Safe, Prolonged Responses Observed with Lurbinectedin Plus Irinotecan in High-Risk Small Cell Lung Cancer

Small cell lung cancer: © Констянтин Батыльчук- stock.adobe.com

Lurbinectedin (Zepzelca) and irinotecan in the second line delivered a favorable risk/benefit profile and high, durable response rates in patients with high risk factors in small cell lung cancer (SCLC), particularly those with a chemotherapy treatment-free interval (CTFI) of more than 30 days, according to data from the dose-expansion portion of the phase 1/2 PM1183-A-014-15 study (NCT02611024).¹

Findings presented during the 2024 ASCO Annual Meeting showed that the doublet produced a 43.6% (95% CI, 33.7%-53.8%) overall response rate by independent review committee (IRC) in the overall population (n = 101), and the median duration of response (DOR) was 7.1 months (95% CI, 4.6-9.4). The median progression-free survival (PFS) was 4.7 months (95% CI, 3.8-5.7) and the median overall survival (OS) was 9.6 months (95% CI, 7.8-13.4). Additionally, the OS rate at 12 months was 43.4% (95% CI, 33.4%-53.4%).

Further assessment of efficacy according to CTFI interval revealed ORRs of 25.0% (95% CI, 14.0%-38.9%), 63.3% (95% CI, 48.3%-76.6%), and 52.7% (95% CI, 40.7%-64.4%) in patients with a CTFI less than 90 days (n = 52), 90 days or greater (n = 49), or greater than 30 days (n = 74), respectively. The median DOR at each respective interval was 6.9 months (95% CI, 3.9-7.6), 8.2 months (95% CI, 4.4-12.4), and 7.6 months (95% CI, 4.6-9.7). The median PFS at each interval was 3.3 months (95% CI, 2.6-5.0), 5.7 months (95% CI, 4.2-8.3), and 5.0 months (95% CI, 4.1-7.2); median OS was 7.5 months (3.5-8.8), 14.0 months (10.1-21.4), and 12.7 months (9.1-14.1). The 12-month OS rates for these respective groups were 25.3% (95% CI, 13.2%-37.5%), 63.1% (95% CI, 49.1%-77.2%), and 52.0% (95% CI, 40.3%-63.8%).

Luis Paz-Ares, MD

“The study demonstrated promising response rates, with a high proportion of patients experiencing prolonged DORs,” lead study author Luis G. Paz-Ares, MD, PhD, chair of the Medical Oncology Department at the Hospital Universitario 12 de Octubre and associate professor at the Universidad Complutense de Madrid, Spain, and colleagues, wrote in a poster presentation of the data. “Particularly notable results were observed in a population characterized by poor prognosis, primarily determined by known prognostic factors such as CTFI, central nervous system [CNS] involvement, and lactate dehydrogenase [LDH] levels.”

Lurbinectedin is approved by the FDA and other global regulatory agencies for the treatment of adult patients with metastatic SCLC who have experienced disease progression on or after platinum-based chemotherapy, and is considered a standard of care in this space. Preclinical studies have demonstrated synergy between lurbinectedin and irinotecan, supporting efforts to further evaluate the safety and clinical efficacy of this combined approach.

PM1183-A-014-15 evaluated the combination in pretreated patients with advanced solid tumors. In the phase 1b portion of this study, the regimen produced positive outcomes, and the recommended phase 2 dose (RP2D) was established as 2 mg/m2 of lurbinectedin on day 1 plus 75 mg/m2 of irinotecan on days 1 and 8. Treatment was administered every 3 weeks along with granulocyte colony–stimulating factor prophylaxis.

Accordingly, an expansion cohort of 101 patients with second-line SCLC was initiated. The combination was administered at the RP2D to patients with confirmed SCLC who had progressed after 1 platinum-containing regimen with or without a prior anti–PD-1 agent. Patients had controlled brain metastases and an ECOG performance status of 0 or 1. The study’s primary end point was ORR as assessed by an IRC.

The median age of patients on the study was 63.0 years (range, 45-77), and 41.6% were 65 years of age or older. The majority of patients were male (60.4%), White (98.0%), had an ECOG performance status of 1 (76.2%), and had extended-stage SCLC at diagnosis (91.1%). The median time from diagnosis was 7.7 months (range, 2.5-21.6), the time from last disease progression was 0.9 months (range, 0.2-3.0), and the time from the start of the last prior treatment to radiological progression was 5.6 months (range, 1.0-13.7). Patients had a median of 4 sites involved (range, 1-8). CNS or liver involvement was observed in 28.7% and 38.6% of patients, respectively. Abnormal LDH was observed in 56.4% of patients, and 40.6% had at least 1 lesion greater than 50 mm.

