Lurbinectedin Combo Active in Chemo-Sensitive SCLC

Martin David Forster, MD, PhD

Martin David Forster, MD, PhD

Second-line treatment with the combination of lurbinectedin (Zepsyre; PM1183) and doxorubicin demonstrated significant clinical activity in patients with small cell lung cancer (SCLC), especially when excluding refractory patients, according to findings presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.¹

In particular, patients with chemotherapy-free intervals (CTFIs) of 90 days or more had a 53% overall response rate (ORR) and PFS of 5.7 months.

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/m²doxorubicin, 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/m²lurbinectedin plus 40 mg/m²doxorubicin on day 1 of each cycle every 3 weeks. Patients continued on 4 mg/m²lurbinectedin after the doxorubicin cumulative dose of 450 mg/m²was 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.

&ldquo;OS shows a remarkable improvement in this second-line setting, especially when excluding refractory patients,&rdquo; the researchers wrote.

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

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

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

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

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)