Background: The programmed cell death 1 (PD-1) pathway is used by tumors to evade immune surveillance. Pembrolizumab is a humanized anti–PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has shown robust antitumor activity against several advanced malignancies, including triple-negative breast cancer. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive, ER+/HER2-negative advanced breast cancer. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is an ongoing multicohort, open-label phase 1b study evaluating the safety and efficacy of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for this cohort include ER+ and HER2-negative tumor status defined by institutional standards, locally advanced or metastatic disease, ECOG performance status of 0 or 1, failure of or inability to receive standard therapy, and PD-L1 expression in stroma or in ≥1% of tumor cells as assessed at a central laboratory using a prototype immunohistochemistry assay with the 22C3 antibody (Merck). Pembrolizumab was administered at a dose of 10 mg/kg every 2 weeks for up to 24 months or until confirmed progression or intolerable toxicity. Response is based on RECIST v1.1 as assessed by investigator review every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary efficacy end point is overall response rate (ORR). Results: Of the 248 patients with ER+/HER2-negative breast cancer who had evaluable tumor samples screened for PD-L1 expression, 48 (19%) had PD-L1–positive tumors. Of these, 25 patients were enrolled. Median age was 53 years (range, 36-79), and 44% of patients had an ECOG performance status of 1. Patients were heavily pretreated, with 76% having received ≥3 prior lines of therapy for advanced disease, including 48.0% who received ≥5 prior lines. Analyses of ORR, duration of response, and adverse events are ongoing and will be completed by September 4, 2015. Conclusion: Data from this KEYNOTE-028 cohort will provide information on the antitumor activity and safety of pembrolizumab in patients with heavily pretreated, PD-L1–positive, ER+/HER2-negative advanced breast cancer. Citation Format: Rugo HS, Delord J-P, Im S-A, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Le Tourneau C, van Brummelen E, Varga A, Saraf S, Pietrangelo D, Karantza V, Tan A. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-07.
Background: Somatic ERBB2 (HER2) mutations occur in approximately 2% of patients with breast cancer and are found in a predominantly mutually exclusive manner with ERBB2 amplification. These mutations result in increased signaling and oncogenic transformation. Neratinib, a pan-ERBB irreversible tyrosine kinase inhibitor, potently inhibits growth of ERBB2 mutant tumor cell lines and xenografts. An ongoing signal-seeking phase II 'basket' study is evaluating neratinib in patients with multiple histologies harboring ERBB2 mutations (NCT01953926). Novel mutations identified in enrolled patients were characterized for biologic activity in a variety of in vitro model systems. A preliminary analysis of the HER2 non-amplified metastatic breast cancer cohort is presented. Methods: Patients with ERBB2 mutant metastatic breast cancer documented by local testing methods received single-agent oral neratinib 240 mg once daily until progression or intolerable toxicity. High-dose loperamide prophylaxis was mandatory during cycle 1. The primary endpoint was the objective response rate at 8 weeks, defined using anatomic (RECIST 1.1) and/or metabolic (PET Response Criteria) assessments. Secondary endpoints were best overall response rate, clinical benefit rate, progression-free survival, duration of response, and safety. Results: 17 patients with metastatic breast cancer were enrolled and received neratinib (13 patients are evaluable for efficacy to date). Patients had a median of 3 prior anticancer regimens. Other baseline characteristics were: median age 59 years; bone involvement 71%; visceral disease 82%. Tumor characteristics were: ductal/lobular 76%/24%; ERBB2 mutation single nucleotide variants/indels 82%/18%; HER2 amplified/non-amplified 0%/100%; hormone receptor positive/negative 82%/18%. Five patients (39%) had an objective response at 8 weeks (95% CI 14–68%). In the patients who responded, ERBB2 mutations were: 1 complete response (L755S); 4 partial responses (L755S, V777L, V777L, and L869R). The most common all-grade adverse events (in ≥15% of patients) across all cohorts (n=93) were: diarrhea (62%), fatigue (28%), nausea (36%), vomiting (30%), anemia (15%), and constipation (29%). The most common grade 3/4 adverse event was diarrhea (14%, all grade 3). Updated efficacy results, centralized genomic analyses on archival tumor samples, and in vitro characterization of novel ERBB2 mutants will be presented. Conclusions: Single-agent neratinib shows encouraging signs of clinical activity in patients with heavily pretreated, ERBB2 mutant, HER2 non-amplified metastatic breast cancer. The breast cancer cohort demonstrated sufficient activity to meet the study's pre-specified efficacy requirements according to a Simon's two-stage design, and suggests that a confirmatory trial of neratinib for targeting ERBB2 driver mutations in metastatic breast cancer is warranted. Safety was acceptable and diarrhea was manageable with loperamide prophylaxis. Citation Format: Hyman DM, Piha-Paul SA, Rodón J, Saura C, Puzanov I, Shapiro GI, Loi S, Joensuu H, Hanrahan AJ, Modi S, Lalani AS, Xu F, Garza SJ, Cutler RE, Bryce R, Meric-Bernstam F, Baselga J, Solit DB. Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-05.
