Targeted Therapies for Advanced NSCLC

Transcription

1 Targeted Therapies for Advanced NSCLC Current Clinical Developments Friday, June 3, 2016 Supported by an independent educational grant from AstraZeneca Not an official event of the 2016 ASCO Annual Meeting Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of Friday, June 3, The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and offlabel uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity.

3 Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply.

4 Learning Objectives 1. Review the molecular pathology of lung cancer and examine its relevance for clinical practice. 2. Outline the safety and efficacy of first-line therapies for advanced NSCLC, including first generation EGFR and ALK inhibitors. 3. Evaluate treatment approaches used to overcome EGFR and ALK resistance in advanced NSCLC, including the safety and efficacy of second- and third-line therapies and recommended molecular testing. 4. Appraise emerging concepts with EGFR TKIs and ALK inhibitors, including their role in adjuvant therapy, combination therapies, and other evolving data.

5 Firstline Therapy for EGFR Mutant and ALK Rearranged NSCLC

6 Tom Stinchcombe, MD Associate Professor Thoracic Oncology Program School of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC

7 Disclosures Consultant for ARIAD and Boehringer Ingelheim Receives Grant/Research Support from Genentech

8 Topics Currently available EGFR TKIs Treatment beyond disease progression EGFR TKI combinations ALK TKI available for first-line use: current options

9 NSCLC Currently Available EGFR TKIs TKIs Gefitinib, Erlotinib Reversible vs irreversible EGFRm EGFRwt HER2 [ErbB2] and ErbB4 binding T790M binding Reversible Afatinib Irreversible Osimertinib Irreversible Hidalgo M, et al. J Clin Oncol. 2001; Ranson M, et al. J Clin Oncol. 2002; Li D, et al. Oncogene. 2008; Kuan FC, et al. Br J Cancer. 2015; Cross DA, et al. Cancer Discov. 2014; Greig L. Drugs

10 LUX-Lung 3 and 6 Phase III Trials Afatinib vs Cisplatin-Based Chemotherapy Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumor tissue* No prior treatment with chemotherapy for advanced/metastatic disease or EGFR inhibitors ECOG PS 0 or 1 Afatinib 40 mg orally once daily Randomization 2:1 Stratification by EGFR mutation type: Del19/L858R/other and by race (LUX-Lung 3 only): Asian/non-Asian Primary endpoint: PFS (independent review) Secondary end points: ORR, DCR, OS, PRO, safety LUX-Lung 3 Cisplatin + pemetrexed up to 6 cycles LUX-Lung 6 Cisplatin + gemcitabine up to 6 cycles *EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I Yang JC, et al. Lancet Oncol

11 LUX-Lung 3 and 6 Phase III Trials Combined OS Analysis Estimated OS Probability Common Mutations (n=631) Afatinib N=419 Chemo N=212 Median, months HR (95%CI), P-value 0.81 ( ), No. of patients Afatinib Chemo Time (months) Yang JC, et al. Lancet Oncol

12 LUX-Lung 3 and 6 Phase III Trials OS Analysis by Mutation Type Estimated OS probability Median, months HR (95%CI) P-value Del19 Afatinib N=236 Chemo N= ( ),.0001 Estimated OS probability Median, months HR (95%CI) P-value L858R Afatinib N=183 Chemo N= ( ).16 0 No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Time (months) Yang JC, et al. Lancet Oncol

13 LUX-Lung 7 Phase IIb Trial Afatinib vs Gefitinib Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumor tissue* No prior treatment for advanced/metastatic disease ECOG PS 0/1 Randomization 1:1 Stratified by mutation type (Del19 vs L858R) and presence of brain metastases (yes vs no) Afatinib 40 mg once daily (N=160) Gefitinib 250 mg once daily (N=159) Primary endpoints: PFS (independent review), TTF, OS Secondary endpoints: ORR, time to and duration of response, duration of disease control, tumor shrinkage, HRQoL, safety Treatment beyond progression allowed if deemed beneficial by investigator Park K, et al. Lancet Oncol

14 LUX-Lung 7 Phase IIb Trial PFS by Independent Review Estimated PFS probability Park K, et al. Lancet Oncol % Afatinib N=160 Gefitinib N=159 Median PFS (months) HR (95%CI), P-value 27%* 18% 0.73 ( ),.0165 *P=.0176; P= Afatinib Gefitinib % Time (months) 0 0

15 LUX-Lung 7 Phase IIb Trial ORR and DCR Efficacy Parameter Afatinib (N=160) Gefitinib (N=159) ORR 70% 56% DCR 91% 87% ORR Exon 19 (N=186) 73% 66% ORR Exon 21 L858R (N=133) 66% 42% P.0083 (OR=1.87).24 (OR=1.55) DCR=disease control rate; OR=odds ratio; ORR=overall response rate. Park K, et al. Lancet Oncol

