Discovery of targetable genomic alterations, including mutations of EGFR, have resulted in improved survival for patients with non-small cell lung cancer (NSCLC).1 Although many patients experience robust responses to EGFR-targeted therapy, acquired drug resistance is almost inevitable. Small cell lung cancer (SCLC) transformation as a mechanism of acquired resistance is reported in up to 14% of patients treated with EGFR TKIs.2,3 Although genetic alterations in TP53 and RB1 are reported as potential predictors of SCLC transformation,4 the mechanisms are unknown. Transformed SCLC is associated with notably poor prognosis, with overall survival of 9 to 10 months after transformation, similar to de novo SCLC. Although EGFR-mutated transformed SCLC is treated with platinum-based systemic chemotherapy with response rates of approximately 50%, almost all tumors progress within several months, and there are no standard treatments at relapse for these patients.5,6
Programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibitors have shown modest antitumor efficacy in SCLC, especially in the setting of recurrence after first-line platinum-based chemotherapy.7,8 One approach to augment the clinical activity of immune checkpoint inhibitors is to modulate the DNA damage response. Accumulating preclinical evidence suggests that DNA double-strand break and cytosolic DNA can induce antitumor immunity through mechanisms including the cGAS-STING pathway activation.9 We previously conducted a phase II clinical trial with the combination treatment of the PD-L1 inhibitor durvalumab and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients with recurrent or relapsed SCLC.10 The study did not meet its primary endpoint of the objective response rate (2 out of 19 [10.5%] evaluable patients with SCLC achieved a partial response with combination durvalumab and olaparib; similar to that with immune checkpoint inhibitor alone in the same setting7,8). However, we observed an exceptionally durable response in a patient with EGFR-mutated transformed SCLC. Paired pre- and post-treatment tumors of this patient demonstrated induction of tumor-infiltrating lymphocytes following treatment. Intriguingly however, none of the 17 patients with EGFR-mutated transformed SCLC had any response with single-agent immune checkpoint inhibitors in a previous retrospective study.6 A recent preclinical study also reported sensitivity of tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutated NSCLC cell lines and animal models to PARP inhibitors.11 Another recent study applied multiomics approaches to identify greater activation of pro-inflammatory and immune-related pathways in transformed SCLC compared with de novo SCLC.12
We recently launched a phase II clinical trial of durvalumab and olaparib in patients with EGFR-mutated transformed SCLC.13 Patients with EGFR-mutated NSCLC and transformation to SCLC are eligible after at least one platinum-based chemotherapy. ECOG performance status should be equal to or less than 2. Patients who previously received immunotherapy are eligible. Patients who have had treatment for a brain metastasis and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled. Patients with a history of autoimmune disease requiring steroid maintenance or a history of primary immunodeficiency, myelodysplastic syndrome, or acute myeloid leukemia are excluded because of toxicity with durvalumab and olaparib, respectively. Patients will receive durvalumab 1,500 mg intravenously every 28 days and olaparib 300 mg twice daily orally in 28-day cycles. Patients are evaluated for toxicity every 4 weeks by CTCAE v5.0 and for response approximately every 8 weeks by RECIST 1.1. Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint is objective response rate.
SCLC transformation will likely be recognized with increasing frequency with more targeted anticancer treatments and with more regular practice of tumor re-biopsy upon disease progression. Our clinical trial may shed light into mechanisms underlying therapeutic responses of these highly recalcitrant cancers and provide patients with a potential treatment option.
- Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640-649.
- Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
- Schmid S, Li JJN, Leighl NB. Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer. 2020;147:123-129.
- Lee J-K, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35(26):3065-3074.
- Ferrer L, Giaj Levra M, Brevet M, et al. A brief report of transformation from NSCLC to SCLC: molecular and therapeutic characteristics. J Thorac Oncol. 2019;14(1):130-134.
- Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J Clin Oncol. 2019;37(4):278-285.
- Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895.
- Chung HC, Lopez-Martin JA, Kao SC-H, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018;36(15)(suppl):8506.
- Sen T, Rodriguez BL, Chen L, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 2019;9(5):646-661.
- Thomas 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(8):1447-1457.
- Marcar L, Bardhan K, Gheorghiu L, et al. Acquired resistance of EGFR-mutated lung cancer to tyrosine kinase inhibitor treatment promotes PARP inhibitor sensitivity. Cell Rep. 2019;27(12):3422-3432.e3424.
- Quintanal-Villalonga A, Taniguchi H, Zhan YA, et al. Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation. bioRxiv. 2020;12.02.408476. https://doi.org/10.1101/2020.12.02.408476
- ClinicalTrials.gov. Olaparib (LYNPARZA) plus durvalumab (IMFINZI) in EGFR-mutated adenocarcinomas that transform to small cell lung cancer (SCLC) and other neuroendocrine tumors. Accessed January 21, 2021. https://clinicaltrials.gov/ct2/show/NCT04538378