Medical Oncology: State of the Art Therapy in Advanced NSCLC: 2011 looking toward 2015

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1 Medical Oncology: State of the Art Therapy in Advanced NSCLC: 2011 looking toward 2015 David R. Gandara, MD University of California Davis Cancer Center

2 Algorithm for Therapy of Advanced Stage NSCLC: 2009 Gandara, Mack, Li, Lara, Herbst: Clin Lung Cancer, 2009

3 Algorithm for Therapy of Advanced Stage NSCLC: 2011? adapted from Gandara, Mack, Li, Lara, Herbst: Clin Lung Cancer, 2009

4 Chemotherapy* +/- Targeted Agent in 1 st -line Advanced Stage NSCLC ( All Comers Design) Target Agent Survival benefit MMPs Prinomastat, others No EGFR (TKI) Gefitinib or Erlotinib No FT (RAS) Lonafarnib No PKCα ISIS 3521 No RXR Bexarotene No VEGFR (TKI) Sorafenib No VEGF (MAb) Bevacizumab Yes EGFR (MAb) Panitumumb No TLR9 agonist PF-351 (2 phase III trials) No EGFR (MAb) Cetuximab (FLEX) Yes** IGF1-R Figitumumab No Vascular (VDA) ASA-404 No *In combination with platinum-based chemotherapy vs chemotherapy **EGFR IHC positive

5 Carboplatin-Paclitaxel (PC) +/- Figitumumab (PCF) in advanced NSCLC (non-adenocarcinoma) Trial Design Endpoints Stratification Study A1016: Global, multicenter, randomized, openlabel Primary: OS Secondary: PFS, ORR, safety, QoL, biomarkers, pharmacoeconomics Gender Histology (Sq vs non-sq) Prior Adj Chemo (Y/N) Key Entry Criteria Histology other than Adenocarcinoma (primarily SCC) Brain mets allowed Adjuvant >12 month prior R A N D O M I Z E (N=820) Figitumumab (20 mg/kg) Paclitaxel Carboplatin (N=410) Paclitaxel Carboplatin (N=410) Jassem J, et al. ASCO Abstract 7500.

6 Survival probability Carboplatin-Paclitaxel (PC) +/- Figitumumab (PCF): Biomarker-associated Negative Effect Median Survival in patients with Free IGF-1 <1.0 ng/ml Favors PC over PCF PCF mos = 7.0 mo PC mos =10.3 mo Event Total PCF PC Censored HR (95% Cl): 1.40 (1.0, 1.9) N=324 (Provision of samples for pharmacodynamics was optional) Time (months) PCF: paclitaxel, carboplatin, figitumumab; PC: paclitaxel, carboplatin Jassem J, et al. ASCO Abstract 7500.

7 Improved Drug Development Paradigms: Marriage of Preclinical-Clinical Development Biomarker Integration N=30 N=300 N=1600 Drug Approval Pre-clinical (~18 mo.) Phase I (~18 mo.) Phase II (~18 mo.) Phase III (~36 mos) Total Time ~90 mos or 7.5 years Phases of Development of New Biomarker linked to New Drug Confirm Target Assay Development Integrate Biomarker Assay Performance Biomarker Informative? Assay Performance Clinical Validation Co-Primary Endpoint Clinical Application of Biomarker Gandara et al: NCI CAPR Workshop, April 2011

8 Major Themes in Therapy of Advanced NSCLC 2011: Interrelationship Between Histology, Biomarkers, and Maintenance Therapy in Non Small Cell Lung Cancer Histology Maintenance Molecular Biomarkers Factors are Interlinking & Not Independent Adpated from Gandara et al: Clin Lung Cancer, 2009

9 Hypothesis: Treatment of NSCLC should be Histology-Based Observation: Differential efficacy of Pemetrexed in Squamous vs Non-Squamous Subtypes of NSCLC JMDB: Pemetrexed-Cisplatin vs Gemcitabine- Cisplatin in 1 st line therapy of Advanced NSCLC JMEI: Pemetrexed vs Docetaxel in 2 nd line therapy of Advanced NSCLC JMEN: Pemetrexed vs Placebo as Maintenance Therapy of NSCLC

