Management Guidelines and Targeted Therapies in Metastatic Non-Small Cell Lung Cancer: An Oncologist s Perspective

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1 Management Guidelines and Targeted Therapies in Metastatic Non-Small Cell Lung Cancer: An Oncologist s Perspective Julie R. Brahmer, M.D. Associate Professor of Oncology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD

2 Learning Objectives To describe the first line therapy options for patients with metastatic NSCLC To describe how histology and other tumor characteristics determine those treatment options To describe the use of specific tumor testing can dictate treatment decisions in NSCLC 2

3 FIRST LINE THERAPY 3

4 Stage IV NSCLC: Slow but Steady Progress 1980s Median survival 4-6 months 1 yr 2 yr 10% months 30%-35% 10%-15% months 50% 20%? With Personalized Medicine and 2012 Combination? Targeted? Therapy? 4

5 Treatment Algorithm for NSCLC 2000 Good PS Platinum Combination Chemotherapy 5

6 Treatment Algorithm for NSCLC 2012 Good PS EGFR Mutation Non Squamous Squamous EML4-ALK Translocation Erlotinib Bevacizumab Eligible Bevacizumab Ineligible Crizotinib Platinum/ Pemetrexed + Bevacizumab Platinum/ Pemetrexed Platinum/Gemcitabine 6

7 Summary Chemotherapy for Stage IV Good performance status (0-1) Platinum-based doublets preferred Cisplatin or carboplatin Combined with docetaxel, gemcitabine, paclitaxel, pemetrexed (non-squamous only) or vinorelbine Choice based on histology, toxicity, scheduling considerations 7

8 First-Line Pemetrexed + Cisplatin vs Gemcitabine + Cisplatin in Stage IIIB or IV JMDB Trial NSCLC (no centralized pathology review) > 1 Measurable lesion per RECIST Prior radiation allowed to < 25% marrow No symptomatic brain metastases No peripheral neuropathy grade 1 ECOG PS 0-1 R A N D O M I Z E Pemetrexed 500 mg/m 2 day 1 Cisplatin 75 mg/m 2 day 1 n = 862 Every 3 weeks up to 6 cycles Gemcitabine 1250 mg/m 2 day 1 & 8 Cisplatin 75 mg/m 2 day 1 n = 863 Non-inferiority design Primary endpoint: overall survival (OS) Secondary endpoints: response rate, duration of response (DOR), progression-free survival (PFS), time to progression, time to treatment failure, toxicity Scagliotti GV, et al. J Clin Oncol. 2008;26:

9 First-Line Pemetrexed + Cisplatin vs Gemcitabine + Cisplatin in Stage IIIB or IV Overall Survival Scagliotti GV, et al. J Clin Oncol. 2008;26:

10 First-Line Pemetrexed + Cisplatin vs Gemcitabine + Cisplatin in Stage IIIB or IV Pre-Planned Histology Analysis Adenocarcinoma (n = 847) Squamous (n = 473) Large cell (n = 153) Indeterminate (n = 252) Pem+Cis Median OS (mos) > Gem+Cis Median OS (mos) HR (CI) ( ) P = 0.03 < ( ) P = 0.05 > ( ) P = ( ) P = Scagliotti GV, et al. J Clin Oncol. 2008;26:

11 TOXICITY BASED ON HISTOLOGY - BEVACIZUMAB 11

12 Phase 2 Trial of Bevacizumab in NSCLC: Trial Design Previously untreated stage IIIb/IV NSCLC CP 6 (n = 32) CP 6 + bevacizumab (7.5 mg/kg) every 3 weeks (n = 32) CP 6 + bevacizumab (15 mg/kg) every 3 weeks (n = 35) PD PD PD Chemotherapy administration Paclitaxel 200 mg/m 2 IV every 3 weeks Carboplatin IV to AUC 6 every 3 weeks following paclitaxel infusion Johnson DH et al. J Clin Oncol. 2004;22:

13 Phase 2 Trial of Bevacizumab in NSCLC: Results CP + Bevacizumab CP (n = 32) 7.5 mg/kg (n = 32) 15 mg/kg (n = 34) Response rate (%) Median time to progression (months) Six (9%) life-threatening pulmonary hemorrhages (4 fatal) in patients who received CP plus bevacizumab In a multivariate analysis, only squamous cell histology was identified as an independent risk factor 4/6 bleeds (19% of enrolled subjects) Median survival (months) Johnson DH et al. J Clin Oncol. 2004;22:

14 Phase III Trial of Bevacizumab in Non-Squamous NSCLC: E4599 Eligibility: Non-squamous NSCLC No Hx of hemoptysis Stratification: RT vs no RT Stage IIIB or IV vs recurrent Wt loss <5% vs >5% Measurable vs nonmeasurable (PC) Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q 3 weeks) (PCB) Paclitaxel: 200 mg/m 2 Carboplatin: AUC = 6 + Bevacizumab (15mg/kg q 3 wks) x 6 cycles x 6 cycles PD NB: Upon PD crossover to Bevacizumab not permitted

15 Bevacizumab in Advanced NSCLC: ECOG 4599 Trial Parameter Efficacy RR PFS, median OS, median 1-yr survival 2-yr survival Toxicity Gr 4 Neutropenia HTN # of deaths *5 related to hemoptysis p< PC (n=431) 10% 4.5 mo 10.2 mo 43.7% 16.9% 17% 0.7% 2 PC+B (n=424) 31% 6.4 mo 12.5 mo 51.9% 22.1% 24% 6% 8* Sandler et al. NEJM 2006

16 EGFR TYROSINE KINASE INHIBITORS IN EGFR-MUTATION-POSITIVE NSCLC 16

17 EGFR Tyrosine Kinase Domain Mutations TK domain Exons Amino acids mutations have been identified 90% are in exon 19 or 21 Pao W, Miller VA. J Clin Oncol. 2005;23:

18 Prevalence of EGFR Mutations Phenotype of NSCLC Patient Prevalence of EGFR Mutation All 10% to 15% Caucasian never-smokers ~35% Asian never-smokers ~65% Jackman DM et al. ASCO 2008 Annual Meeting. Abstract 8035.

19 Gefitinib vs Carboplatin / Paclitaxel (CP) in Never- or Light Ex-Smokers IPASS (Iressa Pan-Asia Study) Measurable stage IIIB or IV Adenocarcinoma histology No prior chemotherapy PS 0-2 < 100 cigarettes / lifetime or < 10 pack / years and stopped > 15 years prior R A N D O M I Z E Gefitinib 250 mg daily Carboplatin AUC 5 or 6 Paclitaxel 200 mg/m 2 Q3wk (max 6 cycles) CP offered for PD Primary endpoint: PFS (non-inferiority) Secondary endpoints: response rate, OS, quality of life Total randomized = 1217 Mok T, et al. N Engl J Med. 2009;361:

20 Gefitinib vs Carboplatin/Paclitaxel for Clinically Selected Chemotherapy-Naive Patients With Advanced NSCLC in Asia (IPASS) Endpoint G (N = 609) mpfs (months) mos (months) ORR (%) C + P (N = 608) HR/OR (95% CI) ( ) P< ( ) P = ( ) P = *Limited to maximum of 6 cycles. 52% of patients in the C + P arm received subsequent TKI therap. y Mok TS et al. N Engl J Med. 2009;361: Ohe Y et al. ASCO 2009 Annual Meeting. Abstract Yang C et al. ESMO 2010 Annual Conference. Abstract LBA2.