Over half of patients (54.5%) received prior radiotherapy, and 41.6% received prior immunotherapy. Prior carboplatin- and cisplatin-based chemotherapy was administered to 78.2% and 21.8% of patients, respectively. The median CTFI was 85 days (range, 0-323), with 48.5% experiencing a CTFI of 90 days or more. Among these patients, 38.6% were categorized as sensitive (CTFI between 90 to 180 days) and 9.9% were very sensitive (CTFI greater than 180 days). For those with a CTFI less than 90 days (51.4%), 26.7% were refractory (CTFI between 0 and 30 days) and 24.8% were resistant (CTFI between 31 and 89 days).

On their last prior platinum-based regimen, 68.3% of patients achieved a partial response, 3.0% had a complete response, 6.9% achieved stable disease, and 11.9% experienced PD.

Patients underwent a median of 6 cycles (range, 1-34) of treatment with lurbinectedin and irinotecan, and 29.7% of patients received more than 10 treatment cycles.

The safety profile of lurbinectedin plus irinotecan was deemed manageable, with a low percentage of treatment discontinuations (3.0%) and no treatment-related deaths were reported. Any-grade treatment-related adverse effects (TRAEs) were reported in 99.0% of patients, 70.3% of which were grade 3 or higher. Grade 3 or higher treatment-emergent AEs were observed in 86.1% of patients. Any-grade serious AEs occurred in 51.5% of patients, 47.5% of which were grade 3 or higher. Any-grade treatment-related serious AEs were reported in 26.7% of patients, of which 23.8% were grade 3 or higher. TRAEs led to dose delays or reductions in 31.7% and 50.5% of patients, respectively.

Drug-related or unknown AEs occurring in 5% of more of patients included fatigue (any-grade, 84.2%; grade 3/4, 18.8%), diarrhea (70.3%; 19.8%), nausea (52.5%; 5.0%), decreased appetite (42.6%; 4.0%), vomiting (35.6%; 6.9%), febrile neutropenia (10.9%; 10.9%), constipation (10.9%; 0.0%), weight decrease (9.9%; 0.0%), mucosal inflammation (6.9%; 0.0%), dysgeusia (5.9%; 0.0%), and arthralgia (5.0%; 1.0%).

Laboratory abnormalities observed included anemia (grade ≥1, 97.0%; grade 3/4, 28.7%), neutropenia (75.2%; 53.5%), lymphopenia (86.1%; 37.6%), thrombocytopenia (55.4%; 11.9%), aspartate aminotransferase increase (52.5%; 6.9%), alanine aminotransferase increase (63.4%; 7.9%), total bilirubin increase (21.8%; 1.0%), creatinine increase (89.1%; 1.0%), and creatine phosphokinase increase (8.9%; 2.0%).

“These encouraging results reinforce the rationale for including this combination as an experimental arm in the ongoing pivotal phase 3 LAGOON trial [NCT05153239] in relapsed SCLC with CTFI greater than 30 days,” investigators concluded.

Disclosures: Dr Paz-Ares reports the following disclosures: a leadership role with ALTUM Sequencing and Stab Therapeutics; stock and other ownership interests with ALTUM Sequencing and Stab Therapeutics; receiving honoraria from Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, Medscape, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Regeneron, Roche/Genentech, Sanofi, Takeda; serving in a consulting or advisory role for Abbvie, Amgen, AstraZeneca, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Pfizer, Pharmamar, Regeneron, Roche, Sanofi, Takeda; serving on a speakers’ bureau for AstraZeneca, BMS, Lilly, Merck Serono, MSD Oncology, Pfizer, Roche/Genentech; receiving institutional research funding from AztraZeneca, Bristol-Myers Squibb MSD, Pfizer, and PharmaMar, other institutional relationships with Amgen, Ipsen, Merck, Novartis, Pfizer, Roche, Roche, Sanofi, SERVIER

REFERENCE:

Paz-Ares L, Gonzalez AF, Navarro A, et al. Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in patients (Pts) with relapsed small cell lung cancer (SCLC): Results from a phase 2 expansion cohort. J Clin Oncol. 2024, 42(16): 8094. 10.1200/JCO.2024.42.16_suppl.8094