FDA approves new drug for metastatic SCLC

By Naveed Saleh, MD, MS
Published July 16, 2020

Key Takeaways

The FDA recently granted accelerated approval to lurbinectedin (Zepzelca, Pharma Mar) for adults with metastatic small cell lung cancer (SCLC) who progress during treatment with, or following treatment with, platinum-based chemotherapy. This accelerated approval was due to the drug’s overall response rate and duration of response; however, its continued approval may be contingent on confirmatory trials.

The efficacy of lurbinectedin was based on results of a multicenter, open-label trial involving 105 patients with metastatic SCLC either being treated with or following treatment with platinum-based chemotherapy. Every 21 days (one cycle), participants received intravenous infusion of 3.2 mg/m2 of lurbinectedin until disease progression or toxicity. Participants were administered a median of four cycles of lurbinectedin, with the number of treatments ranging from between one and 24 cycles.

Clinical trial results

The primary outcome for the study was confirmed overall response rate determined by RECIST 1.1 and response duration. In all 105 patients, the investigators reported an overall response rate (ORR) of 35% (95% CI: 26%–45%) with a median response duration of 5.3 months (95% CI: 4.1–6.4) compared with an ORR of 30% (95% CI: 22%–40%) with a median response of 5.1 months (95% CI: 4.9–6.4), according to results of independent review. 

Complete response in all patients was 0% and partial response was 35% per the researchers, and 0% and 30% per independent review, respectively. Duration of response was 6 months or greater in 35% of patients per initial study results and 25% per independent review committee.

In 45 patients with a chemotherapy-free interval of fewer than 90 days, the ORR was 22% (95% CI: 11%–37%) with a median duration of response of 4.7 months (95% CI: 2.6–5.6) per study results vs 13% (95% CI: 5%–27%) and 4.8 months (95% CI: 2.4–5.3) per independent review. Complete response was 0% per results of study investigators and independent reviewers alike, with partial response being 22% and 13%, respectively. Duration of response was 6 months or greater in 10% of patients per study results and 0% per independent review.

In the remaining 60 patients with a chemotherapy-free interval of 90 days or more, the ORR was 45% (95% CI: 32%–58%) with a median duration of response of 6.2 months (95% CI: 3.5–7.3) per the results of researchers compared with an ORR of 43% (95% CI: 31%–57%) and 5.3 months (95% CI: 4.9–7.0) in independent review. As with all other patients in the population, no patient in the sample showed complete response, and partial response was 45% per the researchers and 43% per independent review. Per study results, duration of response was 6 months or more in 44% of patients compared with that of 31% per independent review.

Drug pharmacology

Lurbinectedin is an alkylating drug that selectively inhibits cancer-cell transcriptions by binding guanine residues in the minor groove of DNA, which forms adducts that cause the DNA helix to bend toward the major groove. This adduct formation initiates a series of actions that impacts subsequent activity of DNA repair pathways and DNA binding proteins, such as some transcription factors, thus interfering with the oncogenic cell cycle and leading to cell death. 

Lab tests showed that the drug suppressed human monocyte activity in vitro and decreased macrophage infiltration in tumors implanted in mouse models.

The most frequent adverse reactions—occurring in 20% or more of patients—included myelosuppression, fatigue, nausea, constipation, decreased appetite, musculoskeletal pain, dyspnea, vomiting, cough, and diarrhea.  Frequent laboratory abnormalities included higher levels of creatinine, liver enzymes, and glucose, as well as decreased levels of albumin, magnesium, and sodium.  

In patients aged 65 and older, the frequency of serious adverse reactions was 49% compared with that of 26% in those younger. In the older age group, these serious reactions were related to myelosuppression and included febrile neutropenia, neutropenia, thrombocytopenia, and anemia.

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