16 LUX-Lung 7 Phase IIb Trial Select Drug-Related AEs AE category Gr 1-2 Gr 3 Gr 4 Gr 1-2 Gr 3 Gr 4 Diarrhea 78% 12% 1% 60% 1% Rash/acne 79% 9% 78% 3% Stomatitis 60% 4% 24% Paronychia 54% 2% 16% 1% Fatigue 15% 6% 14% Nausea 15% 1% 14% Vomiting 11% 3% 1% AST/ALT increased 10% 16% 8% 1% ILD 0% 1% 1% 1% AE = Adverse Event Park K, et al. Lancet Oncol Afatinib Gefitinib Drug-related AE leading to dose reduction: afatinib 39% doses reduced to 30 mg daily, 13% reduced to 20 mg

17 Treatment Beyond Disease Progression

18 ASPIRATION Phase II Trial Post-Progression Erlotinib EGFR mutant NSCLC Stage 4 disease PS 0-2 (N=207) Erlotinib 150 mg daily 93 continued erlotinib (54%) 70 patients with PFS 2 event 14 still on erlotinib 9 patients withdrew Disease progression with symptomatic progression, rapid progression, worsening PS, or life threatening complications Primary end-point: First PFS event (PFS1) Secondary end-points: Second PFS event (PFS2), ORR, OS DCR 78 discontinued erlotinib (46%) Park K, et al. JAMA Oncol

19 ASPIRATION Phase II Trial Results of Erlotinib Continuation Progression-Free Survival Probability PFS1 PFS Time, mo No. at risk PFS PFS Median PFS1: 11.0 (95% CI, ) 93 patients continuing erlotinib Median PFS2: 14.1 (95% CI, ) Difference in median: 3.1 months Patients continuing erlotinib: Patient characteristics (P<0.05): More likely to have recurrent disease at baseline, ECOG PS 0 or 1 at PFS1 Treatment characteristics (P<0.05): Longer PFS1, improved depth of response, longer time from median time from BOR to PFS1 Park K, et al. JAMA Oncol

20 LUX-Lung 7 Phase IIb Trial Treatment Beyond Disease Progression Allowed treatment beyond progression at the discretion of the investigator Results Afatinib 35% (N=56) continued beyond investigator assessed disease progression: median 2.7 months (95% CI, ) Gefitinib 30% (N=47) continued beyond investigator assessed disease progression: median 2.0 months (95% CI, ) Park K, et al. Lancet Oncol

21 EGFR TKI Combination Trials for First-line Therapy

22 JO25567 Phase II Trial Erlotinib +/- Bevacizumab Stage IIIB/IV NSCLC EGFR exon 19 deletion or exon 21 L858R No brain metastases Primary end-point: PFS by IRC Secondary end-points: OS, ORR, DCR, QoL Erlotinib 150 mg daily (N=75) Erlotinib 150 mg daily + bevacizumab 15 mg/kg every 3 weeks (N=75) Seto T, et al. Lancet Oncol

23 JO25567 Phase II Trial PFS by Independent Review PFS probability Time (months) Number at risk EB E EB Median, months HR P-value* 0.54 (95% Cl, ).0374 *log-rank test, two-sided EB E E Seto T, et al. Lancet Oncol

24 JO25567 Phase II Trial Efficacy Data Efficacy Parameter Erlotinib Erlotinib + Bevacizumab P-value (HR) ORR 64% 69%.4951 DCR 88% 99%.0177 PFS 9.7 months 16.0 months.0015 (0.54) PFS exon 19 (N=80) 10.3 months 18.0 months.0011 (0.41) PFS exon 21 L858R (N=72) 7.1 months 13.9 months.1653 (0.67) Seto T, et al. Lancet Oncol

25 JO25567 Phase II Trial Safety Data Erlotinib + Bevacizumab (N=75) Erlotinib (N=77) Adverse event Grade 3 Grade 4 Grade 3 Grade 4 Rash 25% 0% 19% 0% Diarrhea 1% 0% 1% 0% Paronychia 3% 0% 4% 0% Dry skin 3% 0% 0% 0% Stomatitis 1% 0% 3% 0% Liver tests 7% 1% 9% 9% Hypertension 60% 0% 8% 0% Hemorrhagic event 3% 0% 0% 0% Proteinuria 8% 0% 0% 0% Seto T, et al. Lancet Oncol

26 BELIEF Phase II Trial Firstline Erlotinib/Bevacizumab Stage IIIB/IV Exon deletion 19 or exon 21 L858R Erlotinib 150 mg daily + bevacizumab 15 mg/kg every 3 weeks Primary end-points: PFS in pretreatment T790M+ and T790M- T790M mutations centrally tested using TaqMan assay in presence of PNA Patient cohort Number of patients ORR Median PFS (months) Intent-to-treat % 13.8 (95% CI, ) T790M positive 37 70% 16.0 (95% CI, 13.1-NE) T790M negative 72 79% 10.5 (95% CI, ) Stahel RA, et al. ECC

