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Olaparib-temozolomide combination active in relapsed small cell lung cancer
Olaparib in combination with temozolomide demonstrated promising clinical activity among patients with relapsed small cell lung cancer, according to results of a phase 1/phase 2 trial published in Cancer Discovery.
“Small cell lung cancer, which accounts for about 15% of all lung cancers, historically has very poor outcomes, and novel treatment strategies are needed for this aggressive cancer type,” Anna F. Farago, MD, PhD, assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center, said in a press release. “This combinatorial therapy showed encouraging results in patients with relapsed small cell lung cancer, representing a new potential therapeutic strategy for these patients who typically have few effective treatment options.”
Poly(ADP-ribose) polymerase (PARP) inhibitors have shown limited activity in small cell lung cancer preclinical models and early-phase trials; however, DNA-damaging agents such as temozolomide may improve the effectiveness of these inhibitors, researchers noted.
For the single-arm trial, Farago and colleagues enrolled 50 patients (median age, 63 years; range, 39-85; 60% women) with previously treated small cell lung cancer, including 13 patients in the phase 1 dose-escalation study and 37 patients in the phase 2 dose-expansion study. Patients had received a median two (range, 1-7) previous treatments.
Patients in the phase 1 portion were treated using a 3 + 3 dose-escalation design, with a starting dose of 100 mg oral olaparib (Lynparza; AstraZeneca, Merck) twice daily and 50 mg/m2 oral temozolomide once daily.
Researchers administered treatment on days 1 to 7 of each 21-day cycle until disease progression, concurrent illness preventing further treatment or dose-limiting toxicities.
After evaluating four dose levels, researchers established a recommended phase 2 dose of 200 mg olaparib twice daily and 75 mg/m2 temozolomide once daily.
Patients enrolled in the phase 2 trial received the recommended phase 2 dose, with overall response rate serving as the primary endpoint.
Median follow-up was 7.1 months.
Results showed an ORR of 41.7%, including 20 partial responses and no complete responses, among the 48 evaluable patients treated in both phases of the study. Researchers observed responses at all dose levels, with a median duration of response of 4.3 months.
Among all 50 patients, median PFS was 4.2 months (95% CI, 2.8-5.7) and OS was 8.5 months (95% CI, 5.1-11.3).
The 39 evaluable patients treated at the recommended phase 2 dose demonstrated an ORR of 41%.
No dose-limiting toxicities, serious adverse events or grade 4 or grade 5 treatment-related toxicities occurred at any of the dose levels tested. The most common treatment-related adverse events, most of which were grade 1 or grade 2, included thrombocytopenia (68%), anemia (68%) and neutropenia (54%).
Researchers performed a subsequent co-clinical trial with 32 patient-derived xenograft models from 22 patients to determine which molecular signatures may be predictive of response to olaparib in combination with temozolomide.
Results showed that a signature of four inflammatory response genes — CEACAM1, TNFSF10, TGIF1 and OAS1 — distinguished between sensitive and resistant models.
“[Although] 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,” Benjamin Drapkin, MD, PhD, oncologist at Massachusetts General Hospital Cancer Center, said in a press release. “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.”
The single-arm nature of both trials served as the study’s primary limitation.
“This combination showed significant clinical activity in patients with relapsed small cell lung cancer and warrants investigation into a randomized study comparing olaparib plus temozolomide with the standard-of-care option,” Farago said. – by John DeRosier
Disclosures: Farago reports consultant/advisory roles with and/or research funding from AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb, Genentech, Ignyta, Loxo, Merck, Novartis and PharmaMar. Drapkin reports research funding from AbbVie, AstraZeneca, Merck and Novartis. Please see the study for all other authors’ relevant financial disclosures.