10 JMDB Trial: Cisplatin-Pemextexed vs Cisplatin- Gemcitabine in Advanced NSCLC No difference in overall PFS or Survival between study arms Cis/Pem improves Survival over CG in Non-SCCA (HR 0.81, p=0.005) Cis/Gem improves Survival over CP in SCCA (HR 1.23, p=0.05) Scagliotti & Gandara. J Clin Oncol 2008;26:

11 SWOG Database Analysis of Taxane/Vinca-Based Therapy in Adv NSCLC by Histology N=741 S9806, S0003, and CDDP/Vin arm of S9308 No difference in any efficacy outcome by histology Overall Survival Progression-Free Survival Histology N Median Adjusted HR* Median Adjusted HR* Adeno 424 (57%) 8.5 months 1.00 (referent) 4.3 months 1.00 (referent) SCCA 128 (17%) 8.4 months (P=.89) $ months (P=.89) & Large Cell 82 (11%) 7.9 months (P=.83) 4.2 months 1.03 (P=.81) NSCLC, NOS 107 (14%) 9.6 months (P=.79) 5.0 months 0.87 (P=.20) *Hazard ratio (HR) from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex. $ HR for SCCA vs. all others combined, OS: (95% CI , P=.96). & HR for SCCA vs. all others combined, PFS: 1.01 (95% CI , P=.94) Chansky et al: IASLC WCLC 2009

12 Histology is not a predictor of Survival from Anti-microtubule or Gemcitabine-based Therapy Scagliotti G et al. J. Thorac. Oncol. 2009;4:1568

13 Histology will ultimately prove to be Suboptimal for Selecting Chemotherapy (or Targeted Therapy) Histologic subtyping groups tumors based on microscopic pattern recognition by a pathologist (using 1800 s technology) At best, Histology = Crude Molecular Selection Robert Hooke Molecular Profiling

14 Thymidylate Synthetase Expression in Lung Cancer TS SCLC Highest TS Squamous High TS Adeno Low TS Bhattacharjee PNAS 2001

15 Biomarker mrna Expression Levels in NSCLC: AC versus SCCA (Gandara et al: ASCO 2010) ERCC1 (N=1,438) 1,002 AC, 436 SCCA RRM1 (N=1,104) 678 AC, 426 SCCA TS (N=965) 649 AC, 316 SCCA p=0.001 p<0.001 p<0.001 ERCC1 (Reference <1.7 for platinum) % Below Reference Level NSCLC-Total 43.4% NSCLC- Adenoca 46% NSCLC-SCCA 30.7% RRM1 (Reference <0.97 for gemcitabine) % Below Reference Level NSCLC-Total 39.6% NSCLC- Adenoca 42.2% NSCLC-SCCA 13% TS (Reference <2.33 for pemetrexed) % Below Reference Level NSCLC-Total 41.3% NSCLC- Adenoca 45.7% NSCLC-SCCA 25.9%

16 UNIVERSITY OF TORINO DEPT. OF CLINICAL & BIOLOGICAL SCIENCES EPIC (Elderly Patients Individualized Chemotherapy Trial): Prospective Validation of ERCC1, RRM1, TS 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

17 Maintenance Therapy Terminology: A Rose by any other name? Same agent A until PD or toxicity Platinum-based doublet chemotherapy: 4 cycles of Induction Example: Cisplatin + Agent A Continuation Maintenance Different agent C until PD or toxicity Switch Maintenance PD: Progressive Disease

18 Summary of Switch Maintenance Trials Fidias Ciuleanu Capuzzo Miller Perol Zhang Agent/Control Arm N PFS Docetaxel Delayed Docetaxel Pemetrexed Placebo Erlotinib Placebo Erlotinib + Bevacizumab Placebo + Bevacizumab Erlotinib Observation Gefitinib Placebo m HR m p< m HR m p< w HR w p< m HR m p m HR m p m HR m p< Salvage treatment % OS HR p HR p HR p HR p NA HR.91 NA HR p

