Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial

Ciruelos, Eva; Villagrasa, Patricia; Pascual, Tomás; Oliveira, Mafalda; Pernas, Sònia; Paré, Laia; Escrivá-de-Romaní, Santiago; Manso, Luis; Adamo, Bárbara; Martínez, E.; Cortés, Javier; Vázquez, Silvia; Perelló, Antonia; Garau, Isabel; Melé, Mireia; Martínez, Noelia; Montaño, Álvaro; Bermejo, Begoña; Morales, Serafín; Echarri, María J.; Vega, Estela; González-Farré, Blanca; Martínez, Débora; Galván, Patricia; Canes, Jordi; Nuciforo, Paolo; González, Xavier; Prat, Aleix

doi:10.1158/1078-0432.ccr-20-0844

Cited by 89 publications

(76 citation statements)

References 49 publications

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“…For example, combinations of trastuzumab or lapatinib with everolimus have demonstrated encouraging antitumor activity in HER2-overexpressing tumors (49)(50)(51)(52). A recent report demonstrated that trastuzumab in combination with palbociclib exhibits promising survival outcomes in trastuzumab pretreated estrogen receptor-positive (ER þ )/HER2 þ advanced breast cancer (53). As a novel HER2 inhibitor, neratinib has demonstrated powerful therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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Purpose: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2 þ ) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2 þ cancers in vitro and in vivo.Experimental Design: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm.Results: In HER2 þ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors ever-olimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Ka inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2 þ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib.Conclusions: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2 þ cancer.

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Section: Discussionmentioning

confidence: 99%

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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“…Palbociclib also showed promising results in early‐phase clinical trials, 39 and positive results from a randomized, phase II study were recently published 40 . The PATRICIA trial evaluated the role of palbociclib plus trastuzumab in patients with pretreated HER2+ mBC, both ER‐ (cohort A) and ER+ (cohort B).…”

Section: Cdk4‐6 Inhibition In Her2‐positive Breast Cancermentioning

confidence: 99%

“…Interestingly, 83% of tumours were profiled using PAM50, and luminal disease was significantly associated with longer PFS (HR 0.40, P = .003). Due to the promising survival results observed in this subgroup, study enrolment was stopped prematurely, and a new randomized cohort was opened in this population 40 . The observation that luminal subtype had the greatest benefit from palbociclib is intriguing, considering that a previous work by Prat et al showed that most luminal/HER2+ BC share the same genomic and genetic alterations as luminal/HER2‐ BC, except for HER2 amplification 41 …”

Section: Cdk4‐6 Inhibition In Her2‐positive Breast Cancermentioning

confidence: 99%

CDK4/6 and PI3K inhibitors: A new promise for patients with HER2‐positive breast cancer

Agostinetto

Debien

Marta

et al. 2021

Eur J Clin Investigation

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Background HER2‐positive (HER2+) breast cancer represents a heterogeneous breast cancer subtype, including both oestrogen receptor (ER) positive and negative tumours. A deeper understanding of the crosstalk between ER and HER2 receptor pathways has led to the development of treatment strategies consisting of a simultaneous blockade of both signalling pathways, as a reasonable approach to prevent the onset of mechanisms of resistance. Methods This review was based on the material searched on PubMed, MEDLINE and Embase databases and on conference proceedings from major oncology conferences up to 15 December 2020. The search strategy included the following keywords: ‘HER2‐positive breast cancer’, ‘CDK4‐6 inhibitors’ and ‘PI3K inhibitors’, and was adapted for use with different bibliographic databases. Results CDK4/6 and PI3K inhibitors are two classes of agents already approved in patients with hormone receptor positive, HER2‐negative breast cancer. Recently, promising data with their use have been also shown in HER2+ disease. Results from preclinical and clinical studies are shedding light on the role of these classes of agents in HER2+ breast cancer, and are paving the road for a forthcoming change in clinical practice. Conclusions Treatment landscape for HER2+ breast cancer is rapidly changing, and CDK4/6 and PI3K inhibitors represent a new promising strategy to improve patients’ outcomes.

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“…In a phase 1b/2 trial of ribociclib (continuous dosing, 400 mg per day) plus trastuzumab in heavily pretreated patients with HER2+ MBC, limited clinical activity was observed with a median PFS of 1.33 months 21 . The recently reported phase II SOLTI-1303 PATRICIA trial further supports that the activity of CDK 4/6 inhibitors in HER2+ MBC is greater in patients who are also HR+ 22 .…”

Section: Introductionmentioning

confidence: 78%

Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

Spring

Clark

et al. 2021

npj Breast Cancer

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Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1.

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Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial

Cited by 89 publications

References 49 publications

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

CDK4/6 and PI3K inhibitors: A new promise for patients with HER2‐positive breast cancer

Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

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