In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD1-05-PD1-05
Abstract:
Background: HER2 mutations are oncogenic in hormone receptor positive (HR+) metastatic breast cancer (MBC), and may confer resistance to prior endocrine therapy but retain sensitivity to neratinib. Neratinib is an oral, irreversible, pan-HER tyrosine kinase inhibitor with clinical activity either as a single agent or in combination with fulvestrant in HER2-mutated, HER2-non-amplified MBC. Genomic analyses suggest that acquired resistance to neratinib can occur via additional HER2 alterations, which may alter HER2-pathway signaling. We investigated whether dual HER2-targeted therapy could improve clinical benefit in a cohort of patients with HER2-mutant, HR+ MBC treated with neratinib + trastuzumab + fulvestrant (N+T+F) from SUMMIT - a phase 2 basket trial (NCT01953926). Methods: Patients with HR+ MBC with known or suspected pathogenic HER2 mutation(s) identified by genomic sequencing were eligible to receive N+T+F (oral neratinib 240 mg/day, i.v. trastuzumab 8 mg/kg initially followed by 6 mg/kg every 3 weeks, and i.m. fulvestrant 500 mg on days 1 & 15 of month 1, then on day 1 every 4 weeks). Loperamide prophylaxis was mandatory during the first 2 treatment cycles. There was no restriction on the number of prior lines of systemic treatment for MBC. Efficacy endpoints: confirmed objective response rate and clinical benefit rate (RECIST v1.1); duration of response; progression-free survival. Results: As of 22-May-2020, 46 patients were enrolled in the N+T+F cohort and received at least 1 dose of study medication (safety population). 14 unique HER2 allelic variants were identified: 8 kinase domain missense; 1 extracellular domain missense; 2 transmembrane domain missense; 2 exon-20 insertion; 1 exon-19 deletion. The most common HER2 mutant variant was L755S (n=15, 33%) Median number of prior systemic regimens for metastatic disease was 4 (range 0-10); 34 (74%) patients had received prior fulvestrant, and 31 (67%) patients had received prior cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. 16 (35%) patients had ductal histology, 29 (63%) had lobular carcinoma, and 1 (2%) had mixed ductal and lobular carcinoma. At this time, 30/46 patients had RECIST measurable disease and are efficacy evaluable (ongoing patients who did not have the opportunity for their first post-baseline tumor assessment were excluded); clinical activity - see Table. Diarrhea was the most commonly reported adverse event (80% any grade) with 15 (33%) patients reporting grade 3 diarrhea (no grade 4 diarrhea). 10 patients (22%) had a neratinib dose reduction due to diarrhea but no patients discontinued treatment due to diarrhea. Conclusions: The combination of N+T+F demonstrated encouraging clinical activity in heavily pre-treated HER2-mutant, HR+, HER2-non-amplified MBC, including patients who had previously received either fulvestrant and/or CDK4/6 inhibitor-based therapies. While the rate of grade 3 diarrhea was higher than that observed with single-agent neratinib in SUMMIT, this was manageable through loperamide prophylaxis, and no patients discontinued study treatment due to diarrhea. SUMMIT has recently been amended to evaluate N+T+F, T+F and F (1:1:1 randomization) and continues to enroll patients. RECIST measurable and efficacy evaluable patients (n=30)Confirmed objective response,a n (%)12 (40)CR0PR12ORR, % (95% CI)40 (23-59)Best overall response, n (%)18 (60)CR0PR18Best overall response rate, % (95% CI)60 (41-77)Medianb DOR, months (95% CI)8.4 (4.1-NE)Clinical benefit,c n (%)14 (47)CR or PR12SD ≥24 weeks2CBR, % (95% CI)47 (28-66)Medianb PFS, months (95% CI)8.3 (4.2-12.5)aORR is defined as either a CR or a PR that is confirmed no less than 4 weeks after the criteria for response are initially met; bKaplan-Meier analysis; cCBR is defined as confirmed CR or PR or SD for ≥24 weeks; CR, complete response; CBR, clinical benefit rate; DOR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. Citation Format: Komal Jhaveri, Cristina Saura, Angel Guerrero-Zotano, Iben Spanggaard, François-Clement Bidard, Jonathan W Goldman, José A García-Sáenz, Andrés Cervantes, Valentina Boni, John Crown, Adam Brufsky, Sherene Loi, Barbara Haley, Ingrid A Mayer, Stephen Chia, Janice Lu, James Waisman, Noa Efrat Ben-Baruch, Mark E Burkard, Jennifer M Suga, Lucía González-Cortijo, Bruno Perrucci, Feng Xu, Sofia Wong, Jie Zhang, Lisa D Eli, Alshad S Lalani, Hans Wildiers. Latest findings from the breast cancer cohort in SUMMIT - a phase 2 ‘basket’ trial of neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-05.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS20-PD1-05
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
