Individualized therapy in lung cancer Where are we in 2012?

UNIVERSITY OF OF TORINO DEPARTMENT OF ONCOLOGY Individualized therapy in lung cancer Where are we in 2012? Giorgio V. Scagliotti University of Torino Professor of Medical Oncology Department of Oncology giorgio.scagliotti@unito.it

UNIVERSITY OF OF TORINO DEPARTMENT OF ONCOLOGY Cancer Research at the roundabout 1. Cancer is a genetic somatic disease (5% inherited) 2. (Very likely) originates from stem cells 3. It is caused by genetic alterations of a handful of genes (Oncogenes or Driver genes ) 4. It is often possible to identify these genetic lesions by molecular diagnosis 5. Targeted Therapy is only effective when aimed at the alteration of the driver gene(s): Oncogenic Addiction

Chipping away at the lung cancer genome Lung Adenocarcinoma Squamous Cell Carcinoma of the lung Pao W. Nat. Med. 2012 ; Sos M. and Thomas R. Oncogene 2012

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer Adeno LCC/NOS SCC SCLC

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer Chemotherapy and PCI Adeno LCC/NOS SCC SCLC

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer HER2 EGFR mutants ALK ROS/RET b-raf K-ras K-ras Chemotherapy and PCI Adeno LCC/NOS SCC SCLC

EGFR-TKIs and EGFR Mutation -Directed Front - Line Studies Study Entry Criteria HR for PFS (EGFR mut +) IPASS Mok NEJM 2009 First SIGNAL Proc. IASLC 2009 NEJ002 NEJM 2010 Proc. ASCO 2011 WJTOG3405 Lancet Onc. 2010 Asiatic, never- & light smokers, adenocarcinoma (EGFR mut + 59.7%) Adenocarcinoma, Neversmokers (EGFR mut + 44%) 0.48 (0.36-0.66) 0.61 (0.30-1.22) EGFR Mutation + (all) 0.35 (0.25-0.50) EGFR Mutation + (all) 0.520 (0.378-0.715) HR for OS (EGFR mut +) 0.91 * (0.76-1.10) *overall population 0.82 (0.35-1.92) 0.887 (0.634-1.241) 1.185 (0.767-1.829) EURTAC (EU) EGFR Mutation + (all) 0.42 (0.27-0.64)? OPTIMAL (China) EGFR Mutation + (all) 0.16 (0.10-0.26) 1.04 (0.69 1.58) LUX-LUNG 3 EGFR Mutation + (all) 0.58 (0.43 0.78)?

% Decrease or increase from baseline Tumour responses to crizotinib by patient 100 80 A8081001 ORR 61% N=116 1 100 80 PROFILE 1005 ORR 51% N=123 2 60 60 40 40 20 20 0 0 20 20 40 40 60 60 80 80 100 100 best objective response according to RECIST: Progressive disease Stable disease Partial response Complete response 1 Camidge R, et al. Progression-Free Survival (PFS) from a Phase 1 Study of Crizotinib (PF-02341066) in Patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC). Presented at ASCO 2011; Abstract 2501 2 Kim DW, et al. A Global Phase 2 Study Including Efficacy, Safety, and Patient-reported Outcomes with Crizotinib in Patients with ALK-positive Non-small Cell Lung Cancer. Presented at ECCO/ESMO 2011; Abstract 9084

Decrease or Increase From Baseline (%) Crizotinib and Tumor Responses in Patients with Advanced ROS1+ NSCLC (N=14*) 100 80 60 Response Rate 57% 40 20 0 20 40 60 15+ 16+ 18+ 4+ 12+ 8+ PD SD PR CR 22+ 18 44+ 80 100 20+ 35+ 48+ *Response-evaluable population. Tumor ROS1 FISH-positive, but negative for ROS1 fusion gene expression. Crizotinib held for >6 wks prior to first scans which showed PD. Shaw A. et al. Proc. ASCO 2012

Erlotinib in EGFR mutant NSCLC Vemurafenib in BRAF mutant melanomas Crizotinib in ALK rearranged NSCLC

