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MEK Inhibitors and their potential role in relapsed NSCLC

MEK Inhibitors and their potential role in relapsed NSCLC. Ranee Mehra, MD Fox Chase Cancer Center Philadelphia, PA. Disclosures. Consulting – Novartis, Bristol Myers Squib Spouse is employee of GSK Acknowledgment: J. Weiss. Ras-Raf-MEK-ERK1/2 MAP kinase pathway.

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MEK Inhibitors and their potential role in relapsed NSCLC

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  1. MEK Inhibitors and their potential role in relapsed NSCLC Ranee Mehra, MD Fox Chase Cancer Center Philadelphia, PA

  2. Disclosures • Consulting – Novartis, Bristol Myers Squib • Spouse is employee of GSK • Acknowledgment: J. Weiss

  3. Ras-Raf-MEK-ERK1/2 MAP kinase pathway Frémin and Meloche Journal of Hematology & Oncology 2010 3:8   doi:10.1186/1756-8722-3-8

  4. MEK inhibitors in the Clinic Modified from Akinleye et al. J HematolOncol 2013, 6:27

  5. Numerous Molecular Changes Drive Lung Cancer No mutation detected KRAS 22+% AKT1 NRAS MEK1 MET AMP HER2 PIK3CA EML4-ALK 7% EGFR 17% BRAF Double 3% Kris, et al. J Clin Oncol 2011;29:Suppl(Abstr 7506).

  6. KRAS Mutation Subtypes in NSCLC COSMIC From J Weiss: ASCO 2013

  7. Selumetinib • Selumetinib is potent and selective allosteric inhibitor of MEK 1/21 • Tendency for greater sensitivity to selumetinib in BRAF/RAS mutant cell lines2 Cell viability inhibition IC50 (µM) Cell line 1Yeh, et al. Clin Cancer Res 2007 2Davies, et al. Mol Cancer Ther 2007

  8. Selumetinib • Phase I study showed that selumetinib plus docetaxel had a manageable tolerability profile • Preclinically, the combination of selumetinib and docetaxel demonstrated tumor regression in a KRAS-mutant cancer 1.4 Control Selumetinib-25mg kg-1 per qd Docetaxel-15mg kg-1 Combo 1.2 Mean tumour volume (cm3) +/-s.e.m 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 HCT-116 human tumor xenografts (KRAS-mutant) Hainsworth J et al. J ThoracOncol 2010;5:1630–6 Holt et al. Br J Cancer 2012;106:585–66 Kim et al. Mol Can Ther 2011;10:B225

  9. Pre-clinical Activity in TKI resistance British Journal of Cancer (2011) 105, 382–392

  10. Selumetinib study Selumetinib 75 mg BD + docetaxel 75 mg/m2(day 1 of every 21-day cycle)† • Following completion of patient enrollment, the primary endpoint was changed from PFS to OS, without changing the sample size‡ • OS analysis was planned for after approximately 58 events • Patients • Locally advanced or metastatic NSCLC (stage IIIB-IV) that has failed first-line therapy • Confirmed KRAS mutant tumor* • WHO PS 0-1 • Endpoints • Primary • OS • Secondary • PFS • ORR • Duration of response • Change in tumor size • Alive and progression-free at 6 months • Safety and tolerability Randomization(1:1 ratio) Placebo BD + docetaxel 75 mg/m2(day 1 of every 21-day cycle)† *Mutation status determined either by central laboratory (Esoterix, ARMS) or an approved local laboratory †SEL/PBO given until disease progression/intolerable toxicity/other discontinuation criteria met ‡To allow decisions to be made based on OS data without breaking study blinding at the earlier endpoint of PFS Janne, et al.Lancet Oncol2013; 14: 38–47

  11. Baseline Patient Characteristics *Including adenocarcinoma: bronchoalveolar NOS, not otherwise specified

  12. Primaryend-point: OS • There was a numerical increase in OS, hazards non-proportional • 56/83 deaths (67% maturity): selumetinib + docetaxel 29/43, placebo+docetaxel 27/40 Symbols represent censored observations Janne, et al.Lancet Oncol2013; 14: 38–47

  13. Secondaryend-point: PFS • There was a statistically and clinically significant improvement in PFS • 71/85 events: selumetinib + docetaxel 35/43, placebo+docetaxel 36/40 Symbols represent censored observations Janne, et al. Lancet Oncol2013; 14: 38–47

  14. Response p<0.0001† p<0.0158‡ % *11 confirmed, 5 unconfirmed †Fisher’s exact 2-sided mid p value; ‡1-sided p value CR, complete response; PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response; APF6, alive and progression-free at 6 months Janne, et al. Lancet Oncol2013; 14: 38–47