21 Gefitinib vs Carboplatin / Paclitaxel (CP) in Never- or Light Ex-Smokers Probability of Progression-Free Survival Gefitinib EGFR M+ (n = 132) Gefitinib EGFR M- (n = 91) Carboplatin / paclitaxel EGFR M+ (n = 129) Carboplatin / paclitaxel EGFR M- (n = 85) Gefitinib HR = 0.19, 95% CI 0.13, 0.26, P < No. events M+ = 97 (73.5%) No. events M- = 88 (96.7%) Carboplatin / paclitaxel, HR = 0.78, 95% CI 0.57, 1.06, P = No. events M+ = 111 (86.0%) No. events M- = 70 (82.4%) Time From Randomization (months) Mok T, et al. N Engl J Med. 2009;361:

22 Gefitinib vs Carboplatin/Paclitaxel in Never- or Light Ex-Smokers: OS Gefitinib (months) Carbo/Pac (months) P-value OS (all) EGFR mutation EGFR wt EGFR unknown Mok T et al. N Engl J Med. 2009;361:

23 IPASS: OS by EGFR Mutation Status EGFR-Mutation Positive EGFR-Mutation Negative Probability of Overall Survival Gefitinib (N=132) C + P (N=129) Months HR = 0.78 (95% CI, ) Probability of Overall Survival Gefitinib (N=91) C + P (N=85) HR = 1.38 (95% CI, ) Months 28 Mok TS et al. N Engl J Med. 2009;361:

24 Summary of First-Line EGFR TKIs in NSCLC In EGFR-mutation-positive patients: Compared to carboplatin + paclitaxel, a first-line EGFR TKI improves PFS and has a favorable toxicity profile and improved QoL When EGFR mutation status is negative or unknown, cytotoxic chemotherapy remains preferred Erlotinib is an option for first-line therapy in EGFR-mutation-positive patients in the US

25 KRAS Mutations May Be Found in Never Smokers Riely GJ, et al. Clin Cancer Res. 2008;14:

26 Meta-Analysis: Impact of KRAS Mutation on Response to EGFR TKIs N = with KRAS mutations Tested association with absence of response Pooled sensitivity 0.21 (95% CI ) Suggests resistance to EGFR TKIs also occurs with wild type KRAS Pooled specificity 0.94 (95% CI ) Suggests response to EGFR TKIs highly unlikely with KRAS mutation Linardou H, et al. Lancet Oncol. 2008;9:

27 ELM4-ALK Fusion Gene 5% of all NSCLC Mutually exclusive of EGFR and KRAS mutations Majority in never smokers Seen usually in younger patients Crizotinib oral inhibitor No food effect Moderate CYP3A4 inhibitor BID dosing 27

28 Phase I Trial of PF (Crizotinib) in Patients With Advanced Malignancy NSCLC EML4-ALK fusion cohort (n = 82) 96% adenoca, 76% never smokers, mean age 51 Efficacy Overall response rate was 57% (1 CR) Duration of treatment 1-15 mo. Adverse events Increased ALT/AST usually respond to dose reduction Rare visual disturbance Most common N/V and diarrhea Shaw et al. WCLC 2009; abstract A6.4. Kwak EL et al NEJM 2010;363:

29 Overall Survival of ALK-Positive NSCLC Patients Treated With Crizotinib (N = 82) 100% 80% Median OS: Not reached (NR) 1-year OS: 74%; 2-year OS: 54% Median follow-up of 18 months 60% 40% 74% 54% From first crizotinib dose 20% 0% Years Shaw AT et al. ASCO 2011 Annual Meeting. Abstract 7507.

30 Treatment Algorithm for NSCLC 2012 Good PS EGFR Mutation Non Squamous Squamous EML4-ALK Translocation Erlotinib Bevacizumab Eligible Bevacizumab Ineligible Crizotinib Platinum/ Pemetrexed + Bevacizumab Platinum/ Pemetrexed Platinum/Gemcitabine 30

31 First Line Therapy Options for NSCLC Treatment decisions are based on histology Efficacy and toxicity Tissue is needed to perform testing for targeted therapies EGFR mutation Erlotinib EML4-Alk translocation - Crizotinib 31