Kinase oncogene dependence and principles of drug resistance Wagle N. et al. J. Clin. Oncol. 2011; 29:3085

Genotypic Evolution of Lung Cancer Acquiring Resistance to EGFR and ALK Inhibitors A L K A L K E G F R A L K K R A S A L K A L K Sequist L. et al. Sci. Transl. Med. 2011; 3 (75) 75ra26 Doebele R. et al. Proc. ASCO 2012

How to improve results in EGFR mutants? Chemo-naïve advanced NSCLC EGFR mutant EGFR TKI + HD 2 nd -gen EGFR TKI EGFR TKI + BCL-2i EGFR TKI + IGF-1Ri EGFR TKI + METi EGFR TKI + HCQ EGFR TKI (diff dosing schedules) EGFR TKI + chemo EGFR mutant NSCLC with acquired resistance* Potent 2 nd -gen EGFR TKI 2 nd -gen EGFR TKI + cetuximab Chemo EGFR TKI 2 nd -gen EGFR TKI + METi

Many new drugs for use post-crizotinib in development + HSP90 inhibitors, + pemetrexed based regimens Weickhardt and Camidge, Clin Invest 2011

Mechanisms of Acquired Resistance to BRAF Inhibitors [1] [2] NRAS Q61 COT CRAF BRAF inhibitor BRAF V600E [3,4] PDGFRβ or IGF1R or EGFR PI3K PI3Ki or AKTi AKT [4,6,9-11] MEK-dependent progression 1. Nazarian R, et al. Nature 2010. 2. Johannessen CM, et al. Nature. 2010. 3. Poulikakos, et al. Nature 2011. 4. Shi H, et al. Cancer Discov. 2012. 5. Wagle N, et al. J Clin Oncol. 2011. P P MEK MEKi ERK Survival [5] MEK-independent progression [1,6-8] 6. Villanueva J, et al. Cancer Cell. 2010. 7. Prahallad A, et al. Nature. 2012. 8. Corcoran RB, et al. Cancer Discov. 2012. 9. Jiang CC, et al. Clin Cancer Res. 2011. 10. Atefi M, et al. PLoS One. 2011. 11. Su F, et al. Cancer Res. 2012.

Monitoring for resistance in CRC Misale S. et al. Nature 2012; 486 : 532 Diaz LA, Jr. et al. Nature 2012; 486 : 537

K-ras mutation & NSCLC Is k-ras mutation prognostic or predictive? Is there any evidence for excluding k-ras mutants from receiving chemo? K-ras K-ras K-ras mutation not predictive or prognostic in resected early stage NSCLC treated with adjuvant chemotherapy (Shepherd F. et al. Proc. ASCO 2012) Meta-Analysis of 881 Cases - Stages I-IV - RR of 2.35 (1.6-3.2) at 2 years k-ras mutation may be associated with shortened survival but need to be confirmed in well designed multivariate analyses addjusted for known prognostic factors (Huncharek M et al., Carcinogenesis 1999) K-RAS mutational status does not predict benefit from the anti-egfr monoclonal antibody cetuximab (O Byrne Lancet Oncology 2011)

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer DDR2 mutation 0% KRAS mutation 2% Unknown 37% PIK3CA mutation 8% PTEN loss, complete 11% FGFR1 amplification 25% PTEN mutation 17% Target N Frequency 95% CI FGFR1 amplification 13/52 25% 15 38% PTEN mutation 3/18 17% 5 37% PTEN loss, complete 3/27 11% 3 26% PIK3CA mutation 4/52 8% 2 17% KRAS mutation 1/52 2% 1 9% DDR2 mutation 0/18 0% 0 15% SCC Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)

Therapeutic targets in squamous cell lung carcinoma Gene Event type Frequency CDKN2A Deletion/mutation/methylation 72 PI3KCA Mutation 16 PTEN Mutation/Detection 15 FGFR1 Amplification 15 EGFR Amplification 9 PDGFRA Amplification/Mutation 9 CCND1 Amplification 8 DDR2 Mutation 4 BRAF Mutation 4 ERBB2 Amplification 4 FGFR2 Mutation 3 Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

