Hydroxychloroquine in combination with platinum doublet chemotherapy as first-line treatment for extensive-stage small cell lung cancer (Study 15): A randomised phase II multicentre trial

• Published in: European journal of cancer (1990) 2024-12, Vol.215, p.115162, Article 115162
• Main Authors: Lee, Siow Ming, Hewish, Madeleine, Ahmed, Samreen, Papadatos-Pastos, Dionysis, Karapanagiotou, Eleni, Blackhall, Fiona, Ford, Amy, Young, Robin, Garcia, Angel, Arora, Arvind, Hollingdale, Abigail, Ahmad, Tanya, Forster, Martin, Greystoke, Alastair, Bremner, Fion, Rudd, Robin, Farrelly, Laura, Vaja, Simran, Hackshaw, Allan
• Format: Article
• Language: English
• Subjects: Autophagy inhibitor; Chemotherapy; Concurrent and maintenance treatment; Hydroxychloroquine; Randomised trial; Small cell lung cancer
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2024.115162

Most patients with small-cell lung cancer (SCLC) present with extensive-stage (ES) disease and have a poor prognosis despite achieving high initial response rates to platinum-based doublet chemotherapy. This study evaluated whether adding hydroxychloroquine (HCQ) to chemotherapy could improve outcomes. This was a randomised multicentre phase II trial. Eligible patients had untreated ES-SCLC, a performance status 0–2 and measurable disease. Patients were randomly assigned (1:1 ratio) to HCQ (400 mg orally twice daily) plus carboplatin-gemcitabine or carboplatin–etoposide alone. Chemotherapy was administered for up to six cycles, with HCQ given concurrently and then as single agent for up to 30 months. Primary endpoint was PFS, aiming for a hazard ratio (HR) of 0.70. 72 patients were randomised (36 HCQ+chemotherapy and 36 chemotherapy alone). Median HCQ treatment duration was 4.4 months. HCQ did not improve PFS (HR 1·12 95 %CI 0·69–1.84; p = 0·64), with a median of 5.7 months (HCQ+chemotherapy) versus 6.2 months (chemotherapy). The corresponding median OS were 8.9 and 10.2 months (HR 0.83, 95 %CI 0.48–1.45, p = 0.52). Fewer patients in the HCQ arm completed four cycles of chemotherapy due to adverse events (64 % vs. 81 %). Grade ≥ 3 adverse events were higher in the HCQ+chemotherapy arm (83.3 % vs. 27.8 %), primarily anaemia, neutropenia, and thrombocytopenia, partly due to the initially higher gemcitabine dose used Combining HCQ with platinum doublet chemotherapy did not improve PFS or OS outcomes for ES-SCLC, resulting in more patients stopping chemotherapy due to increased adverse events. When considered alongside other randomised studies of HCQ in cancer, the evidence collectively indicates a limited role for HCQ as a therapeutic option. •Study 15 is the 1st & only randomised trial to examine an autophagy inhibitor in SCLC.•Combining HCQ with 1st-line platinum chemotherapy did not improve PFS or OS.•HCQ patients had more grade 3-4 adverse events & fewer completed 4 treatment cycles.•Evidence indicates HCQ has a limited role as an anti-cancer agent in various cancers.•Ongoing autophagy trials should monitor efficacy closely and stop early if futile.