Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Patients with chemotherapy-refractory metastatic colorectal cancer (CRC) positive for HER2 expression may benefit from tucatinib plus trastuzumab, the MOUNTAINEER investigators have reported at the ESMO World Congress on Gastrointestinal Cancer 2022 in Barcelona, Spain.
Presenting the phase II study results, John Strickler, from Duke University Medical Center in Durham, North Carolina, USA, said that the combination “has the potential to become a new standard of care” for this patient population.
He explained that the open-label study initially involved 45 patients given the oral tyrosine kinase inhibitor tucatinib 300 mg twice daily plus trastuzumab 6 mg/kg every 3 weeks, after an initial loading dose of 8 mg/kg. The trial was expanded to include a further 41 patients after preliminary positive findings, although two patients were subsequently excluded from the efficacy analysis when their HER2-positive status was not confirmed.
The 84 participants assessed were aged an average of 55 years, 60.7% were men, and 84.5% had primary left colon and rectum disease. The majority (59.5%) had stage IV disease on their initial diagnosis and over half of the patients had liver (64.3%) or lung (70.2%) metastases at study baseline.
The patients had received a median of three lines of prior therapy including at least one line in the metastatic or recurrent setting; all patients had received fluoropyrimidine and oxaliplatin, 98.8% had received irinotecan, 85.7% an anti-VEGF antibody and 52.5% an anti-EGFR antibody.
Blinded independent central review determined that 3.6% of 84 patients achieved a complete response, 34.5% a partial response and 33.3% stable disease, giving an objective response rate of 38.1% and a disease control rate of 71.4%. The median time to objective response was 2.1 months and the median duration of response was 12.4 months.
After a median follow-up of 20.7 months, the median durations of progression-free survival and overall survival were 8.2 and 24.1 months, respectively, said John Strickler.
Safety data for the full 86-patient cohort indicated the combination was “well tolerated”, the presenter continued, citing “a low discontinuation rate” of 5.8% and a dose modification rate of 25.6%.
Treatment-emergent adverse events (AEs) at grade 3 or worse occurred in 38.4% of patients. Tucatinib-related AEs of this severity occurred in 9.3%, most commonly alanine aminotransferase elevation (2.3%) and diarrhoea (2.3%), while grade 3 or worse trastuzumab-related AEs occurred in 7.0%.
Serious AEs related to tucatinib and trastuzumab occurred in 3.5% and 2.3%, respectively, and there were no AE-related deaths.
AEs of special interest for the combination included diarrhoea, which the investigator described as being “predominantly low grade and manageable”, and hepatotoxicity, consisting of grade 3 or more severe liver enzyme elevations but no cases of Hy’s Law. In addition, cardiotoxicity was reported, with asymptomatic left ventricular ejection fraction decreases leading to dose modification or discontinuations in 3.5% of patients.
“In chemotherapy-refractory patients with HER2+ [metastatic] CRC, tucatinib in combination with trastuzumab demonstrated durable and clinically meaningful antitumor activity”, the presenter summarised.
The open-label phase III MOUNTAINEER-03 trial is now investigating first-line tucatinib plus trastuzumab and modified FOLFOX6 chemotherapy versus usual care of chemotherapy with bevacizumab or cetuximab in patients with HER2-positive metastatic CRC, he added.
- Strickler JH, Cercek A, Siena S, et al. Primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol 2022; 33 (suppl 4): S375-376. DOI: 10.1016/j.annonc.2022.04.440
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