27 1001 Phase II Trial Firstline Gefitinib/Bevacizumab Stage IIIB/IV Exon 19 deletion or exon 21 L858R Gefitinib 250 mg daily + bevacizumab 15 mg/kg every 3 weeks (N=42) Primary endpoint: 1-year PFS rate Efficacy parameter Results ORR 73.8% (95% CI, ) Median PFS 14.4 (95% CI, ) 1-year PFS 56.7% (95% CI, ) Exon 19 (N=24) vs L858R (N=16) 18.0 vs 9.4 months, P=.006 Ichihara E, et al. J Thorac Oncol

28 Dual EGFR Inhibition Phase Ib Trial: Afatinib + Cetuximab Prior erlotinib or gefitinib within 30 days EGFR mutation required in MTD cohort T790M+ and T790M patients enrolled Afatinib 40 mg daily and cetuximab 500 mg/m 2 every 2 weeks (N=126) Janjigian YY, et al. Cancer Discov

29 Afatinib + Cetuximab Efficacy and Safety Data Cohort ORR PFS Expansion cohort (N=126) 29% 4.7 months T790M+ (N=71) 32% (95% CI, ) 4.8 months T790M (N=53) 25% (95% CI, ) 4.6 months Adverse event All Grades Grade 3 Grade 4 Rash 90% 20% 0% Diarrhea 71% 6% 0% Nail effects 57% 0% 0% Stomatitis 56% 1% 0% Fatigue 47% 2% 1% Janjigian YY, et al. Cancer Discov

30 SWOG S1403 Phase II/III Trial Afatinib +/- Cetuximab EGFR mutant NSCLC Stage 4 disease PS of 0-2 Primary objectives: Phase 2: PFS to determine if trial should continue to phase 3 Phase 3: OS Secondary objectives: ORR, safety, treatment failure and time to discontinuation Afatinib 40 mg daily Afatinib 40 mg daily and cetuximab 500 mg/m 2 every 2 weeks Clinicaltrials.gov. Available at:

31 First-line Therapy for ALK Rearranged NSCLC

32 PROFILE 1014 Phase III Study Firstline Crizotinib vs Chemotherapy Key Entry Criteria ALK-positive by central FISH testing Locally advanced, recurrent, or metastatic nonsquamous NSCLC No prior systemic treatment for advanced disease ECOG PS 0 2 Measurable disease Stable treated brain metastases allowed Solomon BJ, et al. N Engl J Med R A N D O M I Z E Crizotinib 250 mg twice daily PO, continuous Dosing (N=172) Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5 6 every 3 weeks for 6 cycles (N=171) Crossover to crizotinib permitted after progression Endpoints Primary PFS (RECIST 1.1, independent radiologic review [IRR]) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ-C30, LC13)

33 PROFILE 1014 Phase III Study PFS as Assessed by IRC 100 Crizotinib N=172 Chemo N=172 Events, n (%) 100 (58) 137 (80) PFS probability (%) Crizotinib Chemotherapy Median, months HR (95%CI) 0.45 ( ) ORR 74% 45% P-value <.0001 No. at risk Crizotinib Chemotherapy Time (months) Solomon BJ, et al. N Engl J Med

34 J-ALEX Phase III Study Alectinib vs Crizotinib ALK + NSCLC ALK treatment naive ALK positive by central testing PS 0-2 Primary end-point: PFS by IRR Secondary end-point: OS, ORR, CNS progression, HRQoL Crizotinib 250 mg po twice daily Alectinib 300 mg po BID JAPIC Clinical Trials Information. Available at:

35 J-ALEX Phase III Study Alectinib vs Crizotinib Crizotinib 250 mg ALK + NSCLC po twice daily ALK treatment naive ALK Closed positive by IDMC by at preplanned interim analysis after 207 central patients testing enrolled since primary end-point of PFS met PS 0-2 Nokihara et al Abstract 9008: Oral abstract Alectinib session 300 mg Monday June 6 po BID Primary end-point: PFS by IRR th 9:45-12:45 Arie Crown Theater Secondary end-point: OS, ORR, CNS progression, HRQoL JAPIC Clinical Trials Information. Available at:

36 Conclusions Erlotinib, gefitinib, and afatinib are all options in the first-line setting. Combination trials reveal promising activity Continuing therapy beyond disease progression is an option for select patients. Most likely delays a change in therapy by 2-3 months Crizotinib is the standard for ALK+ NSCLC, but I eagerly await Monday s presentation.

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