Background: Somatic mutations in ERBB2 are a new class of oncogenic drivers in HER2–non amplified MBC. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits the growth of ERBB2-mutant breast tumors in preclinical models and has encouraging single-agent clinical activity in patients (pts) with ERBB2-mutant, HER2–non amplified MBC. Bi-directional signaling between HER2 and ER may limit the effectiveness of endocrine and HER2 directed therapy, if each is given alone, in ER+ MBC with ERBB2 amplifications/mutations. Preclinical data suggest that dual blockade of ER and HER2 signaling results in enhanced anti-tumor activity in ER+ HER2+ MBC. SUMMIT, a multicenter multi-histology phase II 'basket' trial, is investigating the efficacy of neratinib monotherapy (in ER+ and ER– pts) and neratinib + fulvestrant (ER+ pts only) in ERBB2-mutant MBC. Methods: MBC pts with ERBB2 mutations documented by local testing were eligible and received oral neratinib 240 mg qd. Pts with ER+ MBC received fulvestrant 500 mg, a selective ER degrader, in addition to neratinib on d1 & 15 of month 1 then on d1 q4w. Patients received high dose loperamide prophylaxis during cycle 1. Primary endpoint is objective response rate (ORR) at 8w, defined using RECIST 1.1 and/or modified PERCIST assessments. Secondary endpoints include ORR, clinical benefit rate (CBR), progression free survival (PFS), and safety. Mutation profiling and central confirmation of ERBB2 mutation(s) from available fresh or archival tumor tissues and plasma DNA were performed retrospectively by next-generation sequencing (MSK-IMPACT). Clinicaltrials.gov: NCT01953926. Results: As of 23 Sep 2016, 35 efficacy-evaluable ERBB2-mutant MBC pts received neratinib, either as monotherapy (n=24) or in combination with fulvestrant (n=11). Efficacy findings are shown in the table. The overall safety profile of neratinib + fulvestrant was similar to that previously reported with neratinib monotherapy. Grade 3 diarrhea rate was 24% with neratinib monotherapy and 18% with neratinib + fulvestrant. Neratinib monotherapyNeratinib + fulvestrant(n=24)(n=11)Best Overall Response (confirmed and unconfirmed), n (%)8 (33.3)6 (54.5)[95% CI][15.6–55.3][23.4–83.3]CR3 (12.5)2 (18.2)PR5 (20.8)4 (36.4)aORR at 8 weeks, n (%)8 (33.3)5 (45.5)[95% CI][15.6–55.3][16.7–76.6]CR2 (8.3)2 (18.2)PR6 (25.0)3 (27.3)ORR confirmed, n (%)5 (20.8)2 (18.2)b[95% CI][7.1–42.2][2.3–51.8]CR3 (12.5)1 (9.1)PR2 (8.3)1 (9.1)CBR, n (%)10 (41.7)6 (54.5)[95% CI][22.1–63.4][23.4–83.3]CR, complete response; PR, partial response.aThere was 1 pt with PR at week 16; bAt time of data cut-off 4 pts are still on treatment. Conclusions: Encouraging clinical activity has been observed with neratinib + fulvestrant in heavily pretreated pts with ERBB2-mutant, ER+ MBC. Clinical efficacy in the ER+ MBC cohort met pre-specified efficacy requirements; a confirmatory trial of neratinib + fulvestrant for targeting ERBB2 mutations in ER+ MBC is warranted. The safety profile of neratinib was acceptable and diarrhea was manageable with loperamide prophylaxis. Citation Format: Hyman D, Piha-Paul S, Saura C, Arteaga C, Mayer I, Shapiro G, Loi S, Lalani A, Xu F, Cutler R, Butturini A, Bryce R, Meric-Bernstam F, Baselga J, Solit D. Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-08.
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