FGFR1 amplification in squamous cell lung carcinoma Abstract No of cases Histology subtype Disease stage(s) Technique Definition of amplification 7041 101 Squamous I IV FISH Median of 6 or more gene copies 7061 447 Squamous I IV FISH Mean of 6 or more gene copies 7063 119 Squamous I IV Quantitative PCR Predicted CNV of 2 in 1 exon 7545 177 Squamous I IV FISH Copy number >2 and <9 (low); >9 (high) % amplified % polysomy (if available) 6.9 43/94 8.3-24.4-25.2 - CNV, copy number variation Martinez Marti et al. J Clin Oncol 30, 2012 (suppl; abstr 7041) Toschi et al. J Clin Oncol 30, 2012 (suppl; abstr 7061) Cote et al. J Clin Oncol 30, 2012 (suppl; abstr 7063) Wei et al. J Clin Oncol 30, 2012 (suppl; abstr 7545)

Therapeutic targets in squamous cell lung carcinoma Gene Event type Frequency CDKN2A Deletion/mutation/methylation 72 PI3KCA Mutation 16 PTEN Mutation/Detection 15 FGFR1 Amplification 15 EGFR Amplification 9 PDGFRA Amplification/Mutation 9 CCND1 Amplification 8 DDR2 Mutation 4 BRAF Mutation 4 ERBB2 Amplification 4 FGFR2 Mutation 3 Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

2002-2012 Changes in the therapeutic landscape of stage IV lung cancer Histology still guide the therapeutic choice for the vast majority of our patients K-ras K-ras Adeno LCC/NOS SCC

Updated Treatment Algorithm for Advanced-Stage NSCLC (2012) Proposed Treatment Algorithm EGFR Mutation Positive or ALK Positive Molecular Good PS Clinical (PS) Poor PS Erlotinib or Crizotinib Non-squamous Histologic Squamous Single-Agent Chemotherapy Bevacizumab Eligible Bevacizumab Ineligible Platinum/Pemetrexed (or Other*) ± Bevacizumab Clinical Platinum/Pemetrexed (or Other*) Platinum/Gemcitabine (or Other*) Firstline Progression Bevacizumab, Erlotinib, Pemetrexed or Observation End of First-line Chemotherapy Erlotinib or Pemetrexed or Observation Erlotinib or Observation Based on Prior Therapy Maintenance Chemotherapy by Algorithm Based on Prior Therapy Based on Prior Therapy Based on Prior Therapy Secondline *Other docetaxel, paclitaxel, vinorelbine Gandara, Mack, Li, Lara, Herbst. Clin Lung Cancer, 2009

Cis/Pem vs. Cis/Gem in Advanced NSCLC Scagliotti GV et al. J. Clin. Oncol 2008; 26:3543

Relative expre. levels Relative expre. levels Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase p<0.0001 P<0.001 Adenocarcinoma Squamous P<0.001 Ceppi et al. Cancer 2006

TS in Lung Cancer : a Japanese Large-Scale Study 2621 Japanese lung cancer patients Laser capture microdissected sections cut from primary tumors, surrounding normal lung tissues and involved nodes Tanaka F. et al. Ann. Oncol. 2011 Feb. 14 ahead of print

Summary of the Effect of Pemetrexed in Patients with Advanced NSCLC by ALK Status Reports from three small, retrospective analyses suggest pemetrexed given as a single agent or in combination with chemotherapy may be effective in ALK-positive NSCLC 1 3 Report Camidge et al 2 Lee et al 3 Treatment Pemetrexed single agent or combination therapy, any line Second-line or later single-agent pemetrexed Study populations and comparator populations N ORR (%) Time to event, months (95% CI) ALK-positive NSCLC 19 42 PFS, 9.0 (95% CI: 3 12) ALK/EGFR/KRAS-triple negative NSCLC Altavilla et al 1 Pemtrexed + cisplatin ALK-positive NSCLC, adenocarcinoma 37 14 PFS, 4.0 (95% CI: 3 5) ALK-positive NSCLC 15 47 TTP, 9.2 (95% CI: 4.7 13.7) EGFR wild-type NSCLC 37 TTP, 2.9 8 25 TTP, 9.0 ALK-negative NSCLC 32 TTP, 6.2 TTP, time to progression 1. Altavilla G, Santarpia M, Arrigo C, et al. J Clin Oncol 2010;28 (Abstract 7610) 2. Camidge DR, Kono SA, Lu X, et al. J Thorac Oncol 2011;6:774 780 3. Lee JO, Kim TM, Lee SH, et al. J Thorac Oncol 2011;6:1474 1480

