Results from an interim analysis of data from an ongoing, multiple basket trial showed clinical activity and generally good tolerability for the combination of pertuzumab plus trastuzumab in the cohort of patients with HER2-amplified metastatic colorectal cancer.

Trastuzumab-based HER2-targeted treatment regimens have been approved by the US Food and Drug Administration (FDA) in breast cancer, as well as in gastric and gastroesophageal junction adenocarcinoma. One of the baskets included in the ongoing multicenter, open-label, nonrandomized, phase 2a MyPathway trial (ClinicalTrials.gov Identifier: NCT02091141) is currently evaluating dual anti-HER2 therapy in patients with HER2-amplified metastatic colorectal cancer using the combination of 2 antibodies against HER2, trastuzumab and pertuzumab, which bind to different regions of the HER2 receptor. Of note, it is estimated that only 2% to 6% of patients with metastatic colorectal cancer have disease characterized by HER2 amplification or HER2 overexpression.

The results presented in this paper are from an interim analysis of 57 patients with

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HER2-amplified disease enrolled in the MyPathway study who initiated treatment between October 20, 2014, and June 22, 2017. These patients had heavily pretreated disease (ie, median number of lines of previous therapy was 4 lines), and were considered to have no other suitable therapeutic options.

The primary end point of this study is overall response rate (ORR) by RECIST v1.1 criteria, with secondary end points including duration of response, progression-free survival (PFS), overall survival (OS), and safety.

At a median follow-up of 7.3 months from initiation of treatment, the ORR in this cohort was 32% with 1 patient (2%) achieving a complete response. In addition, the median duration of response was 5.9 months, including 4 patients with responses lasting longer than 12 months. Median PFS and median OS were estimated at 2.9 months (95% CI, 1.4-5.3) and 11.5 months (95% CI, 7.7-not estimable), respectively.

With respect to these findings, the study authors noted that “outcomes observed with pertuzumab plus trastuzumab are particularly striking when compared with the low proportion of patients with a response (<5%) from treatments currently indicated for metastatic colorectal cancer after the second line.”

Interestingly, a post-hoc exploratory analysis of tumor KRAS status showed that only 1 of the 18 patients achieving an objective response had KRAS-mutant disease (ie, tumors of the remaining 17 patients had KRAS wild-type tumors). However, one limitation of this study was that determinations of HER2 and KRAS tumor status were performed on archival tumor tissue collected up to 37 months prior to patient enrollment in the MyPathway trial, which may not reflect subsequent development of mutations (eg, KRAS) in tumor tissue.

Treatment-emergent adverse events, including common reports of low-grade diarrhea, fatigue, and nausea, observed in this cohort of patients were generally consistent with those reported for patients with breast cancer receiving the combination of pertuzumab and trastuzumab. Grade 3/4 treatment-emergent adverse events, including hypokalemia and abdominal pain, were reported in 37% of patients. No treatment-related grade 5 adverse events occurred.

The activity data suggest that “early assessment of HER2 status, and earlier-line use of HER2-targeted therapy [in patients with HER2-amplified metastatic colorectal cancer], should be considered,” the authors concluded.

Reference

  1. Meric-Bernstam FHurwitz HRaghav KPS, et al. Pertuzumab plus trastuzumab for HER2 amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study [published online March 8, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30904-5