Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study

Abstract

Background: Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).

Patients and methods: Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days).

Results: Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease.

Conclusion: Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.

Keywords: PM01183; lurbinectedin; phase I study; small-cell lung cancer.

Figure 1.

Waterfall plot showing maximum variation of target lesions and progression-free survival in patients with at least one radiological tumor assessment (n = 26). Sixteen patients had target lesion decrease >30%: 15 with CR or PR, and 1 with PD who had response in extracranial lesions and disease progression in the brain. Red stars = treatment switch to PM01183 alone. 2nd/R, second-line therapy and resistant disease; 2nd/S, second-line therapy and sensitive disease; 3rd/R, third-line therapy and resistant disease; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2.

Kaplan–Meier plot of progression-free survival with doxorubicin/PM01183. 2nd/R, second-line therapy and resistant disease; 2nd/S, second-line therapy and sensitive disease; 3rd/R, third-line therapy and resistant disease; C, censored; CI, confidence interval; PFS, progression-free survival.