Pembrolizumab plus eribulin in hormone-receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer (KELLY): An open-label, multicentre, single-arm, phase Ⅱ trial

Peréz-García, José Manuel; Llombart–Cussac, Antonio; Cortes, M. Gion; Curigliano, Giuseppe; López-Miranda, Elena; Alonsó, José Luis; Bermejo, Begoña; Calvo, Lourdes; Carañana, Vicente; Sánchez, Susana de la Cruz; Vázquez, Raúl Márquez; Prat, Aleix; Ruíz-Borrego, Manuel; Sampayo-Cordero, Miguel; Seguí-Palmer, Miguel Ángel; Soberino, Jesús; Malfettone, Andrea; Schmid, Peter; Cortés, Javier

doi:10.1016/j.ejca.2021.02.028

Cited by 28 publications

(16 citation statements)

References 21 publications

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“…Of the 44 patients in the trial treated with eribulin and pembrolizumab, 21 (48%) had irAEs, including 2 patients who experienced both immune-related colitis and grade 5 sepsis 6 . Compared to other trials of ICIs with chemotherapy in metastatic breast cancer, this irAE frequency was similar to ENHANCE-1 (pembrolizumab with eribulin; 43%) 38 and IMpassion130 (atezolizumab with nab-paclitaxel; 57%) 8 but higher than KELLY (pembrolizumab with eribulin; 25%) 39 and KEYNOTE-355 (pembrolizumab with nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin; 26%) 40 , indicating wide heterogeneity that may be attributable to the lack of a standardized definition for irAEs 41 , 42 . In the present trial, patients with vs. without irAEs had no difference in PFS or OS (HR for progression 0.8, 95% CI 0.5–1.4, p = 0.5; HR for death 0.8, 95% CI 0.4–1.4, p = 0.4; Supplementary Data File 1 : Supplementary Table 8 ), which differs from previous studies showing that irAEs correlate with improved ICI responses 43 , 44 , likely because our analysis addressed the possibility of guarantee-time bias 45 .…”

Section: Resultssupporting

confidence: 52%

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

et al. 2021

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Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.

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Section: Resultssupporting

confidence: 52%

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

et al. 2021

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“…Objective response rates (ORRs) to ICB monotherapy in metastatic ER + breast cancer (including all histological subtypes) range from 3 to 12% (refs. 14 , 15 ) to 27 to 41% in combination with eribulin 16 , 17 . Notably, in the KEYNOTE-028 trial for patients with metastatic PD-L1 + ER + breast cancer, two of three responders were patients with ILC 15 .…”

Section: Mainmentioning

confidence: 99%

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

et al. 2023

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Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.

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“…In this study, an objective response was observed in 18 patients (40.9%), with a median PFS of 6 months and a 1-year OS of 59.1%. 229 Given the low RR of ICI monotherapy in HR-positive MBC, more recent studies have evaluated the combination of ICI with other treatment modalities, including PARP inhibitors, CDK4/6 inhibitors, and radiation therapy (RT). PARP inhibitors have antitumor activity through activation of the stimulator of interferon genes (STING) pathway, which has been shown to increase PD-L1 expression in cancer cell lines.…”

Section: Immunotherapymentioning

confidence: 99%

Systemic therapy for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative early stage and metastatic breast cancer

Huppert

Gümüşay

Idossa

et al. 2023

CA A Cancer J Clinicians

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Hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR‐positive/HER2‐negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late‐stage disease. Combinations with cyclin‐dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody‐drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR‐positive/HER2‐negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR‐positive/HER2‐negative breast cancer, including treatment algorithms based on current data.

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Pembrolizumab plus eribulin in hormone-receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer (KELLY): An open-label, multicentre, single-arm, phase Ⅱ trial

Cited by 28 publications

References 21 publications

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

Systemic therapy for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative early stage and metastatic breast cancer

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