Adjuvant Therapies for Lung Cancers: New Directions Mark G Kris, MD Member and Attending Physician William and Joy Ruane Chair in Thoracic Oncology Memorial Sloan-Kettering Professor of Medicine, Weill Cornell Medical College New York, New York USA
New Directions for Adjuvant Therapies of Lung Cancers Disclosures Consultant/Trial Support: Pfizer, Genentech/Roche, Novartis, Clovis, Ariad Stock/Royalties: None
New Directions for Adjuvant Therapies of Lung Cancers Additional Disclosures I was born a medical oncologist but was raised by thoracic surgeons I am a chemotherapy guy who has gone molecular
Memorial Sloan-Kettering Thoracic Oncology Service Charles Rudin, MD, PhD Service Chief Mark G. Kris, MD Lee M. Krug, MD Naiyer A. Rizvi, MD Gregory J. Riely, MD, PhD Maria C. Pietanza, MD Paul K. Paik, MD Jamie Chaft, MD Marjorie Zauderer, MD Alexander E. Drilon, MD Helena A. Yu, MD Stephen Veach, MD Kenneth Ng, MD John Fiore, MD Stephanie Smith-Marrone, MD Afsheen Iqbal, MD Stefan Berger, MD Michael Fannuchi, MD
New Directions for Adjuvant Therapies of Lung Cancers Introduction All stages need more cures Eradicating metastases the goal EGFR as a target Results in patients with early stages Trials in progress and proposed Seizing the opportunities
Bending the survival curve in lung cancers Rudin Proc IASLC 2013
Do Good Prognosis Lung Cancers Exist? T Stage (all N0M0) Primary Size N 5 Year Survival Clinical Stage 5 Year Survival Pathological Stage T1a 2 cm 1816 53% 77% T1b > 2-3 cm 1563 47% 71% T2a > 3-5 cm 2822 43% 58% T2b > 5-7 cm 825 36% 49% T2c >7 364 26% 35% Rami-Porta J Thorac Oncol 2007
Prognostic Factors in Lung Cancers There are no good prognosis lung cancers 23% of patients with tumors less than 2 cm (Stage pt1an0m0) are dead at 5 years. All patients with breast cancer with this degree of risk are recommended additional therapy with primary treatment.
EGFR Mutations in Early Stage Lung Cancers Metastases: #1 Cause of Failure Rates of Systemic Failure by Disease Extent at Presentation - Local 80% - Regional 80% - Advanced 100%
NSCLC Adjuvant Trials Post 1995 Meta-Analysis Survival With Adjuvant Chemotherapy # Pts 5 yr (%) HR 95% CI p Meta95 1394 5 0.87 0.74-1.02 0.08 1209 3 0.96 0.81-1.13 0.59 1867 4 0.86 0.76-0.98 0.03 482 15 0.70 0.52-0.92 0.01 JNCI 03; NEJM 04; NEJM 05; JCO 09; Lancet Oncol 06 344 2 0.80 0.60-1.07 0.10 840 8 0.79 0.66-0.95 0.01 Meta07 4584 4 0.89 0.82-0.96 0.005
Strategies to Select Drugs for Use With Surgery in Early Stage Lung Cancers Driver mutations Histologic type Repair/Metabolism genotype Gene expression profiles Assess radiographic response in induction window of opportunity
Actionable Targets in Lung Adenocarcinomas 1999 2004 2005-2013 Unknown 75% Unknown 60% EGFR KRAS Unknown 35% KRAS RET EGFR ROS1 MEK HER2 ALK MET PIK3CA Kris M et al. IASLC 2012 Targeted BRAF Therapies Conference
EGFR-mutant Lung Cancers Following the GIST Playbook Single driver mutation Sensitivity to kinase inhibitors Eventual acquired resistance Development of 2 nd site mutations Continued clinical benefit from kinase inhibitors after progression Survival benefit of adjuvant TKI
Adjuvant Imatinib in GIST Imatinib 1 Year vs 3 Years Recurrence-free survival Overall survival Joensuu NEJM 2012
SELECT* : A multicenter phase II trial of adjuvant erlotinib in 100 EGFR-mutant lung cancers Neal Proc ASCO 2012
Months on Erlotinib Duration of Erlotinib Treatment duration and dose reductions Reasons for discontinuation 1 Travel precluded participation 2 Diarrhea 3 Rash/Diarrhea 4 Diarrhea/fatigue 5 Prostate cancer radiotherapy 6 Patient preference 7 Rash 8 Disease progression 9 Patient preference 10 Rash
