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G. Shankar



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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      MINI30.12 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Non-Squamous NSCLC (ID 1432)

      18:30 - 20:00  |  Author(s): G. Shankar

      • Abstract
      • Presentation
      • Slides

      Background:
      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.

      Methods:
      Overall, 158 patients were randomized to receive carboplatin (area under the curve [AUC] = 6 mg/ml/min), paclitaxel (200 mg/m[2]), 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.

      Results:
      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).

      Conclusion:
      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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      MINI30.13 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Squamous NSCLC (ID 1653)

      18:30 - 20:00  |  Author(s): G. Shankar

      • Abstract
      • Presentation
      • Slides

      Background:
      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.

      Methods:
      Overall, 160 patients were randomized to receive carboplatin (target area under the curve [AUC] = 6 mg/ml/min) and paclitaxel (200 mg/m[2]) 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.

      Results:
      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.

      Conclusion:
      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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