Olaparib Combo Shows Promise in Small Cell Lung Cancer

Anna Farago, MD, PhDD

Combining the PARP inhibitor olaparib (Lynparza) with temozolomide (Temodar) led to an overall response rate (ORR) of 41.7% in patients with relapsed small cell lung cancer (SCLC), according to findings from a phase I/II trial published in Cancer Discovery.^1,2

The ORR comprised 20 partial responses among 48 evaluable patients. The median duration of response among the 20 responders was 4.3 months (95% CI, 2.8-5.4).

“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,” study author Anna 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 SCLC, representing a new potential therapeutic strategy for these patients who typically have few effective treatment options.”

Researchers are exploring methods of enhancing the effect of PARP inhibitors in SCLC, as preclinical and early phase research has shown limited clinical activity. Farago and coinvestigators hypothesized that PARP activity might be increased through the addition of the DNA-damaging agent temozolomide.

Fifty patients with SCLC were enrolled in the single-arm trial between October 2015 and April 2018. The median patient age was 63 (range, 39-85), and there were 20 males and 30 females. The majority (n = 43) of patients had an ECOG performance status (PS) of 1, with six patients having a PS of 0, and 1 patient having a PS of 2.

The study accrued a pretreated population who had received a median of 2 prior treatments (range 1 to 7). Thirty-six patients were platinum sensitive and 14 were platinum resistant. Twenty patients had baseline brain metastases, with 8 being treated for the metastases and 12 not being treated.

The phase I dose-escalation part of the study treated 13 patients with the goal of determining the recommended phase II dose (RP2D). The phase II dose-expansion part of the study enrolled 37 patients who received the RP2D.

In both parts of the study, patients received olaparib and temozolomide, both orally, on the first 7 days of each 21-day cycle until disease progression or unacceptable toxicity. The RP2D was 200 mg of olaparib twice daily and temozolomide at 75 mg/m² daily.

Beyond the 41.7% ORR, the stable disease rate was 37.5% (n = 18) and the progressive disease rate was 20.8% (n = 10). In all 50 enrolled patients, the median progression-free survival (PFS) was 4.2 months (95% CI, 2.8-5.7) and the median overall survival (OS) was 8.5 months (95% CI, 5.1-11.3).

In the 34 platinum-sensitive patients who were evaluable, the ORR was 47.1%, the median PFS was 4.5 months, and the median OS was 9.4 months. Among the 14 evaluable platinum-resistant patients, the ORR was 28.6%, the median PFS was 2.9 months, and the median OS was 7.4 months.

The most common treatment-related adverse events (AEs) across all patients were thrombocytopenia (68%), anemia (68%), and neutropenia (54%). In the phase II part of the study, there were 2 patient deaths (pneumonia, neutropenic sepsis) that the researchers considered to potentially be related to treatment.

The researchers also sought to identify predictive efficacy biomarkers for the olaparib/ temozolomide regimen through a co-clinical trial involving patient-derived xenograft models. Four inflammatory response genes (CEACAM1, TNFSF10, TGIF1, and OAS1) emerged as potential indicators for response. Further, resistance to both standard frontline chemotherapy for patients with SCLC and the olaparib/temozolomide combination was linked to low basal expression of these biomarkers.

“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,” study author Benjamin Drapkin, MD, PhD, oncologist at Massachusetts General Hospital Cancer Center, said in the 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.”

References

1. Combinatorial Therapy Shows Early Promise in Patients With Relapsed Small Cell Lung Cancer. American Association for Cancer Research. Published August 15, 2019. Accessed August 15, 2019. https://bit.ly/2KzKppu.
2. Farago AF, Yeap BY, Stanzione M, et al. Combination olaparib and temozolomide in relapsed small cell lung cancer [published online August 15, 2019]. Cancer Discov. doi: 10.1158/2159-8290.CD-19-0582.