Olaparib/Durvalumab Fails to Improve DCR, Potentially Improves Survival in SCLC

Treatment with olaparib (Lynparza) and durvalumab (Imfinzi) did not meet the prespecified target for 12-week disease control rate (DCR), however, it demonstrated potential for improved overall survival (OS) in patients with pretreated small cell lung cancer (SCLC), according to data from the phase 1/2 MEDIOLA trial (NCT02734004).

Grade 3 or higher adverse effects occurred in 80% of patients enrolled in the phase 1/2 MEDOLA trial.

In an efficacy population of 38 patients, the 12-week DCR rate was 28.9% (90% CI, 17.2%-43.3%). Additionally, the overall response rate (ORR) was 10.5% (95% CI, 2.9%-24.8%). Investigators also reported a median progression-free survival (PFS) of 2.4 months (95% CI, 0.9-3.0) and an OS of 7.6 months (95% CI, 5.6-8.8).

In the safety population (n = 40), grade 3 or higher adverse effects (AEs) occurred in 80% of patients including anemia (40.0%) and lymphopenia (12.5%). Common AEs included anemia (75.0%), nausea (47.5%), and fatigue (40.0%).

The open-label, single-arm, multicenter, international basket study took place in 18 centers across the United States, United Kingdom, France, Israel, the Netherlands, South Korea, and Switzerland. To enroll in the trial, patients needed to be 18 years or older with histologically or cytologically confirmed relapsed limited- or extensive-stage SCLC. Additional inclusion criteria included measurable disease by CT or MRI via RECIST 1.1 criteria, sensitivity to platinum-based chemotherapy, an ECOG performance status of 0 or 1, a life expectancy of 12 weeks or longer, and reasonable baseline organ and bone marrow function.

Those who had undergone treatment with chemotherapy, received another systemic anticancer therapy, or radiotherapy within 4 weeks of starting treatment were not able to participate in the study.

Patients were treated with 300 mg of oral olaparib twice daily for 4 weeks with a subsequent 300 mg dose twice daily plus 1500 mg of intravenous durvalumab every 4 weeks until disease progression or intolerable toxicity. Patients who experienced AEs associated with olaparib could receive supportive care or dose interruptions/reductions to either 250 mg or 200 mg twice daily. Dose re-escalation was not possible.

The study’s primary end points were safety/tolerability and 12-week DCR rate. Secondary end points included 28-week DCR rate, ORR, duration of response, PFS, change in tumor size at 12 and 28 weeks, and time to treatment discontinuation or death.

The median patient age was 62.5 years (range, 44-76), and 55.3% of patients were male. Additionally, most patients had previously received 1 line of chemotherapy (71.1%) and radiotherapy (78.9%), had extensive-stage disease (86.8%), and had an ECOG performance status of 1 (76.3%).

Investigators screened a total of 64 patients between May 2016 to December 2016, 40 of whom met the study’s criteria and were included in the SCLC group. In the safety analysis group, all patients received at least 1 dose of olaparib, and 92.5% received at least 1 dose of durvalumab. It was reported that 2 patients from the safety set were excluded from the full analysis set due to disease relapse less than 12 weeks following previous treatment with platinum-based chemotherapy. In this population, all patients were treated with olaparib and 87.5% were given durvalumab.

No patients remained on treatment as of the trial’s clinical cutoff of June 2019. Common reasons for discontinuation in the olaparib and durvalumab arms, respectively, were disease progression (68.4% vs 74.3%), AEs (21.1% vs 17.1%), patient decision (2.6% vs 2.9%), and other reasons (7.9% vs 5.7%). Death led to study termination in 90% of patients.

The median treatment duration was 12.1 weeks for olaparib and 8.0 weeks for durvalumab. A total of 7.5% of patients were not treated with durvalumab in the combination portion of the study because of disease progression (n = 2) or gastric hemorrhage as a fatal serious AE (n = 1).

Investigators reported grade 4 pneumonia related to durvalumab in 1 patient and lymphopenia related to both study drugs in another. Moreover, 3 patients developed grade 5 AEs, including pancytopenia related to olaparib.

Reference

Krebs MG, Delord JP, Evans TRJ, et al. Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): an open-label, multicenter, phase 1/2, basket study. Lung Can. Published online April 23, 2023. doi:10.1016/j.lungcan.2023.107216