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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
MINI30.12 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Non-Squamous NSCLC (ID 1432)
18:30 - 20:00 | Author(s): N. Fadeeva
In non-squamous non-small cell lung cancer (NSCLC), PI3-kinase (PI3K) pathway activation, including downregulation of phosphatase and tensin homolog (PTEN) expression, may promote cell survival and enhance chemotherapy resistance. Additionally, mutations in KRAS have been shown preclinically to confer resistance to PI3K inhibition. The pan-PI3K inhibitor pictilisib potentiates the activity of taxanes, platinum agents, and antivascular endothelial growth factor therapy in preclinical models of NSCLC. This phase II hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin, paclitaxel, and bevacizumab in patients not treated for advanced or recurrent non-squamous NSCLC.
Overall, 158 patients were randomized to receive carboplatin (area under the curve [AUC] = 6 mg/ml/min), paclitaxel (200 mg/m), and bevacizumab (15 mg/kg) every 3 weeks (q3w) with 340 mg oral pictilisib (n=79) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Bevacizumab q3w with daily pictilisib or placebo was continued until disease progression or unacceptable 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 PTEN null/low expression (assessed by immunohistochemistry). Overall survival (OS), objective response rate (ORR), and safety were secondary endpoints. Pre-planned exploratory analyses included efficacy in the KRAS-wildtype subgroup. 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 6.9 months in the pictilisib arm and 5.9 months in the placebo arm (HR 0.82; 90% CI 0.59–1.13), while median OS was 13.6 months (pictilisib arm) versus 16.1 months (placebo arm) (HR 1.12; 90% CI 0.79–1.59). In patients with PTEN null/low expression, median PFS was 5.9 months (pictilisib arm) and 5.7 months (placebo arm) (HR 0.74; 90% CI 0.41–1.32). In the KRAS-wildtype subgroup, median PFS was 9.7 months (pictilisib arm) versus 5.7 months (placebo arm) (HR 0.70; 90% CI 0.45–1.09); median OS was 14.5 months in both arms. ORR in the ITT population was 37% (pictilisib arm) versus 29% (placebo arm). In the pictilisib arm, common grade ≥3 adverse events (AEs) included neutropenia (23%), rash (20%), thrombocytopenia (8%), febrile neutropenia (5%), and hyperglycemia (5%). AEs led to higher rates of discontinuation in the pictilisib arm (26% versus 16% in the placebo arm), particularly during the first 4 cycles. However, the proportion of AE-related deaths was higher in the placebo arm (9 [12%] versus 5 [6%] in the pictilisib arm).
This phase II trial of first-line pictilisib plus chemotherapy and bevacizumab in patients with non-squamous NSCLC showed a modest trend for improved PFS, with additional toxicity and no OS benefit. The safety profile was consistent with other pictilisib trials. PTEN null/low expression was not a predictive biomarker, although its prognostic value cannot be excluded. A trend for improved PFS, but not OS, was observed in the KRAS-wildtype subgroup, especially during the maintenance phase of treatment.
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