Olaparib/Temozolomide Shows Activity in Patients With Relapsed Small Cell Lung Cancer
Small cell lung cancer accounts for approximately 15% of all lung cancers and has high metastatic potential and poor clinical outcomes. While untreated small cell lung cancers are usually highly sensitive to cytotoxic chemotherapy—with response rates of between 50% and 70%—patients often relapse, necessitating novel treatments strategies.
A phase I/II study of a combination of the poly ADP ribose polymerase (PARP) inhibitor olaparib and the chemotherapy agent temozolomide in patients with relapsed small cell lung cancer has found that the therapy had substantial clinical activity in these patients. In addition, a clinical study in animal models to identify molecular signatures that may be predictive of response to the therapy has found that a specific molecular signature of four inflammatory response genes could distinguish sensitive from resistant models in both the discovery and validation cohorts, and may provide a molecular signature of those tumors most likely to respond to olaparib/temozolomide. The study by Farago et al is published in Cancer Discovery.
Study Methodology
In the single-arm study, researchers enrolled 50 patients with previously treated small cell lung cancer between October 2015 and April 2018. The number of prior lines of treatment was between one and seven (median = two). Thirteen patients were enrolled in the phase I dose-escalation study, with the primary objective of identifying the recommended phase II dose. Thirty-seven patients were enrolled in the phase II dose-expansion portion of the trial, with the primary objective of evaluating efficacy.
The patients received oral olaparib and temozolomide on days 1 through 7 of a 21-day cycle, which was repeated until disease progression or unacceptable toxicity occurred. Four dose levels were evaluated in the phase I portion of the study, and the recommended phase II dose was determined to be 200 mg of olaparib twice daily with 75 mg/m2 of temozolomide once daily.
To identify molecular signatures that may be predictive of response to the combination of olaparib/temozolomide, the researchers conducted a co-clinical trial in 32 patient-derived xenograft models from 22 patients.
Results
The researchers found that the overall response rate (ORR) among the 48 evaluable patients treated in both portions of the study was 41.7% (20 partial responses, no complete responses). Among all 50 patients enrolled in the study, the median progression-free survival and median overall survival were 4.2 months and 8.5 months, respectively. Among evaluable patients treated at the recommended phase II dose (39 patients), the ORR was 41.0%.
Across both arms of the study, the most common treatment-related adverse events were thrombocytopenia (68%), anemia (68%), and neutropenia (54%). Two grade 5 adverse events occurred in the phase II portion of the study, which were possibly attributable to the study drugs (one due to pneumonia and one due to neutropenic sepsis).
The researchers determined from patient-derived xenografts that a specific molecular signature of four inflammatory response genes (CEACAM1, TNFSF10, TGIF1, and OAS1) could distinguish sensitive from resistant models in both the discovery and validation cohorts. Additionally, low basal expression of these genes was associated with resistance to both the investigational combination and to platinum/etoposide, the standard first-line chemotherapy for patients with small cell lung cancer.
“While biomarkers for drug response have been identified for several cancers, we don’t have any good biomarkers of response for small cell lung cancer treatments,” said co-lead study author Benjamin J. Drapkin, MD, PhD, a medical oncologist at Massachusetts General Hospital Cancer Center, in a statement. “Our co-clinical trial in animal models was an important first step in the identification of a potential prognostic signature of response to both the standard first-line chemotherapy and for our investigational combination.”
Disclosure: For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.
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