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J Thorac Oncol. 2019 May 4. pii: S1556-0864(19)30361-2. doi: 10.1016/j.jtho.2019.04.026. [Epub ahead of print]

Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study.

Author information

1
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: anish.thomas@nih.gov.
2
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
3
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
4
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
5
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
6
Interventional Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland.
7
Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.
8
Cancer and Hematology Centers of Western Michigan, Grand Rapids, Michigan.
9
Thoracic Medical Oncology, Perlmutter Cancer Center, New York University, New York, New York.
10
Western Maryland Regional Medical Center, Schwab Family Cancer Center, Cumberland, Maryland.
11
Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
12
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
13
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
14
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

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:

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

PMID:
31063862
DOI:
10.1016/j.jtho.2019.04.026

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