Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m 2 daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8-5.7]; and median overall survival was 8.5 months (95% CI, 5.1-11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatoryresponse genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/ platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond. SIGNIFICANCE:We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC.

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

“…Reproducibility across datasets can be tested with CellMinerCDB by plotting the same gene (expression, copy number, or promoter methylation), drug, or microRNA on the x and the y axes. For instance, Schlafen 11 ( SLFN11 ), whose expression is highly predictive of response to a broad range of frontline treatments of SCLC (etoposide, topotecan, cis- and carboplatin) as well as drugs under investigation such as the poly(ADP-ribose polymerase) inhibitors ( Farago et al, 2019 ; Gardner et al, 2017 ; Murai et al, 2019 ; Zoppoli et al, 2012 ) measured by RNA-seq in the UTSW database, shows a 0.92 Pearson correlation with its measured values by Affymetrix microarray in the NCI database ( Figure 2B ). SLFN11 promoter DNA methylation in the NCI database also shows a Pearson correlation of 0.9 with its value in the GDSC ( Figure 2C ).…”

“…Analyses of SCLC-Global reveals lack of MGMT expression in 33% (N = 38) of the cell lines ( Figure S6D ). Notably, the non-NE SCLC cell lines all express MGMT, indicating that the SCLC-P- and -Y cancer cells are predicted to be poor candidates for TMZ-based therapies ( Farago et al, 2019 ).…”

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer

“…However, a recent trial published data, showing the safety and activity of a combination treatment of the PARP inhibitor Olaparib with the DNA damaging alkylating agent temozolomide in patients with relapsed SCLC. The combination was confirmed as safe and active, with an overall response (defined as >30% decrease in the sum of the longest diameter of target legions) in 41.7% of patients and median overall survival of 8.5 months (116). It has also been suggested that a combination of PARP1 inhibitors with immunotherapies may also be an effective combination treatment for lung cancers, particularly in tumors with other DNA repair defects, such as ERCC1 deficiency (117).…”

Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC)

“…NCT03041311 is investing combination carboplatin, etoposide, atezolizumab, and trilaciclib in ES-SCLC. PARP inhibitors have demonstrated, though modest, activity in SCLC patients (83). In addition to combinations with other cytotoxic agents, olaparib is being studied in combination with durvalumab.…”