Lurbinectedin/Pembrolizumab Shows Significant Activity in Relapsed SCLC

"...The reported feasibility and activity of this combination warrant further evaluation in switch maintenance in the metastatic setting or consolidation after definite chemoradiation for patients with limited-stage SCLC," according to the study authors.

Combining lurbinectedin (Zepzelca) with pembrolizumab (Keytruda) elicited significant activity in a small cohort of patients with relapsed small cell lung cancer (SCLC), according to data from the phase 1/2 LUPER study (NCT04358237) published in Journal of Thoracic Oncology.¹

Among 28 evaluable patients, the unconfirmed objective response rate (ORR) was 46.4% (95% CI, 27.5%-66.1%), with complete responses (CRs) in 10.7% and partial responses (PRs) in 35.7%. In the platinum-sensitive disease subgroup (n = 14), treatment yielded an ORR of 57.1% (95% CI, 28.9%-82.3%) and a clinical benefit rate (CBR) of 78.6% (95% CI, 49.2%-95.3%); these respective rates were 35.7% (95% CI, 12.8%-64.9%) and 42.9% (95% CI, 17.7%-71.1%) for patients with platinum-resistant disease (n = 14).

Data showed a median duration of response (DOR) of 7.8 months (95% CI, 2.8-19.1) across the overall population, 11.9 months (95% CI, 2.8-not achieved [NA]) in the platinum-sensitive population, and 4.4 months (95% CI, 0.9-NA) in the platinum-resistant population. Approximately 40% of those with a response had sustained responses following 12 months of treatment.

The median progression-free survival (PFS) and overall survival (OS) was 4.6 months (95% CI, 2.7-6.0) and 10.5 months (95% CI, 6.9-17.6) across the overall population, respectively. In the platinum-sensitive and platinum-resistant populations, respectively, the median PFS was 8.0 months (95% CI, 2.7-15.2; P = .012) and 2.8 months (95% CI, 1.2-5.6), and the median OS was 15.7 months (95% CI, 7.7-NA; P = .058) and 7.1 months (95% CI, 1.4-11.1). According to exploratory analyses, PFS and OS benefits occurred in patients with an ECOG performance status of 0 and those with baseline IL-6 levels within or under the normal range.

“In the LUPER phase 1/2 study, the combination of lurbinectedin and pembrolizumab reported promising efficacy and manageable safety as a second-line treatment for patients with SCLC who had not received prior immunotherapy,” lead study author Antonio Calles, MD, MSc, from the Medical Oncology Department at Hospital General Universitario Gregorio Marañón of Instituto de Investigación Sanitaria Gregorio Marañón in Madrid, Spain, wrote with coauthors.¹ “The study is limited by its single-arm design with no control group and the relatively small cohort of patients…Despite these limitations, the reported feasibility and activity of this combination warrant further evaluation in switch maintenance in the metastatic setting or consolidation after definite chemoradiation for patients with limited-stage SCLC.”

In the single-arm, open-label, multicenter phase 1/2 LUPER trial, patients received lurbinectedin at the recommended phase 2 dose (RP2D) of 3.2 mg/m² plus pembrolizumab at 200 mg intravenously every 3 weeks.

The trial’s primary end points included the maximum-tolerated dose and RP2D in phase 1 and ORR per investigator assessment using RECIST v1.1 criteria in phase 2. Secondary end points included CBR, DOR, PFS, and OS.

Patients 18 years and older with histologically confirmed SCLC and progressive disease following frontline chemotherapy, at least 4 weeks since receipt of the last anticancer therapy, and available archival tumor tissue sample were eligible for enrollment on the trial.² Other eligibility criteria included having an ECOG performance status of 0 or 1, adequate organ function, and measurable disease based on RECIST v1.1 guidelines.

The median patient age was 65.5 years (range, 41.0-78.0), and most patients were male (53.6%). Additionally, most of the study population had extensive disease (89.3%), an ECOG performance status of 1 (64.3%), former smoking status (64.3%), no prior treatment with PD-1 or PD-L1 inhibitors (100.0%), no central nervous system involvement (78.6%), and no liver metastases (53.6%).

Per iRECIST criteria, the immune ORR was 50.0% (95% CI, 30.6%-69.4%), the immune CBR was 75.0% (95% CI, 55.1%-89.3%), and the median immune PFS was 5.4 months (95% CI, 3.0-7.4).

Investigators administered subsequent antitumor therapy to 32.1% (n = 9) of patients who experienced disease progression on lurbinectedin/pembrolizumab, with the most common agents including topotecan (Hycamtin; 44.4%) and irinotecan (Camptosar; 33.3%) as third-line treatment and carboplatin/paclitaxel (28.6%) as fourth-line therapy. The median time to next treatment was 7.1 months (range, 4.6-11.1) across the overall population, 11.2 months (95% CI, 4.6-NA; P = .022) in the platinum-sensitive population, and 5.1 months (95% CI, 1.4-10.0) in the platinum-resistant population. Among patients who received subsequent therapy following the LUPER trial regimen, the median time to progression was 3.7 months (95% CI, 1.4-NA).

In the phase 2 portion of the trial, any-grade treatment-emergent adverse effects (TEAEs) affected 100.0% of patients, and 82.1% experienced grade 3 to 5 toxicities. The most common any-grade and grade 3 to 5 TEAEs, respectively, included blood and lymphatic system disorders (82.1% vs 60.7%), general disorders and administration site conditions (78.6% vs 10.7%), fatigue (75.0% vs 7.1%), gastrointestinal disorders (71.4% vs 3.6%), and neutropenia (67.9% vs 46.4%).

Overall, 17.9% of patients discontinued study therapy due to TEAEs. Additionally, investigators reported 2 deaths due to TEAEs that were unrelated to study treatment, which included COVID-19 infection and febrile neutropenia with respiratory failure. One death related to lurbinectedin occurred due to sepsis induced via Pseudomonas aeruginosa.

References

1. Calles AA, Navarro A, Doger de Speville Uribe BG, et al. Lurbinectedin plus pembrolizumab in relapsed SCLC: the phase I/II LUPER study. J Thorac Oncol. 2025:S1556-0864(25)00064-4. doi:10.1016/j.jtho.2025.02.005.
2. Lurbinectedin (PM01183) combined with pembrolizumab in small cell lung cancer. (LUPER). ClinicalTrials.gov. Updated February 21, 2025. Accessed April 21, 2025. https://tinyurl.com/3put7k7e