19 Continuation Maintenance Trials Study Year Induction Therapy Maintenance Therapy Median PFS Brodowicz 2006 Gemcitabine 1250 mg/m 2 d 1, 8 + cisplatin 80 mg/m 2 d 1 x 4 Gemcitabine 1250 mg/m 2 d 1,8 BSC 6.6 months 5.0 months (p<.001) Median OS 13.0 months 11.0 months Main grade 3/4 toxicities Maintenance Gem: ANC14.9%, Plts 1.7%; blood transfusion 20% gemcitabine vs. 6.3% BSC Belani 2010 Gemcitabine 1000 mg/m2 d 1,8 + carboplatin AUC 5 d1 x 4 Gemcitabine 1000 mg/m 2 d 1,8 BSC 7.4 months 7.7 months (p=.575) 8.0 months 9.3 months (p=.838) ANC 15% chemo, 2% BSC; Plts 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC Perol 2010 Gemcitabine 1250 mg/m 2 d 1, 8 + cisplatin 80 mg/m 2 d 1 x 4 Gemcitabine 1000 mg/m 2 d 1,8 BSC 3.3 months 1.9 months (p<.001) NR NR At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares 2011 Pemetrexed 500 mg/m 2 d 1 + cisplatin 75 mg/m 2 d 1 x 4 Pemetrexed 500 mg/m 2 d 1 BSC 4.1 months 2.8 months (p=.0006) NR NR Fatigue:4.2% pem, 0.6% BSC, Anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC Fidias, J Clinc Oncol 28:

20 Continuation Pemetrexed Maintenance: PARAMOUNT (Independently Reviewed PFS from Maintenance) Paz-Ares : IASLC WCLC 2011 Paz-Ares L.G. et al. Oral Presentation ASCO 5 June 2011 Abstract #CRA Pem + BSC 0.9 Placebo + BSC Survival Probability Pemetrexed: median =3.9 mos ( ) Placebo: median =2.6 mos ( ) Log-rank P= Unadjusted HR: 0.64 ( ) Time (Months)

21 Maintenance Therapy : Options after Platinum-based Therapy with Non-Progressive Disease: Watch & Wait vs Maintenance/Consolidation/Sequencing R Who decided that 4 cycles of therapy is optimal? 4-6 cycles chemo Stop Watch & Wait Continue same chemo Continuation Maintenance Options: Bevacizumab, Cetuximab, Pemetrexed R R 4-6 cycles chemo Stop Watch & Wait Different chemo or another drug Switch Maintenance Options: Docetaxel, Pemetrexed, Erlotinib/Gefitinib 4-6 cycles chemo Stop Watch & Wait Different chemo or another drug Early 2 nd Line Therapy Gandara: Best of ASCO 2011

22 Issues to consider regarding Maintenance Therapy The big question about maintenance therapy is WHO to treat and WHEN to treat? How do these trials relate to the patients I am treating in my office? If 6 cycles of platinum chemotherapy are given, are the maintenance data relevant? If a patient achieves no response (Stable Disease) and remains symptomatic, is subsequent therapy maintenance or early second line therapy? If a patient achieves response and becomes asymptomatic, is maintenance therapy always better than watch and wait? In the emerging era of personalized therapy, these decisions should be made on an individual basis: One size does not fit all

23 Major Themes in Therapy of Advanced NSCLC: Interrelationship Between Histology, Maintenance Therapy and Biomarkers Histology Maintenance Therapy Molecular Biomarkers Looking Forward to 2015: Moving from Empiric to Individualized Therapy from One Size Fits All to Tailored Therapy

24 Transition from Empiric to Rationally Selected & Individualized Cancer Therapy Empiric Therapy Molecular-Based & Individualized Therapy Patient Characteristics Physician Experience Physician Experience Tumor Molecular Profiling Prognostic & Predictive Biomarkers Availability of Adequate Tumor Tissue for Molecular Testing Early development of Drug-specific Predictive Biomarkers Integration of the Individual Patient into the process Gandara, Scagliotti et al: Clin Lung Cancer, 2009

25 Transition from Empiric to Rationally Selected & Individualized Cancer Therapy Patients with the same Diagnosis &Clinical Features (Stage IV Non-small Cell Lung Cancer) 65 y/o male Smoker Squamous KRAS Mt 39 y/o female Never-Smoker Adenoca EGFR Mt In 2011: Most Oncologists would agree that these patients have very different malignancies Most Oncologists would agree that these patients should receive different therapy Yet most Phase III Clinical Trials testing new drugs will still lump these patients together (unless new drug is EGFR-directed). Example: Chemotherapy +/- IGF1Ri

