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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
MINI30.13 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Squamous NSCLC (ID 1653)
18:30 - 20:00 | Author(s): F. Denis
In squamous non-small cell lung cancer (NSCLC), the PI3-kinase (PI3K) pathway may be activated via several mechanisms including PIK3CA amplification and downregulation of phosphatase and tensin homolog (PTEN) expression; activation of this pathway can promote cell survival and enhance chemotherapy resistance. Pictilisib, a pan-PI3K inhibitor, potentiates the activity of taxanes and platinum agents in preclinical NSCLC models. This phase II, hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin and paclitaxel in patients with advanced or recurrent squamous NSCLC.
Overall, 160 patients were randomized to receive carboplatin (target area under the curve [AUC] = 6 mg/ml/min) and paclitaxel (200 mg/m) every 3 weeks with 340 mg oral pictilisib (n=81) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Pictilisib or placebo was continued daily until disease progression or intolerable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PIK3CA amplification (assessed by chromogenic in situ hybridization [CISH]). Overall survival (OS), objective response rate (ORR), safety, and PFS in the PTEN null/low subgroup were secondary endpoints. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.
Median PFS in the ITT population was 5.6 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.82; 90% CI 0.60–1.12). Median OS was 11.7 months in the pictilisib arm and 12.2 months in the placebo arm (HR 1.10; 90% CI 0.77–1.57). PFS and OS analyses in patients with PIK3CA amplification will be presented. Median PFS for the PTEN null/low subgroup was 6.7 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.69; 90% CI 0.42–1.13). ORR in the ITT population was 28% in the pictilisib arm and 34% in the placebo arm. Common grade ≥3 adverse events (AEs) included neutropenia (18%), rash (8%), and thrombocytopenia (7%). AEs led to higher proportion of discontinuations (22% in the pictilisib arm vs. 15% in the placebo arm) and AE-related deaths in the pictilisib arm (12 [14%] vs. 2 [3%] in the placebo arm). Deaths were due to disease progression or AEs typically reported in lung cancer. No unexpected safety signals were identified for pictilisib.
In this first phase II trial of a PI3K inhibitor in first-line squamous NSCLC, the combination of pictilisib with chemotherapy introduced additional toxicity with a minimal PFS improvement and no OS benefit in the ITT population. The safety profile was consistent with other pictilisib trials. PTEN null/low expression did not identify a subgroup with significantly improved efficacy, although the prognostic value of PTEN as a biomarker in squamous NSCLC cannot be excluded. Efficacy analysis in the PIK3CA amplification subgroup is ongoing and will be presented at the conference.
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