  15. Safety and tolerability *Main causes of hospitalization were febrile neutropenia/neutropenic infections,respiratory infections and respiratory disorders Janne, et al. Lancet Oncol2013; 14: 38–47

  16. FrequentlyreportedAEs *AEs defined as most frequent were those having an incidence of ≥25% in either study arm †Taken from laboratory values, n=43 ‡CTC grade ≥2; protocol allowed inclusion of patients with grade 1 anaemia to enrol ‡ Including neutropenic infection Janne, et al. ASCO 2012

  17. Two parallel randomized Phase II studies of Selumetiniband Erlotinibin NSCLC selected by KRAS mutations 77 patients Mutated KRAS 39 patients KRAS Wild Type 38 patients Combination therapy erlotinib 100 mg PO daily + selumetinib 150 mg PO daily Monotherapy selumetinib 75 mg PO bid Combination therapy erlotinib 100 mg PO daily + selumetinib 150 mg PO daily Monotherapy Erlotinib 150 mg POqdd 9 pts 30 pts 19 pts 19 pts Carter, ASCO 2013, 8026

  18. Results Carter, ASCO 2013, 8026

  19. Phase I Trial of GSK1120212 (Trametinib) with Expanded Cohort • Phase I trial to establish MTD • Toxicity • Pharmacokinetics Expanded cohort: BRAF-mutant melanoma Pancreatic cancer KRAS-mutant NSCLC • GSK1120212: a potent reversible inhibitor of MEK1/2 • RAF/RAS mutation a strong predictor of sensitivity in cell lines • GSK1120212 2 mg daily the recommended dose for phase II trials MTD, maximum tolerated dose 1. Falchook, et al. ESMO; 2010; 2. Jing, et al. Mol Cancer Ther. 2012;11(3):720-972. 19

  20. PFS in KRAS-Mutant NSCLC, Trametinib vs. Docetaxel • In patients with KRAS-mutant NSCLC, no statistically significant difference in PFS was observed between trametinib and docetaxel Blumenschein et al, ASCO 2013, abstract 8029 Slide courtesy of J. Weiss.

  21. Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant and WT NSCLC Study Design from Gandaraet al: ASCO 2013, abstract 8028 CONFIDENTIAL – DO NOT DISTRIBUTE

  22. Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant and WT NSCLC updated from Bennouna et al: IASLC WCLC 2013 Gandara, Santa Monica 2014

  23. Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant & WT NSCLC Maximum Tumor Reduction by Mutation Type KRAS Mut+ KRAS WT EGFR Mut+ ALK+ ‡ C § ‡ ‡ C C C C ‡ C ‡ C C * * * * * * * * * C KRAS G12C ‡ Squamous histology § Best response was CR, single target lymph node <10mm Best response PD Seven patients did not have a post-baseline disease assessment. * RR, Response rate (CR+PR),includes confirmed and unconfirmed response; DCR, Disease control rate (CR+PR+SD) CR, complete response; PR, partial response; SD, stable disease; PFS, Progression free survival updated from Bennouna et al: IASLC WCLC 2013; Gandara Santa Monica 2014

  24. Trametinib plus pemetrexed in kRAS Mutant+ Kelly et al., ASCO 2013, abstract 8027 Gandara et al, ASCO 2013 Modified from slide courtesy of J. Weiss. CONFIDENTIAL – DO NOT DISTRIBUTE

  25. PD-0325901 • 44 patients treated – advanced NSCLC • PR 0% • PFS 1.8 months • OS 7.8 months • Diarrhea, fatigue, rash Haura et al. CCR 2010

  26. MEK162: Summary of PK data • Rapid absorption, plasma Tmax ~1.5 hrs • Cmax and AUC at 45mg BID was comparable to historical data • Metabolite < 25% of MEK162 exposure • Moderate inter-patient variability of exposure • Modest accumulation on Day 15 Concentration profiles on Day 15 (45 mg BID) Ascierto et al ASCO 2012 Oral Presentation Abstract #8511

  27. Preliminary Results • Standard 3+3 Design • 30 mg BID • 45 mg BID • 60 mg BID • 80 mg BID • N: 19 pts • 2 DLTs at 80 mg BID • Central serous-like retinopathy (n = 1; G3) • Dermatitis acneiform (n = 1; G3 despite maximal treatment measures) • Initial: MTD 60 PO BID Bendell et al. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA

  28. Preliminary Results • Main AEs: GI, rash, elevated CK, and retinal Disorders • 1/15 pts with PR • MEK 162 demonstrated desirable PK properties • Evidence of PD changes. • Study expanded in KRAS and Braf mutant tumors. • All DLTs resolved with drug interruption and patients tolerated re-challenge at a lower dose Bendell et al. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA

  29. Summary in KRAS Mutants

  30. MEK inhibition in KRAS WT

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