26 Potential Druggable Molecular Targets? Lung Cancer Molecular Consortium (LCMC) Lung Adenocarcinomas Mutations found in 54% (280/516) Emerging Druggable Targets in NSCLC-Squamous Subtype Gene Event Type Frequency FGFR1 Amplification 20-25% FGFR2 Mutation 5% PIK3CA Mutation 9% LUME 1 Trial (Adv NSCLC-squamous-enriched) PTEN Mutation-Deletion 18% CCND1 Amplification 8% Docetaxel +/- BIBF1120 CDKN2A Deletion/Mutation 45% PDGFRA Amplification-Mutation 9% EGFR Amplification 10% MCL1 Amplification 10% BRAF Mutation 3% DDR2 Mutation 4% ERBB2 Amplification 2% Hammerman et al: IASLC WCLC 2011

27 Moving Toward 2015: Collaborative Advanced Stage Tissue Lung Cancer (CASTLE) Network CASTLE Biospecimens Core Biopsy Plasma RNA/DNA CASTLE Network Serum RNA DNA ResponseDX TM Submissions VeriStrat Submission ERCC1 gene expression RRM1 gene expression KRAS mutation analysis EGFR amplification TS expression EGFR-TKI: a) candidate or b) contraindicated Biorepository Biorepository clinical research Genomics/Proteomics/Clinical Outcomes ALCMI (Addario Lung Cancer Medical Institute)

28 Patient LG0703 (EGFR amt with acquired EGFR-TKI resistance): Next Generation Sequencing Gene sets with prominent alterations Apoptosis Regulation Anti-apoptosis p53-signaling DNA repair DNA replication Death pathway EGFR signaling PTK pathway PI3K-AKT pathway Erk-MAPK pathway mtor signaling pathway Ras signaling Signal transduction regulation Fas signaling 3790 sequences divergent from reference 1428 in coding sequences 206 synonymous (no aa change) 516 nonsynonymous 98 at good confidence 11 at mutation/wt ratio similar to EGFR Gene Symbol Chromosome Position Reference Base Genotype Call Codons Amino Acid Substitution Unanswered Questions A C G T How many resistance mechanisms exist between one patient and the next? How many resistance mechanisms exist with the same patient tumor? EGFR chr T GT Logodds ratio CTG- CgG L858R SNP Type Nons ynony mous from Mack et al: Genomics Shared Resource UC Davis Cancer Center

29 Analysis of EGFR mutation testing in France 2010 June 2009: Gefitinib approval in France for EGFR MT+ NSCLC patients National testing provided free of charge INCa allocated 1.7M for the platforms Over 16,000 tests performed EGFR mutation+: 10.3% Uninformative tests: 5.7% Time line for obtaining results: average 10 days (4.5 to 20 days) Methods: exons 19 and 21, 100% exon 18, 66%; exon 20, 71% Sequencing, 59%; alternative methods, 41% By courtesy, F Nowak INCa

30 EGFR TKIs vs Chemotherapy as First Line Therapy Trial/Patient group Median PFS (m) Overall survival (m) OPTIMAL China, EGFR mutant N Gefitinib Chemo HR (95%ci) Erlotinib Gefitinib Erlotinib ( ) Not reached Chemo Selected These by results Clinical Factors in EGFR-selected patients represent a Major I-PASS East Asian, ( ) Advance but also present a Major Challenge light/nonsmoker, either adeno Clinical Targeting or Molecular Targeting result in Although First-SIGNAL Korean, nonsmoker, adeno ( ) a doubling of PFS, there is no change in Overall Survival Selected Even by in Molecular these patients parameter with EGFR activating MTs, resistance emerges within ~10-14 months NEJ002 Japan, ( ) The response EGFR rate mutant in EGFR Mt+ patients is ~75% (not 100%) WJTOG3405 Japan, ( ) 30.9 Not How do we address this challenge and convert a high response EGFR mutant reached rate & improved PFS into improved Overall Survival or Cure? Not reached Spain Spain, EGFR mutant