All ALK-neg TS2 TS Expression in ALK+ versus ALK- NSCLC TS Expression N Median 95% CI Range p Value ALK+ Patients 63 2.02 1.60-2.11 0.55-19.44 ALK- Patients 1698 3.32 3.15-3.45 0.36-53.51 <0.0001 20 60 50 15 40 10 30 20 5 10 0 TS in patients with ALK+ cancers 0 TS in patients with ALK- cancers Gandara D. et al. Proc. ASCO 2012

Biomarkers & outcome in the Norwegian Study Carbo/Pem vs. Carbo/Gem Grønberg B. et al. Proc. ASCO 2011

ITACA Adjuvant Trial Pharmacogenomics: Yes or No? Taxanes High Profile 4 Control ERCC1 High TS Low High Profile 3 Profile 2 Pem Control Cis/Gem Low TS Control Cis/Pem Low Profile 1 Control Control = investigators choice of cisplatin-based doublet Primary endpoint = OS; Sample size = 700 patients

Phase II Study of Preoperative Cis/Pem in Stage IIIa N2 non-squamous NSCLC N=33 Stage IIIa N2 by Med (+CT Scan + PET) Cis 75 mg/ m2 & Pem 500 mg/m2 x 3 q3wks Restaging by CT scan and PET Surgery Biomarker Assessment TS, TTF-1, E2F1, ERCC1, BRCA1 (Functional Imaging Changes) Primary end point : ORR Secondary end points :pcr,pfs,os, tumor downstaging, toxicity

EPIC Trial Elderly Patients Individualized Chemotherapy Trial 2:1 Randomization Individualized Arm Control Arm EGFR Mut + Squamous Cell Carcinoma Treatment based on Investigators Preference Yes Yes No EGFR Mut + Off Study Yes ERCC1 low RRM1 high ERCC1 high RRM1 low ERCC1 low RRM1 low ERCC1 high RRM1 high No Carboplatin Gemcitabine Carbo/Gem Taxane ERCC1 low TS high ERCC1 high TS low ERCC1 low TS low ERCC1 high TS high Carboplatin Pemetrexed Carbo/Pem RRM1 low RRM1 high PIs : G. Simon & G. Scagliotti University of South Carolina (Hollings Cancer Center) & University of Torino Gemcitabine Taxane

Conclusion (1) In 15-20% of NSCLC (mainly adenocarcinoma) a driver mutation may be detected and already druggable. Other mutations are detactable in adenocarcinoma and more than 60% of SCCs present with some genetic abnormality. A differential activity by histology has been consistently reported for pemetrexed and makes a platinum-pemetrexed doublet a reference combination for non-squamous NSCLC without driver mutations. TS is a good candidate pharmacogenomic marker for pemetrexed activity and this hypothesis is currently prospectively validated. The definition of homogeneous genetic subgroups of tumors and the search for individualized approaches is the way to substiantially increase survival expectancy in this disease.

Relevant Predictive Biomarkers and NSCLC Class Agent Biomarkers Robustness Cytotoxic drugs Cisplatin ERCC1 RRM1 BRCA1 Gemcitabine RRM1 + ++ + + Pemetrexed Paclitaxel FPGS TS MAPtau Beta-tubulin III - + + + Targeted therapies Erlotinib EGFR mutation FISH EGFR K-Ras wt RASSF1A / 9pLOH Bevacizumab Circulating VEGF - ++ + + +