Reply to Yan et al.
Authors: Anish Thomas
Journal: Journal of Thoracic Oncology (2019)

I thank Yan et al.1Yan Y. Chen X. Wei J. Gong Z. et al.Immunotherapy combinations in patients with small cell lung cancers.J Thorac Oncol. 2019; 14: e244-e245Scopus (5) Google Scholar for their comments on our recent article in the Journal of Thoracic Oncology.2Thomas A. Vilimas R. Trindade C. et al.Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study.J Thorac Oncol. 2019; 14: 1447-1457Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Poly(ADP-ribose) polymerase inhibition increased programmed death ligand 1 (PD-L1) expression, augmented cytotoxic T-cell infiltration, and potentiated the antitumor effect of PD-L1 blockade in SCLC in preclinical studies.2Thomas A. Vilimas R. Trindade C. et al.Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study.J Thorac Oncol. 2019; 14: 1447-1457Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar In our clinical trial however, olaparib plus durvalumab did not improve responses in patients with relapsed SCLC compared with in historical controls of immune checkpoint blockade alone. 3Sen T. Rodriguez B.L. Chen L. et al.Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer.Cancer Disc. 2019; 9: 646-661Crossref PubMed Scopus (386) Google Scholar, 4Ready N. Farago A.F. de Braud F. et al.Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032.J Thorac Oncol. 2019; 14: 237-244Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar I agree with Yan et al.1Yan Y. Chen X. Wei J. Gong Z. et al.Immunotherapy combinations in patients with small cell lung cancers.J Thorac Oncol. 2019; 14: e244-e245Scopus (5) Google Scholar that with 20 patients, we cannot draw definitive conclusions in terms of efficacy of the combination. However, it is notable that the response rates were similarly low (four of 38 patients [11% response rate]) in a phase II basket study of olaparib plus durvalumab (the MEDIOLA trial). There were some differences in the patient populations studied (our trial included both platinum-sensitive and platinum-resistant patients, whereas the MEDIOLA trial included patients who relapsed ≥12 weeks after platinum-based therapy) and the schedule of drug administration (in our trial the drugs were administered concurrently, in the MEDIOLA trial olaparib monotherapy was administered for 4 weeks followed by combination with durvalumab). Yet, the combined data from both trials suggest that that only approximately 10% of unselected patients with relapsed SCLC derive durable benefit from the combination of poly(ADP-ribose) polymerase inhibitor and immune checkpoint blockade. Our study identified an important link between CD8-positive T-cell infiltration in SCLC and antitumor activity. Tumor responses were observed in all cases in which pretreatment tumors were T-cell–inflamed, suggesting that a preexisting CD8-positive T-cell response may be predictive of benefit. I agree with Yan et al.1Yan Y. Chen X. Wei J. Gong Z. et al.Immunotherapy combinations in patients with small cell lung cancers.J Thorac Oncol. 2019; 14: e244-e245Scopus (5) Google Scholar that this observation needs to be confirmed in a larger cohort. However, the combination did not result in an immune response in cases in which there was no preexisting immune response as evidenced by PD-L1 expression and or T-cell infiltration. I agree with Yan et al.1Yan Y. Chen X. Wei J. Gong Z. et al.Immunotherapy combinations in patients with small cell lung cancers.J Thorac Oncol. 2019; 14: e244-e245Scopus (5) Google Scholar that DNA damage repair mutations warrant consideration as a candidate biomarker and it is possible that the clinical benefit in the complete responder with a deleterious somatic BRCA1 mutation may be related to olaparib alone, not to the immunotherapy combination. Although the depth and durability of tumor regression suggest a contribution from an immune-mediated response, as acknowledged in the discussion, lack of a comparator group limits our ability to attribute the relative contribution of each drug to the clinical and biomarker response. Immunotherapy Combinations in Patients with Small Cell Lung CancersJournal of Thoracic OncologyVol. 14Issue 10PreviewThe study by Thomas et al.1 adds to the growing body of evidence that preexisting CD8-positive T-cell infiltrates in tumor cells could be predictive of benefit from immune checkpoint blockade combinations in patients with SCLC. Identification of tumor CD8-positive T-cell signatures may therefore help inform choice of treatment of patients with SCLC with an increased possibility of clinical response to immunotherapy-based approaches. However, several points should be investigated separately and comprehensively. Full-Text PDF Open Archive