SELECT Overall Survival
MSK Patients with EGFR Mutant Lung Cancers Use of Adjuvant Gefitinib or Erlotinib Stage I-III with EGFR mutant lung cancers N=146 Exon 19 deletions 56% Exon 21: L858R (71) and L861Q (2) 44% Received adjuvant chemotherapy 30% Received adjuvant gefitinib (21) or erlotinib (32) 32% Median time on gefitinib or erlotinib (months) 16 (0.7 to 30) Janjigian J Thorac Oncol 2011
Disease Free Survival (%) Adjuvant Gefitinib and Erlotinib Impact on Disease Free Survival 100 80 60 40 No adjuvant gefitinib/ erlotinib Adjuvant gefitinib/erlotinib Adjusted Hazard Ratio=0.53 (95%CI, 0.28-1.03) p=0.06* Events: gefitinib/erlotinib 13(23%) no gefitinib/erlotinib 43(39%) 20 0 12 24 36 48 60 72 84 96 Time (months) Number at Risk no G/E therapy 95 G/E therapy 51 Janjigian J Thorac Oncol 2011; 6:569 52 37 28 18 17 5 11 2 6 0 5 0
Proportion Disease Free Surviving 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Overall Surviving 0.0 0.2 0.4 0.6 0.8 1.0 242 MSK Patients with EGFR Mutant Lung Cancers Use of Adjuvant Gefitinib or Erlotinib DISEASE FREE SURVIVAL Adjuvant gefitinib/erlotinib OVERALL SURVIVAL No TKI no g/e, n=202 g/e, TKI n=56 adjusted HR: 0.48 (0.29, 0.80), p=0.005 Adjusted HR: 0.40, p=.005 No TKI no g/e, n=202 g/e, TKI n=56 Adjusted HR: 0.56 (0.27, 1.17), p=0.123 Adjusted HR: 0.56, p=.123 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Number at Risk No no TKI g/e 159 g/e 74 TKI 94 58 46 39 Months 22 14 18 8 11 2 6 0 4 0 1 0 Number at Risk No no TKI g/e 163 g/e 79 TKI 117 65 64 46 Months 44 30 28 12 19 6 9 0 6 0 1 0 D Angelo J Thorac Oncol 2012
No EGFR TKI Acquired Resistance in Patients Completing Adjuvant EGFR TKIs
EURECA Erlotinib Used as Adjuvant Therapy in REsected EGFR Mutant Lung Carcinomas Lung Cancer Mutation Consortium PI: Christopher Azzoli, MD Resected stage I-III EGFRmutation positive lung cancer with activating EGFR mutation (exon 19 deletion, L858R, L861Q, G719X) Perioperative cytotoxic chemotherapy and radiation therapy as indicated Stratify by stage and perioperative chemotherapy N=286 Adjuvant erlotinib up to 24 months with CT chest every 6 months, then yearly N=190 CT chest every 6 months for 24 months, then yearly N=96 CT scan at 30 months Follow patients for recurrence and death. Patients with recurrence will be biopsied to confirm recurrence and test for molecular determinants of acquired resistance Record subsequent chemotherapies.
EURECA: Trial Design Innovations Primary Endpoint: Pathologic Documentation of Recurrence Internet-Based Data Collection No pathology review needed mutation presence only required No scan data collection needed No blood testing needed
Adjuvant Chemotherapy for NSCLCs ELIGIBLE: N = 945 Resected I-IIIA ( lobectomy) IHC/FISH for EGFR required Ongoing Trials: RADIANT Adjuvant Chemotherapy allowed STRATIFIED: Histology Gender Age EGFR Status Smoking Adj Chemo R A N D O M I Z E 2:1 Erlotinib 150 mg po qd x 2 years Observation DFS as primary endpoint Completed Sep 09 www.clinicaltrials.gov. NCT00373425
Adjuvant Chemotherapy for NSCLCs Ongoing Trials: The MAGRIT study of GSK1572932A Antigen-Specific Immunotherapeutic Product ELIGIBLE: N = 2270 Resected IB-IIIA ( lobectomy) Tumor MAGE-A3 gene expression No prior chemo No RT R A N D O M I Z E Other adjuvant therapy not defined in trial registry GSK1572932A 13 injections over 27 months Placebo 13 injections over 27 months MAGE-A3 (Melanoma AntiGEn-A3) is expressed by many tumors but not normal tissues. Primary endpoint = DFS www.clinicaltrials.gov. NCT00480025..
