Lurbinectedin Combo Induces Clinical Activity in Chemo-Sensitive SCLC

Martin David Forster, MD, PhD

Lurbinectedin (Zepsyre; PM1183) plus doxorubicin demonstrated significant clinical activity as a second-line therapy for patients with small cell lung cancer (SCLC), especially when excluding refractory patients.

In particular, patients with chemotherapy-free intervals (CTFIs) of 90 days or more induced a 53% overall response rate (ORR) and PFS of 5.7 months, according to findings that were presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.¹

Lurbinectedin is an investigational agent that received FDA orphan drug designation to treat patients with SCLC in August 2018. The agent inhibits RNA polymerase II, and by blocking trans-activated transcription, it induces apoptosis.²

“In transcriptionally addicted tumors, like SCLC, [lurbinectedin] cause a detachment of transcription factors from their promoters inhibiting its transactivity,” Martin Forster, MD, medical oncologist, University College London Hospitals, and colleagues wrote.

In a multicenter, phase Ib, 3+3 dose-escalation study, investigators administered 3-mg to 5-mg full-dose lurbinectedin plus 50 mg/m² doxorubicin, followed by dose expansion at radiotherapy dose to patients with select advanced diseases, including SCLC.

Findings of cohort A of this trial demonstrated clinical activity in the second-line setting among patients with SCLC with an objective response rate (ORR) of 67%. The partial response (PR) rate was 57% and the complete response (CR) rate was 10% (95% CI, 43%-85%). This activity was particularly significant in sensitive patients (chemotherapy-free interval [CTFI] >90 days), who induced an ORR of 100% (n = 11; PR, 82%; CR, 18%; 95% CI, 71.5%-100%).

The researchers conducted an expansion cohort with a reduced dose to improve efficacy and safety in the endometrial cancer and SCLC subgroups, which were also presented at this meeting (cohort B).

The trial included 28 patients aged <75 years with an ECOG performance score of 0 or 1 and with no more than 1 prior chemotherapy line and stable brain metastases who were treated with 2 mg/m² lurbinectedin plus 40 mg/m² doxorubicin on day 1 of each cycle every 3 weeks. Patients continued on 4 mg/m² lurbinectedin after the doxorubicin cumulative dose of 450 mg/m² was reached.

The majority of patients were male (75%), with a median age of 64 years (49-77). In addition, 68% had an ECOG performance score of 1, 4% had central nervous system (CNS) involvement, and 75% has bulky disease (>50 mm).

Median CTFI was 3.4 months (0-15.9), of which 36% were resistant (CTFI <90 days), and 64% were sensitive (CTFI >90 days). Median time to progression to the first-line platinum-based combination was 6.8 months (1.4-18.9).

The overall ORR was 37%—11% in resistant patients (n = 9) and 50% in the sensitive cohort (n = 18). When patients with CTFI <30 days were excluded, overall ORR was 48%, 33% in resistant patients (n = 3) and 50% in sensitive patients (n = 18).

Overall median progression-free survival (PFS) was 3.4 months (95% CI, 2-6), 1.5 months in the resistant cohort (95% CI, 1-5), and 5.7 months in the sensitive cohort (95% CI, 3-8). Overall 6-month PFS was 37% (95% CI, 19-55), 11.1% in resistant patients (95% CI, 0%-32%) and 50% in sensitive patients (95% CI, 27%-73%).

When the investigators excluded patients with CTFI <30 days, median PFS in the overall population improved to 5.3 months (95% CI, 2-7), and to 1.9 months (95% CI, 1-6) in the resistant cohort. Similarly, 6-month PFS improved to 47.6% in the entire cohort, and to 33.3% in resistant patients (95% CI, 0%-87%).

Overall median OS was 7.9 months (95% CI, 5-12), 4.9 months in resistant patients (95% CI, 2-7), and 11.5 months in sensitive patients (95% CI, 6-17). Moreover, overall 6- and 12-month OS rates were 59.2% (95% CI, 40%-79%) and 22.4% (95% CI, 4%-41%), respectively, 33% (95% CI, 3%-64%) and 0% (95% CI, 0%-0%) in resistant patients, and 75.4% (95% CI, 54%-97%) and 33.9% (96% CI, 8%-60%) in sensitive patients.

Excluding patients with CTFI <30 days, overall OS was 10.2 months (95% CI, 6-12), 6.7 months in resistant patients (95% CI, 5-8) and 11.5 months in sensitive patients (95% CI, 6-17). Overall 6- and 12-month OS was 73.6% (95% CI, 54%-95%) and 27.8% (95% CI, 5%-50%), respectively, 66.7% (95% CI, 13%-100%) and 0% (95 CI, 0%-0%) in the resistant group, and 75.4% (95% CI, 54%-96%) and 33.9% (95% CI, 8%-60%) in the sensitive group.

“OS shows a remarkable improvement in this second-line setting, especially when excluding refractory patients,” the researchers wrote.

The most common grade 4 adverse events (AEs) included neutropenia (68%), thrombocytopenia (11%), febrile neutropenia (7%), and aspartate aminotransferase (4%).

“Main hematological toxicity was myelosuppression, (which was) well-managed with (granulocyte colony-stimulating factor) and dose reductions,” the researchers added.

A phase III clinical trial (ATLANTIS, NCT02566993) is currently ongoing evaluating this combination in patients with relapsed SCLC.

“(The) lurbinectedin/doxorubicin combination showed remarkable activity (in the) second-line setting in SCLC, especially in sensitive patients,” the researchers wrote. “Activity is higher than reported for CAV (cyclophosphamide, doxorubicin [Adriamycin], and vincristine) or topotecan.”

References

1. Forster M, Moreno V, Calvo E, et al. Overall survival with lurbinectedin plus doxorubicin in relapsed SCLC: results from an expansion cohort of a phase Ib trial. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract P1.12-20.
2. Perez JMT, Leary A, Besse B, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): Results from a phase 2 study. J Clin Oncol. 2018;36(suppl; abstr 8570)