31 Mechanisms of EGFR TKI Resistance More Questions than Answers: How do we best address these mechanisms Secondary of resistance EGFR in EGFR Mt+ patients? mutation (i.e. T790m) How do we account for intra-patient heterogeneity? Is the EGFR MT present in all cells of a cancer? Are there multiple mechanisms for resistance in a single patient? Bypass signaling via ERBB3 C-MET overexpression PIK3CA Mutation/AKT and others

32 UC Davis-JAX NSG PDX Platform for Drug Testing: EGFR-driven Therapies P0 P1 P2 ~50 NSCLC tumors engrafted 10 models selected for Drug Testing & Molecular Assessment EGFR WT Model EGFR amt+ Models KRAS MT Model LG0551 EGFR WT Resistant LG0631 EGFR amt+ (L858R) Sensitive LG0703 EGFR amt+ (L858R) Acquired Resistance LG0651 EGFR amt+ (L858R + T790M) De novo Resistance LG0567 EGFR WT KRAS Gly12Cys Resistant Regimens A, B, C Regimens A, B, C Regimens A, B, C Regimens A, B, C Regimens A, B, C

33 EGFR TKI resistant NSCLC with aegfr MT: Rationale for Afatinib (BIBW2992) + Cetuximab in the presence of T790M MT Regales et al. JCI 2009

34 EGFR TKI-resistant aegfr MT+ NSCLC: Afatinib (BIBW2992) + Cetuximab NOTE: Preliminary Efficacy Appears Equivalent in T790M- cancers Horn et al: IASLC WCLC 2011

35 FLEX: Chemotherapy +/- Cetuximab in first line therapy of Advanced NSCLC Cetuximab + Cisplatin + Vinorelbine Stage IIIB or IV EGFR POSITIVE R n = 550 Cisplatin + Vinorelbine Survival n = 550 Eligibility Criteria: EGFR-expressing, advanced stage NSCLC; No prior CT Primary Endpoint: Median overall survival (845 events needed) Secondary Endpoints: Survival rate (1 and 2 y), PFS rate (6 and 12 mo), response rate, safety, QoL Sample Size: 1100 in 170 centers in EU, Latin America, Asia Pirker et al. WCLC 2011, # O 01.06

36 FLEX: Response & OS by IHC Score

37 S0342: Cetuximab + Paclitaxel/Carboplatin: Analysis by EGFR FISH EGFR FISH Response (CR/PR) DCR (CR/PR/SD) FISH - 26% 55% FISH + 45% 81% (p=0.02) 100% 80% 60% 40% 20% 0% Progression Free Survival by FISH Score Group PFS Median Events / N in Months 1-4 Low 31 / 31 3 (2,4) 5-6 High 41 / 45 6 (5,7) Logrank P-value = Months After Enrollment 100% 80% 60% Overall Survival by FISH Score Group OS Median Events / N in Months 1-4 Low 25 / 31 7 (4,11) 5-6 High 29 / (10,19) Logrank P-value =.04 40% Hirsch, 12 June 2007 Gandara et al: JCO % 0% Months After Enrollment

38 S0819: Chemotherapy +/- Cetuximab & Predictive Biomarker Validation EGFR FISH Stratify Randomize Marker testing Marker + Marker - Chemo Chemo/Cetux Chemo Chemo/Cetux M+ M+ M- M- Chemotherapy: Paclitaxel/Carboplatin Co-primary endpoints: OS for entire study PFS for EGFR FISH Integrated: EGFR IHC score PI: R. Herbst

39 We are making progress Progress requires continuing change Culture Change Lung Cancer Therapy: 2011 Looking Forward to 2015 Requirement for more tumor tissue (Molecular Profiling) Ungroup NSCLC into individual patients (Personalized Therapy) Change in how we develop new cancer drugs (New Paradigms) Account for complexity of underlying biologic systems Account for inter- and intra-patient heterogeneity Reality: The transition from Empiric to Rationally Selected and Personalized Therapy is challenging In every challenge there are opportunities We must take advantage of each of these opportunities if we are to advance the cure of patients with lung cancer