E1505: Phase 3 Adjuvant Chemotherapy Bevacizumab Resected IB (>4cm) IIIA Adequate MLND sampling All pts: level 7 Left: level 5 or 6 Right: level 4 N = 1500 R A N D O Chemotherapy* x 4 cycles Closed to accrual M 7 October 2013 I Z Chemotherapy* x 4 cycles + E bevacizumab x 1 year Cisplatin and vinorelbine Cisplatin and docetaxel Cisplatin and gemcitabine Cisplatin and pemetrexed Primary endpoint: overall survival Interim results anticipated in 2016
Adjuvant Afatinib: 3 months vs 2 years Lecia Sequist, PI Resected Stage I-III EGFR+ lung cancer s/p completion of standard adjuvant chemotherapy +/-RT Baseline CT NED R A N D O M I Z E Afatinib oral daily x 3 months CT chest every 6 months x 3 years and then annually Afatinib oral daily x 2 years RFS at 5 years 92 patients will be stratified for pathologic stage (I, II, III) powered to detect a recurrence free survival improvement of 20%
Proposed ALCEMIST Schema Register post-op Register pre-op ALCEMIST Trial Assess & obtain FFPE tissue SOP for FFPE tissue Collect blood; Central EGFR & ALK genotyping Patients on adjuvant trials followed separately Follow q6 months for 5 years Optional fresh/ frozen tissue FFPE tissue & blood specimen FFPE tissue from recurrence biopsy Advanced genomics at the NCI Center for Cancer Genomics 6000-8000 patients will be screened over 4-5 years
ALCHEMIST-Related Adjuvant Trials Alliance A081105 Govindin Stage IB- IIIA NSCLC Complete Surgical Resection Screen for EGFR mutation+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Erlotinib X 2 years Placebo ECOG E4517 Ramalingam Stage IB- IIIA NSCLC Complete Surgical Resection Screen for ALK+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Crizotinib X 2 years Placebo
LCMC: Oncogenic Drivers Detected in 63% of Patients With Lung Adenocarcinomas Kris Proc WCLC 2013
Use of Molecular Characteristics to Select Available Adjuvant Therapies for Patients With Lung Cancers
Induction (Neoadjuvant) vs Adjuvant Factors Favoring Induction Chemotherapy Attacks micrometastases at earliest time Better drug delivery and tolerability Ability to assess sensitivity of agents used in induction and planned for adjuvant Platform for new agent testing Surgical findings an outcome surrogate Time to identify unsuspected metastases and comorbidities before local therapy Randomized trials equivalent or better Provides quicker answers
In breast cancers, trials using pathologic complete response (pcr) after induction yields quicker results Trial Intervention Outcome measured Time from enrollment to publication of data NSABP B-18 Surg Chemo Vs Chemo Surg Overall Survival 10 years NSABP B-27 Buzdar et al NSABP B-40 GBG44 NeoSphere AC Surg Doce Vs AC Doce Surg Chemo Surg Vs Chemo + Tras Surg Chemo Surg Vs Chemo + Bev Surg Chemo Surg Vs Chemo + Bev Surg Chemo+Tras Surg VS Chemo+Tras+Pertuzumab Surg Overall Survival pcr pcr pcr pcr pcr 11 years 8 years 4 years 5 years 5 years 4 years Fisher B et al, JCO 1998 Bear HD et al, JCO 2006 Bear HD et al, JCO 2003 Buzdar et al, JCO 2005 Bear HD et al, NEJM 2010 Von Minckwitz G et al, NEJM 2010 Gianni L et al, Lancet Oncol 2012 FIRST therapy to be approved by FDA based on path CR
P e rc e n t s u rv iv a l We can do it too Major pathologic response (mpr) correlates with overall survival in patients with lung cancers MD Anderson all stages MSKCC stage IIIA only O v e r a ll S u r v iv a l 1 0 0 < /= 1 0 % re s id u a l tu m o r (n = 1 2 ) 5 0 A ll o th e rs (n = 1 1 7 ) 0 0 2 0 4 0 6 0 8 0 S u rv iv a l (m o n th s ) Pataer et al, JTO 2012 Hellmann Lancet Oncology (in press) Chaft IASLC WCLC 2013 Hellmann IASLC WCLC 2013
Bending the survival curve in lung cancers Stage IV EGFR-mutant Lung cancers - Today Stages I - III EGFR-mutant Lung cancers - Tomorrow Rudin Proc IASLC 2013
New Directions for Adjuvant Therapies of Lung Cancers Conclusions All patients with lung cancers need adjuvant therapies Data demonstrates practicality, safety, and disease free survival benefit for adjuvant TKI use in EGFR mutant lung cancers, likely survival benefit as well GIST data shows survival benefit. Longer duration better Multiplex testing finds an actionable target in 63% While both induction and adjuvant therapies are effective, induction has many advantages The time is now to use and test therapies directed against oncogenic drivers: EGFR, ALK and others too! It s good to go molecular. Let s bend the curve.
Bending the survival curve in lung cancers Rudin Proc IASLC 2013
Bending the survival curve in lung cancers Stage IV EGFR-mutant Lung cancers Rudin Proc IASLC 2013
ALCHEMIST: Linked Trials E4512 A081105 Target ALK+ EGFR mutation + Agent Crizotinib Erlotinib n 336 410 Primary Endpoint DFS OS Power 80% 85% One-sided α 0.025 0.05 HR 0.67 0.67 Correlative Studies Peripheral screening for ALK; RTPCR to identify fusion partners Targeted sequence and kinome analysis; PRO and QOL