Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers
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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Sneha Phadke1, Kathy D Miller2, Ami Shah3
1Carver College of Medicine Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, C21GH, Iowa City, IA, 52242, USA. Sneha-Phadke@uiowa.edu.
Purpose:
Metastatic triple negative breast cancer has a poor prognosis with limited targeted treatment options. In preclinical studies PI3K inhibition led to increased DNA damage and subsequent sensitization to PARP inhibition. This study aimed to investigate the safety and efficacy of the combination of an mTOR/pan-PI3K inhibitor, gedatolisib, with the PARP inhibitor, talazoparib, in patients with advanced triple negative breast cancer or advanced HER2 negative breast cancer and a germline BRCA1/2 mutation.
Methods:
The primary objective of the safety run-in was safety and tolerability of the combination and for dose escalation to find the maximum tolerated dose. A 3 + 3 design was utilized for dose escalation. The primary objective of the phase II study was objective response rate (ORR) in the patients with wildtype germline BRCA1/2. The prespecified efficacy threshold was 20%. Secondary objectives included progression-free (PFS) and overall survival (OS) as well as correlative testing, examining homologous recombination deficiency (HRD) status.
Results:
The combination of gedatolisib and talazoparib carried manageable toxicities with a low incidence of grade 3 adverse events. The most common adverse events of all grades were anemia, fatigue, and oral mucositis. The ORR in the phase II study was 12%. There were no new safety signals identified in the phase II study. mPFS was 2.5 months (95% CI 1.71, 9.89), and mOS was 7 months (95% CI 4.3, NA) in the full phase II cohort. HRD status was analyzed by high (≥ 33) or low (< 33) genomic instability score, and there was no difference in response rate between the groups.
Conclusion:
The combination of gedatolisib and talazoparib is safe but did not meet the prespecified efficacy threshold for objective response rate. Additional preclinical studies of these pathways are warranted prior to future clinical trials of the combination.
Trial Registration:
ClinicalTrials.gov ID: NCT03911973, Date of registration: 2019-04-11.
Insights
The combination of gedatolisib and talazoparib showed manageable toxicity in advanced breast cancer patients but did not meet the objective response rate threshold. Further preclinical research is recommended before future clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Metastatic triple-negative breast cancer (TNBC) presents a poor prognosis with limited targeted therapies.
- Preclinical data suggested PI3K inhibition enhances DNA damage, sensitizing tumors to PARP inhibitors.
- This study evaluated a novel combination therapy for advanced breast cancer.
Purpose of the Study:
- To assess the safety and efficacy of combining gedatolisib (an mTOR/pan-PI3K inhibitor) with talazoparib (a PARP inhibitor).
- To investigate this combination in patients with advanced triple-negative breast cancer or HER2-negative breast cancer with a BRCA1/2 mutation.
Main Methods:
- A Phase I safety run-in utilized a 3+3 dose escalation design to determine the maximum tolerated dose.
- Phase II primary objective was to evaluate the objective response rate (ORR) in patients with wildtype germline BRCA1/2.
- Secondary objectives included progression-free survival (PFS), overall survival (OS), and correlative analysis of homologous recombination deficiency (HRD) status.
Main Results:
- The gedatolisib and talazoparib combination exhibited manageable toxicities, with anemia, fatigue, and oral mucositis as common adverse events.
- The ORR in the Phase II study was 12%, falling below the 20% efficacy threshold.
- Median PFS was 2.5 months and median OS was 7 months; no difference in response was observed based on HRD status.
Conclusions:
- The combination of gedatolisib and talazoparib is safe but did not achieve the predefined objective response rate.
- Further preclinical investigation into these targeted pathways is warranted before initiating new clinical trials.
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