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

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.

Conflict of interest statement

Disclosures: The authors declare no potential conflicts of interest

Published by Elsevier Inc.

Figures

Figure 1.

Efficacy of durvalumab plus olaparib in relapsed SCLC. (A) Study schema and biomarker analyses. (B) Waterfall plot showing change of tumor burden from baseline (investigator assessed; N = 19). One patient was not evaluable for response due to rapidly progressive disease before first restaging scans. Bar length represents decrease/increase in target lesion size. Bar color is the best overall response (according to RECIST 1.1). Indicated by asterisk is a patient who came off treatment after one cycle for brain-only disease progression but who had a partial response in the systemic disease-sites that lasted six months with no additional systemic therapy. Boxes above the waterfall plot indicate the smoking status, platinum sensitivity, RECIST response, PD-L1 expression and immunophenotype of pre-treatment tumors. (C) Spider plot of change in the sum of unidimensional tumor measurements over time. The red lines represent confirmed responders; blue lines represent patients with progressive disease; grey lines represent patients with stable disease. Light brown squares indicate the time points when patients came off treatment due to progressive disease in the brain. + indicates patients who are receiving treatment at data cut-off. * indicates the patient who came off treatment after one cycle for brain-only disease progression but who had a PR in the systemic disease-sites. One patient who was not evaluable is not included.

Figure 1.

Efficacy of durvalumab plus olaparib in relapsed SCLC. (A) Study schema and biomarker analyses. (B) Waterfall plot showing change of tumor burden from baseline (investigator assessed; N = 19). One patient was not evaluable for response due to rapidly progressive disease before first restaging scans. Bar length represents decrease/increase in target lesion size. Bar color is the best overall response (according to RECIST 1.1). Indicated by asterisk is a patient who came off treatment after one cycle for brain-only disease progression but who had a partial response in the systemic disease-sites that lasted six months with no additional systemic therapy. Boxes above the waterfall plot indicate the smoking status, platinum sensitivity, RECIST response, PD-L1 expression and immunophenotype of pre-treatment tumors. (C) Spider plot of change in the sum of unidimensional tumor measurements over time. The red lines represent confirmed responders; blue lines represent patients with progressive disease; grey lines represent patients with stable disease. Light brown squares indicate the time points when patients came off treatment due to progressive disease in the brain. + indicates patients who are receiving treatment at data cut-off. * indicates the patient who came off treatment after one cycle for brain-only disease progression but who had a PR in the systemic disease-sites. One patient who was not evaluable is not included.

Figure 1.

Efficacy of durvalumab plus olaparib in relapsed SCLC. (A) Study schema and biomarker analyses. (B) Waterfall plot showing change of tumor burden from baseline (investigator assessed; N = 19). One patient was not evaluable for response due to rapidly progressive disease before first restaging scans. Bar length represents decrease/increase in target lesion size. Bar color is the best overall response (according to RECIST 1.1). Indicated by asterisk is a patient who came off treatment after one cycle for brain-only disease progression but who had a partial response in the systemic disease-sites that lasted six months with no additional systemic therapy. Boxes above the waterfall plot indicate the smoking status, platinum sensitivity, RECIST response, PD-L1 expression and immunophenotype of pre-treatment tumors. (C) Spider plot of change in the sum of unidimensional tumor measurements over time. The red lines represent confirmed responders; blue lines represent patients with progressive disease; grey lines represent patients with stable disease. Light brown squares indicate the time points when patients came off treatment due to progressive disease in the brain. + indicates patients who are receiving treatment at data cut-off. * indicates the patient who came off treatment after one cycle for brain-only disease progression but who had a PR in the systemic disease-sites. One patient who was not evaluable is not included.

Figure 2.

Representative responses. (A) CT images and (B) dynamic changes in circulating free DNA at the corresponding time points in a patient (#6) with a complete response. The right supraclavicular lymph node is indicated by red circles.

Figure 3.

Biomarker status and responses. SCLC immunophenotypes visualized on pre- and on-treatment (2-4 weeks later) biopsies stained immunohistochemically for the presence of PD-L1, CD3+ and CD8+ T cells (A) Immune inflamed phenotype in a patient with transformed SCLC (#19) and an ongoing partial response. Pre- and on-treatment biopsies stained immunohistochemically for the presence of PD-L1, CD3+ and CD8+ T cells (40X magnification). (B) Immune desert phenotype in a patient (#20) who had progressive disease. Pre- and on-treatment tumors show no T cell infiltration or PD-L1 expression (10X magnification). (C) Immune-excluded phenotype in a patient (#9) with arrows indicating the tumor-stroma margin with T cell infiltration post-treatment (10X magnification).