUNTAINEER trial?

Strickler: HER2 [overexpression] is seen in approximately 3% of patients with mCRC and we’ve seen rates up to 10% or more in patients with RAS and BRAF wild-type disease. The tyrosine kinase inhibitor tucatinib is a highly selective oral therapy that’s already shown activity in other tumor types, [such as] breast cancer, and in preclinical xenograft models of HER2-positive CRC. It’s been noted that the combination of trastuzumab and tucatinib is a potent inhibitor of tumor growth and is more active than either trastuzumab or tucatinib alone.

Please expand on the trial design and patient population of MOUNTAINEER.

MOUNTAINEER was an open-label, global, phase 2 study. It enrolled patients with RAS wild-type mCRC that had progressed on prior [fluoropyrimidines], oxaliplatin, irinotecan, and anti-VEGF [monoclonal] antibodies. All patients enrolled had HER2-positive disease by local testing, and that could have been immunohistochemistry, FISH [fluorescence in situ hybridization], or next-generation sequencing [NGS].

These patients were initially enrolled into cohort A, which was a pilot cohort of tucatinib and trastuzumab in combination. Based on very favorable results from that initial experience, the study was expanded. There was a randomization when the study was expanded to cohort B, which was the tucatinib/trastuzumab combination or cohort C, which was tucatinib by itself.

What key results were presented at the ESMO Congress?

What we presented prior [to the congress] were the response rates for cohorts A and B. [Patients in those cohorts received the] combination of tucatinib and trastuzumab which showed a robust ORR of 38%, confirmed by blinded independent central review.

What we show [here are] the [data from] cohort C of tucatinib monotherapy. In that cohort, we [saw] a lower response rate of 3% for tucatinib [alone. However,] this study did allow those patients assigned to cohort C to cross over to the tucatinib/trastuzumab combination [cohort] if they had not responded by 12 weeks of treatment. Post crossover, the ORR was [approximately] 18% with a DCR of 82%, so we did see [more favorable] responses after combining tucatinib with trastuzumab.

For patients experiencing [AEs] and toxicity [from] chemotherapy, this is a welcome relief. Most [AEs] are manageable, and it’s fairly rare for [AEs] to lead to tucatinib discontinuation or dose reduction. [Tucatinib plus trastuzumab] represents not just an active regimen, but a regimen that provides many patients [with] a high quality of life.

How might these results change the current treatment landscape for this patient population?

Our initial goal with MOUNTAINEER was to make tucatinib and trastuzumab an option for patients with HER2-positive mCRC. [One] exciting component of [our analysis] is that we [observed] much higher response rates than expected [beyond the first-line] setting. [These] response rates [were also observed] in a tolerability profile that’s very favorable. [Accordingly, we hope] that this will become a standard-of-care option in the future for these patients.

What next steps are planned for this research?

Based on these very promising results from the MOUNTAINEER study…we will be launching MOUNTAINEER-03 [NCT05253651]. [This] first-line study will [evaluate] tucatinib and trastuzumab [in combination] with [modified FOLFOX6]. Patients will be [randomly assigned to either] tucatinib, trastuzumab, and mFOLFOX6 or standard of care in the frontline setting. We’re hoping that [resulting] data, [will also support] this [therapy as] a potential first-line option.

What should your colleagues ultimately take away from this presentation?

The key takeaway is that HER2 is an actionable target. [It] is a biomarker that we can use to select patients away from certain therapies that will be less active, [such as] anti-EGFR therapies, but it’s also a biomarker that we can use to select for therapies that will be more active [in some] patients. These anti-HER2 regimens [often] offer patients strong clinical benefit and high response rates. In some cases [they even offer] long duration of response and a very favorable tolerability profile.

Reference

Strickler JH, Cercek A, Siena S, et al. Additional analyses of MOUNTAINEER: a phase II study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol. 2022;33(suppl 7):S1394. doi:10.1016/j.annonc.2022.08.023