Abstract
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles. Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.
Highlights
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers and is a leading cause of cancer-related mortality [1]
While objective response rates (ORRs) to first line combination chemotherapy, such as cyclophosphamide, doxorubicin, vincristine (CAV), cyclophosphamide, doxorubicin, etoposide, or cisplatin/carboplatin plus etoposide are robust at 60–70% in those with extensive stage disease, eventually resistance develops to chemotherapy and relapses typically occur early within 3–6 months [2]
Another topoisomerase inhibitor approved in Japan for relapsed SCLC, was shown to be superior to topotecan in a study done in the Japanese population [6], but the results were not replicated in the Western population [7]
Summary
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers and is a leading cause of cancer-related mortality [1] This disease follows an aggressive course with median survival ranging from 12–20 months in patients with limited stage disease, with only 6–12% of patients living beyond 5 years. Platinum-sensitive relapse is frequently defined as relapse that occurs beyond 90 days of completion of platinumbased combination chemotherapy. In such patients, early trials of reinduction chemotherapy with the same regimen used at initial diagnosis produced an ORR of 50% [4]. Platinum-resistant relapse is defined as relapse that occurs within the first 90 days of completion of platinum-based combination chemotherapy. Objective responses to single agent newer chemotherapy agents range from 14 to 29% [8]
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