Original Research| Volume 86, P186-196, November 2017

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A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer

Published:October 06, 2017DOI:


      • Pictilisib is a potent class I pan-PI3K inhibitor.
      • The pictilisib combination treatments were feasible from a safety perspective.
      • No drug–drug interactions were observed in the combination treatment regimens.
      • Encouraging preliminary anti-tumour activity was observed.



      The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.

      Patients and methods

      A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.


      All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a ‘14 days on, 7 days off’ schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.


      Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.


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        • Stewart B.W.
        • Wild C.P.
        World cancer report 2014.
        International Agency for Research on Cancer (WHO), Lyon, France2014
        • Perez-Moreno P.
        • Brambilla E.
        • Thomas R.
        • Soria J.C.
        Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities.
        Clin Cancer Res. 2012; 18: 2443-2451
        • Masters G.A.
        • Temin S.
        • Azzol2i C.G.
        • Giaccone G.
        • Baker Jr., S.
        • Brahmer J.R.
        • et al.
        Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update.
        J Clin Oncol. 2015; 33: 3488-3515
      1. NCCN clinical practice guidelines in oncology (NCCN guidelines®): non-small cell lung cancer. Version 4. 2016 (Available from:)
        • Reck M.
        • Popat S.
        • Reinmuth N.
        • De Ruysscher D.
        • Kerr K.M.
        • Peters S.
        • et al.
        Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2014; 25 (iii27–39)
      2. Approved drugs. Pembrolizumab (KEYTRUDA) checkpoint inhibitor. Available from:

      3. SEER cancer statistics review 1975-2013. Table 15.14. non-small cell cancer of the lung and bronchus (invasive): 5-year relative and period survival by race, sex, diagnosis year, age and stage at diagnosis. Available from:

        • Fumarola C.
        • Bonelli M.A.
        • Petronini P.G.
        • Alfieri R.R.
        Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer.
        Biochem Pharmacol. 2014; 90: 197-207
        • Folkes A.J.
        • Ahmadi K.
        • Alderton W.K.
        • Alix S.
        • Baker S.J.
        • Box G.
        • et al.
        The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer.
        J Med Chem. 2008; 51: 5522-5532
        • O'Brien C.
        • Wallin J.J.
        • Sampath D.
        • GuhaThakurta D.
        • Savage H.
        • Punnoose E.A.
        • et al.
        Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.
        Clin Cancer Res. 2010; 16: 3670-3683
        • Spoerke J.M.
        • O'Brien C.
        • Huw L.
        • Koeppen H.
        • Fridlyand J.
        • Brachmann R.K.
        • et al.
        Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models.
        Clin Cancer Res. 2012; 18: 6771-6783
        • Sarker D.
        • Ang J.E.
        • Baird R.
        • Kristeleit R.
        • Shah K.
        • Moreno V.
        • et al.
        First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.
        Clin Cancer Res. 2015; 21: 77-86
      4. Common terminology criteria for adverse events (CTCAE). Version 3.0. 2009 (Available from:)
        • Ware J.A.
        • Jin J.Y.
        • Lu D.
        • Cheeti S.
        • Lum B.
        • Ding X.
        • et al.
        Exploratory assessment of the drug-drug interaction (DDI) risk using SIMCYP and population PK simulation for the pan-phosphatidylinositide-3 kinase (PI3K) inhibitor GDC-0941, a potential CYP2C8 inhibitor. American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meeting.
        2011 (Abstract and poster presentation PI-38)
        • Joerger M.
        • Huitema A.D.
        • Richel D.J.
        • Dittrich C.
        • Pavlidis N.
        • Briasoulis E.
        • et al.
        Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European Organization for Research and Treatment of Cancer-pharmacology and molecular mechanisms group and new drug development group.
        Clin Cancer Res. 2007; 13: 6410-6418
        • Besse B.
        • Luft A.
        • Fadeeva N.
        • Mezger J.
        • Beck J.T.
        • Bidoli P.
        • et al.
        A phase II trial of pictilisib with chemotherapy in first-line non-squamous NSCLC. World Conference on Lung Cancer.
        2015 (Poster presentation 1432)
        • Spigel D.R.
        • Luft A.V.
        • Vynnychenko I.
        • Fadeeva N.
        • Mark Z.
        • Ponce S.
        • et al.
        A phase II trial of pictilisib with chemotherapy in first-line squamous NSCLC. World Conference on Lung Cancer.
        2015 (Poster presentation 1653)
        • Krop I.E.
        • Mayer I.A.
        • Ganju V.
        • Dickler M.
        • Johnston S.
        • Morales S.
        • et al.
        Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial.
        Lancet Oncol. 2016; 17: 811-821
        • Vuylsteke P.
        • Huizing M.
        • Petrakova K.
        • Roylance R.
        • Laing R.
        • Chan S.
        • et al.
        Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study.
        Ann Oncol. 2016; 27: 2059-2066
        • Fruman D.A.
        • Rommel C.
        PI3K and cancer: lessons, challenges and opportunities.
        Nat Rev Drug Discov. 2014; 13: 140-156
        • Martini M.
        • Ciraolo E.
        • Gulluni F.
        • Hirsch E.
        Targeting PI3K in cancer: any good news?.
        Front Oncol. 2014; 3: 1-9
        • Rodon J.
        • Dienstmann R.
        • Serra V.
        • Tabernero J.
        Development of PI3K inhibitors: lessons learned from early clinical trials.
        Nat Rev Clin Oncol. 2013; 10: 143-153