Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers
Mené sur 23 patients atteints d'un cancer du poumon de stade avancé (âge médian : 60 ans), cet essai multicentrique de phase I évalue la dose maximale tolérée de SNX-5422 (un inhibiteur de HSP90 dispensé par voie orale) en combinaison avec le carboplatine et le paclitaxel et l'efficacité, du point de vue du taux de réponse, de cette combinaison suivie d'un traitement d'entretien par SNX-5422
Résumé en anglais
Objectives : Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity inoncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxelf ollowed 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/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤ 4 cycles; carboplatin(AUC 5)-paclitaxel (175 mg/m2) 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/m2 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/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-relatedgrade 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, 55%(10/18) stable disease, and 11% (2/18) progressive disease. Patients who remainedon single-agent SNX-5422 maintenance therapy ≥ 2 months (n=9) had cancers enrichedfor 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 maintenanceSNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for whichdisease control on single-agent SNX-5422 maintenance was observed were enriched foroncogene-driven NSCLCs.
