Combination therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) and the chemotherapeutic agent temozolomide may offer a promising new therapeutic strategy in patients with previously treated small-cell lung cancer (SCLC), according to the results of a new phase I/II trial. 

Interestingly, the trial also revealed a molecular signature of SCLC tumors most likely to respond to the combination therapy.

Cancer cells. Source: Getty

“Small cell lung cancer, which accounts for about 15% of all lung cancers, historically has very poor patient outcomes, and novel treatment strategies are needed for this aggressive cancer type,” study author Anna F. Farago, MD, PhD, Assistant Professor of Medicine at Harvard Medical School in Boston, said in a statement “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.”

Reporting in a recent issue of Cancer Discovery, the investigators noted that although PARP inhibitors have demonstrated limited clinical efficacy in pre-clinical SCLC models and early-phase trials, the investigators noted, the addition of DNA-damaging agents such as alkylating drugs like temozolomide may enhance the activity of PARP inhibitors.  

To help test this hypothesis, the researchers enrolled 50 patients with previously treated SCLC into the single-arm trial between October 2015 and April 2018. Most participants (86%) had an Eastern Cooperative Oncology Group Performance Status of 1; the number of prior lines of cancer therapy ranged from one to seven (median two).  

Thirteen patients were included in the phase 1 dose-escalation study, which sought to identify the recommended drug dose for the second phase. The remaining 37 patients were enrolled in the trial’s second phase, whose objective was to evaluate the efficacy of the drug combination. 

Patients took olaparib and temozolomide on days one through seven of a 21-day cycle that was repeated until disease progression or unacceptable toxicity. A total of four dose levels were tested in the study’s first phase; the recommended olaparib dose was determined to be 200 mg twice daily, along with once-daily 75 mg/m2 temozolomide. 

Among the 48 evaluable patients who were treated in both portions of the study, the overall response rate was found to be 41.7%, comprising 20 partial responses and no complete responses. 

Similarly, among all 50 patients enrolled in the study, the median progression-free survival was 4.2 months, while median overall survival was 8.5 months. Among the 39 evaluable patients treated with the recommended phase-II dose, the objective response rate was 41.0%.

The most common treatment-related adverse events across both arms of the study were thrombocytopenia and anemia, each of which affected 68% of patients. Neutropenia was noted in 54% of patients. Two grade 5 adverse events occurred during the phase II portion of the study: one due to pneumonia and one due to neutropenic sepsis; both were deemed to be possibly attributable to the study drugs. 

The researchers also sought to identify molecular signatures that may be predictive of response to the olaparib-temozolomide combination. To do so, they conducted a co-clinical trial in 32 patient-derived xenograft models, which were derived from 22 patients. 

This analysis revealed that a molecular signature of four inflammatory response genes -- CEACAM1, TNFSF10, TGIF1, and OAS1 -- could distinguish between sensitive and resistant models; these results were consistent across both the discovery and validation cohorts. What’s more, low basal expression of these four genes was also associated with resistance to both the investigational combination as well as the platinum etoposide, the standard first-line chemotherapy for patients with SCLC. 

As the researchers noted, these results demonstrate a potential new therapeutic strategy in SCLC.

“This combination showed significant clinical activity in patients with relapsed small cell lung cancer,” Farago noted, “and warrants investigation in a randomized study comparing olaparib plus temozolomide with the standard-of-care option.” 

AstraZeneca was among the several sponsors of the study. Farago has served in consulting/advisory positions for several pharmaceutical companies, including AstraZeneca.