Additional analyses of the phase 2 MOUNTAINEER trial further support the early administration of tucatinib in combination with trastuzumab as an optimal treatment strategy for patients with previously treated HER2-positive metastatic colorectal cancer.
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.
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.
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 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.
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.
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.
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.
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