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SAN ANTONIO -- A combination of neratinib (Nerlynx), fulvestrant, and trastuzumab (Herceptin) showed encouraging clinical activity in patients with hormone receptor (HR)-positive, HER2-negative, HER2-mutant metastatic breast cancer (MBC) who had previously been treated with CDK4/6 inhibitors, a researcher reported.

In updated results from the phase II SUMMIT trial, there was an objective response rate (ORR) of 42.4% in patients treated with the regimen, with a median duration of response (DoR) of 14.4 months, and median progression-free survival (PFS) of 7.0 months, according to Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City.

A combination of neratinib and trastuzumab was active in HER2-mutant triple-negative breast cancer (TNBC), she said in a presentation at the San Antonio Breast Cancer Symposium.

Neratinib is an oral, irreversible, pan-HER tyrosine kinase inhibitor approved for use in HER2-positive (amplified/overexpressed) adjuvant and MBC. While it has demonstrated preclinical, as well as encouraging clinical activity, as a single agent or in combination with fulvestrant in HER2-mutated, HER2-non-amplified MBC, Jhaveri said that data also suggest the combination of neratinib and fulvestrant plus trastuzumab may be even more effective.

is an open-label, multicenter, multinational, phase II basket study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in participants with HER (EGFR, HER2) mutation-positive solid tumors.

This analysis included a cohort of 26 HR-positive/HER2-negative patients (non-randomized) to receive the triple therapy of neratinib, fulvestrant, and trastuzumab.

The investigator-assessed ORR for this cohort was 46.2% (12/26), with a clinical benefit rate of 57.7%, a median DoR of 14.4 months, and a median PFS of 8.2 months.

In order to evaluate the contribution of neratinib to this triple therapy, the investigators also included a small, randomized, Simon 2-stage comparison of three cohorts (each with seven patients) that received either the triple therapy, fulvestrant and trastuzumab, or fulvestrant alone.

In the randomized cohort of seven patients who received the triple regimen, two (28.6%) achieved an objective response, including one complete response (CR), while there were no responses in the non-neratinib containing regimens.

Those results suggest that neratinib appears to be critical for the inhibition of HER2 mutations, Jhaveri said. "And based on these results, the independent monitoring committee recommended to close the non-neratinib containing cohorts and further expand the triplet arm."

Efficacy findings for the entire cohort of 26 randomized and seven non-randomized patients (n=33 total) who received the triple regimen showed that 14 achieved an objective response (13 partial and and one CR), for the 42.4% ORR, and a clinical benefit rate of 51.5%.

This analysis also included patients with HER2-mutant TNBC who were enrolled in a nonrandomized cohort and received neratinib plus trastuzumab. Of those 18 patients, six (33.3%) experienced a confirmed objective response, including one CR and five partial responses. The clinical benefit rate in this group was 38.9%.

The median DoR has not been reached in those patients and the median PFS was 6.2 months.

Despite the requirement of loperamide prophylaxis for patients in this study, diarrhea was the main adverse event (AE) of any grade for the 33 patients taking the triple regimen, occurring in 30 (90.9%), with half of the cases either grade 3 or 4 AEs. Seven patients (21.2%) required dose reductions due to diarrhea, and one patient had to discontinue therapy.

"Grade 3 diarrhea was higher than anticipated with the triple combination and compliance with loperamide prophylaxis is imperative," Jhaveri said.

During a post-presentation discussion, Hope Rugo, MD, of the University of California San Francisco, called the results "remarkable" and wondered whether the regimen is ready for prime time.

"It's still being studied, but would you do this outside of a clinical trial, tomorrow?" she asked Jhaveri.

"At this point I'm not doing this outside of a clinical trial," Jhaveri said. "But I do agree that this seems to be a finding that we are really seeing consistently with this drug, and the efficacy we are certainly seeing even in post-CDK4/6 inhibitor patients. So it's certainly tempting, but we are continuing to do it clinical trials at this point."

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