Original Article
Small Cell Lung Cancer
Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study

https://doi.org/10.1016/j.jtho.2019.04.026Get rights and content
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Abstract

Purpose

Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade.

Methods

A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells in direct contact with tumor).

Results

A total of 20 patients were enrolled. Their median age was 64 years, and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, two were observed to have partial or complete responses (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four patients (21.1% [95% confidence interval: 6.1%–45.6%]) with confirmed responses or prolonged stable disease (≥8 months). The most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leukopenia (50%). Nine of 14 tumors (64%) exhibited an excluded phenotype; 21% and 14% of tumors exhibited the inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no during-treatment increase in T-cell infiltration or programmed death ligand 1 expression on tumor-infiltrating immune cells was observed.

Conclusions

The study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.

Keywords

Small cell lung cancer
PARP inhibitors
immune checkpoint blockade
tumor immune phenotype
DNA repair

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Disclosure: Dr. Thomas reports grants from AstraZeneca to the National Cancer Institute/National Institutes of Health during the conduct of the study. Dr. Trindade owns stock in Gilead, Celgene, Exelixis, Clovis, and Trevena, and he is an employee of the Food and Drug Administration outside the submitted work. Dr. Chen reports personal fees from AstraZeneca, Genentech, Brystol-Myers Squibb, Merck, Norvatis, Takeda, Eli Lilly and Company, Guardant Health, Pfizer, and Array Biopharma, as well as grants from AstraZeneca, ISPEN, Roche, and Brystol-Myers Squibb outside the submitted work. Dr. Velcheti reports personal fees from BMS, Genentech, AstraZenca, Merck, Celgene, Foundation Medicine, Taekeda Oncology, Reddy Labs, Alkermes, and Novartis outside the submitted work. Dr. Pommier reports grants from AstraZeneca to the National Cancer Institute during conduct of the study. Dr. Lee reports grants from AstraZeneca to the National Cancer Institute, National Institutes of Health during the conduct of the study. The remaining authors declare no conflict of interest.

Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.