Abstract
IntroductionThis trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and MethodsA run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). ResultsIn the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. ConclusionThe combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes.
Highlights
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor that accounts for approximately 15% of all lung cancer cases.[1]
Because myelosuppression is an established toxicity of carboplatin exposure in SCLC patients,[25] the carboplatin dose was reduced from an AUC of 6 to an AUC of 5
While the toxicities seen with combination treatment reflected those previously reported for LM and carboplatin, a higher incidence of serious infections with fatal outcomes was observed in patients receiving the triplet regimen
Summary
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor that accounts for approximately 15% of all lung cancer cases.[1] SCLC has a high propensity to metastasize early during disease development. At diagnosis, it is classified into either limitedstage disease (LD) or extensive-stage disease (ED). In an effort to improve outcomes in ED-SCLC, a number of alternative approaches have been evaluated, such as 3-drug combinations, sequential combination therapies, and dose-intensified schedules.[8,9,10] To date, none of these alternate modalities has demonstrated a significant survival advantage over current combination therapy; the development of new strategies to effectively combat SCLC represents a critical unmet medical need
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