Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Objectives: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methods: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m(2)) was dosed every other day (qod) for 21 days (28-day cycle) for <= 4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m(2)) was administered once every 3 weeks for <= 6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m(2) SNX-5422 monotherapy qod for 21 days (28-day cycle). Results: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had >= 1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m(2) qod in combination with carboplatinpaclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/ 15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy >= 2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n =1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). Conclusions: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.