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BACKGROUND: Preliminary results with MK3475 (pembrolizumab) in heavily pretreated Estrogen Receptor (ER)-positive/ Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients have shown promising antitumor activity. However, no data are available with anti-Programmed Death-Ligand 1 (PD-L1) agents in combination with chemotherapy in this tumor subtype in the metastatic setting. The aim of this trial is to evaluate the efficacy of pembrolizumab in combination with eribulin in patients with Hormone Receptor (HR)-positive/HER2-negative MBC who have been previously treated with an anthracycline and a taxane. TRIAL DESIGN: This is an open-label, non-randomized, multicenter phase IIA clinical trial. Patients will receive intravenously pembrolizumab (200 mg) followed by eribulin (1.23 mg/m2) on day 1 of each cycle (every three weeks). Eribulin will also be administered alone on day 8 of each cycle until progression or unacceptable toxicity. The end of study will be 12 months after last study dose or progressive disease experienced in all patients. The principal selection criteria are: (1) HR-positive/HER2-negative inoperable locally recurrent or MBC; (2) prior therapy with an anthracycline and a taxane in the early or metastatic disease setting unless contraindicated; (3) at least one, but not more than two, previous chemotherapeutic regimens for locally recurrent and/or MBC; (4) measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1; (5) available tumor tissue for PD-L1 biomarker analysis. The primary objective of the study is to assess the efficacy of this combination as determined by the clinical benefit rate (CBR) defined as the percentage of patients who achieve complete response, partial response, or stable disease ≥24 weeks based on RECIST v.1.1. Secondary objectives evaluate: (1) safety-related outcomes and (2) efficacy measures as progression-free survival (PFS), overall survival, overall response rate (ORR), and duration of response in the intention-to-treat population and in patients with PD-L1 positive tumors. Exploratory objectives include: (1) the analysis of PFS and ORR based on irRECIST; and (2) the identification of new predictive factors of response to the combination of pembrolizumab and eribulin based on gene signatures, mutational load, and circulating tumor cells. The trial uses an exact single-stage design. We hypothesized that excluding a CBR ≤30% while targeting an improvement of the CBR to ≥50% would be an optimal approach to evaluation of the study strategy. At least 17 patients with clinical benefit among 39 evaluable patients will be adequate to justify the investigation of this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 44 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. TRIAL REGISTRATION: NCT03222856. Date of registration: July 19th, 2017. First Patient First Visit: December 14th, 2017. Citation Format: José Manuel Pérez García, Antonio Llombart, José Luis Alonso, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Giuseppe Curigliano, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Peter Schmid, Miguel Ángel Seguí, Javier Cortés, Esther Holgado. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT152.

BACKGROUND: Studies of checkpoint inhibitor monotherapy have shown only modest activity in hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) metastatic breast cancer (MBC). However, pembrolizumab (P) added to standard neoadjuvant therapy significantly improved the estimated pathologic complete response rate in HR+/HER2- early breast cancer in the I-SPY-2 trial. The KELLY trial aimed to evaluate the efficacy and safety of P in combination with eribulin (E) in anthracycline- and taxane-pretreated patients (pts) with HR+/HER2- inoperable locally recurrent or MBC irrespective of programmed death-ligand 1 (PD-L1) status. METHODS: This is an open-label, single-arm, multicenter phase IIA clinical trial (ClinicalTrials.gov identifier: NCT03222856). Eligible pts had HR+/HER2- inoperable locally recurrent or MBC, who were previously treated with endocrine therapy and at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease, and with prior anthracycline/taxane exposure either in the early or metastatic setting. Pts received E 1.23 mg/m2 intravenously (IV) on days 1 and 8 with P 200 mg fixed dose IV on day 1 of a 21-day cycle until unacceptable toxicity or disease progression. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety and tolerability of the combination. Exploratory objectives included: (1) the analysis of PFS and ORR based on immune-related RECIST (irRECIST) and (2) the associations of PFS and OS to CBR/ORR, prior exposure to CDK4/6, mTOR, or PI3K inhibitors, PD-L1 status, tumor-infiltrating lymphocytes (TILs), gene signatures, mutational load, and circulating tumor cells. RESULTS: Between January 2018 and October 2018, 44 pts were enrolled in the study. The median age was 54.1 years (range: 46-60.5 years), 70.5% were ECOG 0, 90.1% had visceral disease (86.4% with liver metastases), and 54% with ≥3 involved organ sites. The median number of prior endocrine therapies was two (range: 1-6) and 52.3% of patients had previously received two chemotherapeutic regimens for treatment of locally recurrent and/or MBC. With a median follow-up of 6.64 months (mo.) (range: 1-14.2 mo.), E and P combination met primary endpoint (CBR 53.7%, 95%CI: 36.9-67.3%). ORR and median PFS were 36.4% (95%CI: 22.8-52.3%) and 6.03 mo. (95%CI: 3.7-8.4 mo.), respectively. All-cause adverse events occurred in 100% of pts (G3-4, 56.8%), without treatment-related deaths. ORR and median PFS based on irRECIST were 36.4% (95%CI: 22.8-52.3%) and 6.1 mo. (95%CI: 4.2-8.5 mo.), respectively. OS data are immature (13 deaths, 29.5%). A significant difference in median PFS has been observed between pts with and without clinical benefit (8.5 Vs. 2.2 mo., p<0.001) and responders compared with non-responders (8.3 Vs. 3.4 mo., p=0.024). Previous exposure to CDK4/6, mTOR, or PI3K inhibitors was not associated with differences in PFS (TABLE 1). Updated data, including results about PD-L1 status and TILs will be presented. CONCLUSIONS: E plus P was a safe and active regimen for pts with previously treated HR+/HER2- locally recurrent or MBC that merits further investigation. Exploratory biomarker analysis is pending. TABLE 1Prior treatmentNEvents (%)Median PFS, mo. (95%CI)p-valueCDK4/6 inhibitorsNo2316 (69.2)6 (3.7-10.4)0.832Yes2115 (71.4)6.1 (2.5-NA)mTOR or PI3K inhibitorsNo2620 (76.9)6 (3.7-8.47)0.727Yes1811 (61.1)6 (2.5-NA) Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Esther Holgado, Giuseppe Curigliano, Elena López Miranda, José Luis Alonso-Romero, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Miguel Àngel Seguí, Jesus Soberino, Andrea Malfettone, Peter Schmid, Javier Cortés. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-03.