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Outcomes of Neratinib + Fulvestrant + Trastuzumab and Biomarker Analysis in Patients With HR+/HER2−, HER2-Mutant MBC
TAKE-HOME MESSAGE
- This was a prospective basket study that evaluated data from patients with solid tumors with mutations in HER2. A cohort of 71 patients with HR+/HER2− metastatic breast cancer (MBC) who had previously received a CDK4/6 inhibitor received neratinib, fulvestrant, and trastuzumab (N + F + T; n = 57) versus F + T (n = 7) versus F alone (n = 7). The overall response rate among patients who received N + F + T was 39%, compared with no responses in either of the other two arms. When the patients in the other arms crossed over to N + F + T, responses were observed.
- Patients with HR+/HER2− MBC with mutations in HER2 now have a targeted option for therapy with N + F + T that provides meaningful clinical outcomes and further delays the receipt of chemotherapy. These findings further underscore the importance of next-generation sequencing in patients with HR+/HER2− MBC.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
HER2 mutations are targetable alterations in patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib+fulvestrant, or neratinib+fulvestrant+trastuzumab (N+F+T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (7 in each arm) from a randomized substudy of fulvestrant versus fulvestrant+trastuzumab (F+T) versus N+F+T.
PATIENTS AND METHODS
Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6 inhibitor therapy received N+F+T (oral neratinib 240 mg/d with loperamide prophylaxis, intramuscular fulvestrant 500 mg days 1, 15, 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F+T or fulvestrant alone. Those whose disease progressed on F+T or fulvestrant could crossover to N+F+T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.
RESULTS
ORR for 57 N+F+T-treated patients was 39% (95%CI 26-52); median PFS was 8.3 months (95% CI 6.0-15.1). No responses occurred in fulvestrant- or F+T-treated patients; responses in patients crossing over to N+F+T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal ctDNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.
CONCLUSIONS
The benefit of N+F+T for HR+ HER2-mutant MBC after progression on CDK4/6 inhibitors is clinically meaningful and, based on this study, N+F+T has been included in National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
Additional Info
Disclosure statements are available on the authors' profiles:
Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial
Ann. Oncol 2023 Aug 17;[EPub Ahead of Print], K Jhaveri, LD Eli, H Wildiers, SA Hurvitz, A Guerrero-Zotano, N Unni, A Brufsky, H Park, J Waisman, ES Yang, I Spanggaard, S Reid, ME Burkard, S Vinayak, A Prat, M Arnedos, FC Bidard, S Loi, J Crown, M Bhave, SA Piha-Paul, JM Suga, S Chia, C Saura, JÁ Garcia-Saenz, V Gambardella, MJ de Miguel, EN Gal-Yam, A Rapael, SM Stemmer, C Ma, AB Hanker, D Ye, JW Goldman, R Bose, L Peterson, JSK Bell, A Frazier, D DiPrimeo, A Wong, CL Arteaga, DB SolitFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
There remains an unmet need for additional endocrine-based therapeutic options for patients with HR+/HER2− metastatic breast cancer. One mechanism of resistance in this subset of patients with breast cancer is the occurrence of activating mutations in HER2 without gene amplification or increased protein expression. Interestingly, HER2 mutations tend to occur more frequently in tumors of lobular histology; however, they are also found in at least 3% to 5% of patients with ductal cancers. Prior reports from multiple small trials, including the SUMMIT study, have demonstrated clinical responses in patients treated with neratinib, a small-molecule tyrosine kinase inhibitor of HER2, in combination with fulvestrant.
In the current report by Jhaveri et al, a larger cohort of patients with a variety of HER2 mutations was enrolled in the SUMMIT trial, receiving the three-drug combination of neratinib, fulvestrant, and trastuzumab, with a strong rationale for the use of the triplet combination based on prior preclinical and clinical observations. They observed a substantial objective response rate of 39% and a clinically meaningful median progression-free survival duration of 8.3 months. The clinical responses observed in a small crossover group supported the use of the three-drug combination as the optimal therapy. Interestingly, in sequential circulating tumor DNA analyses, additional resistance mechanisms to the triplet combination were observed, including new PIK3CA alterations and additional HER2 alterations, suggesting the need for future strategies to maintain treatment response.
These findings emphasize the need for performing comprehensive genomic profiling in patients after progression on first-line CDK4/6 inhibition therapy to probe for actionable alterations that can result in substantial clinical benefits for patients. I think that the combination of neratinib, fulvestrant, and trastuzumab is a perfectly reasonable combination to consider in the second-line or beyond treatment setting for patients with HR+/HER2− metastatic breast cancer with HER2 mutations.