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Department of Thoracic/Head & Neck

Mutational Analysis in NSCLC Adenocarcinoma to Guide Therapy. Anne S. Tsao, M.D. Associate Professor. Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program. The University of Texas. Department of Thoracic/Head & Neck. MD ANDERSON. Medical Oncology. CANCER CENTER.

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Department of Thoracic/Head & Neck

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  1. Mutational Analysis in NSCLC Adenocarcinoma to Guide Therapy Anne S. Tsao, M.D. Associate Professor Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program The University of Texas Department of Thoracic/Head & Neck MD ANDERSON Medical Oncology CANCER CENTER

  2. Outline: NSCLC Epidemiology Histology Molecular Profiling Background IPASS EURTAC LUX LUNG 3 EGFR mutants EML 4 ALK, ROS 1 Crizotinib Upcoming agents

  3. Lung Cancer During 2013, ~228,190 new cases and ~159,480 deaths are expected in the United States Second most common cancer and leading cause of cancer death 5-Year Relative Survival Rate by Stage at Diagnosis 100 90 80 70 60 53% Localized (stage I/II) 15% Survival (%) Distant (stage IV) 56% 50 40 24% 30 20 Regional (stage III) 22% 4% 10 0 Localized Regional Distant Stage at Diagnosis American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society; 2013; Siegel. CA Cancer J Clin.61(4):212.

  4. 2004 WHO Classification of Lung Tumors Emerging data indicate that specific regimens show greater benefit depending on tumor histology. BAC=bronchioloalveolar carcinoma; LCC=large cell carcinoma; LCNEC=large cell neuroendocrine carcinoma; SCC=squamous cell carcinoma; SCLC=small cell lung cancer; WHO=World Health Organization. American Cancer Society. Cancer Facts and Figures 2008. Atlanta: American Cancer Society; 2008; Travis, ed. WHO Pathology & Genetics Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004; Kufe. Cancer Medicine 7. Hamilton, Ontario: BC Decker, Inc.; 2006:1185; Georgoulias. Lancet. 2001;357:1478; Scagliotti. J Clin Oncol. 2008;26(21):3543; Ciuleanu. Lancet. 2009;374(9699):1432.

  5. Lung Cancer Mutation ConsortiumOrganization • Headquarters: University of Colorado • Paul Bunn, Principal Investigator • 14 Sites: SPORE, P01, NCI Intramural Programs • Plan: Genotype 1000 patients with advanced lung adenocarcinoma, 2009-2011 • Assay 10 “driver” mutations in CLIA-certified laboratories: EGFR, KRAS, BRAF, HER2, AKT1, NRAS, PIK3CA, MEK1, EML4-ALK, MET amp Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01 Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

  6. LCMC Objectives • Characterize 1000 tumor specimens from patients with lung adenocarcinoma for KRAS, EGFR, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK1, and EML4-ALK, and MET amplification • To use the information in real time to either select erlotinib with EGFR mutations or recommend a clinical trial of an agent targeting the specific mutation identified Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01 Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

  7. Lung Cancer Mutation Consortium Incidence of Mutations Detected (n=516) HER2 A driver mutation was found in 54% (280/516) of tumors completely tested (CI 50-59%) Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01 Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

  8. Lung Cancer Mutation Consortium Conclusions • An actionable driver mutation in 54% of patients with lung adenocarcinoma • 23% KRAS mutations 2% BRAF mutations • 18% EGFR mutations 2% PIK3CA mutations • 9% EML4-ALK • EGFR mutations correlate with younger age, female gender, and never smokers • KRAS mutations correlate with older age and smoking history • Plans are underway to expand the scope of the LCMC when ARRA funding ends-LCMC 2.0 Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01 Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

  9. Outline: NSCLC Epidemiology Histology Molecular Profiling Background IPASS EURTAC LUX LUNG 3 EGFR mutants EML 4 ALK, ROS 1 Crizotinib Upcoming agents

  10. Tsao Algorithm: Histology and Molecular Profiling NSCLC PATIENT SCC Non-SCC Neuroendocrine Adenocarcinoma Avoid pemetrexed or bevacizumab Platinum-etoposide; Switch Maintenance: pemetrexed, erlotinib EGFR mutation EGFR wild-type Consider 2nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) EML 4 ALK or ROS 1 EGFR TKI 1st or 2nd line Maintenance (IPASS, BR.21, SATURN) crizotinib Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

  11. EGFR mutations • Found in 10% - 15% of all lung cancer patients and 85% who clinically respond to EGFR TKIs • Found more commonly in never-smokers, adenocarcinomas, BAC, women, Asians • Predominantly located in EGFR exons 19 - 21 • EGFR mutations are not the same. There are sensitive mutations and acquired resistance mutations (T790M). • 85% of EGFR mutations are either deletion exon 19 or L858 mutation. Pao, Miller. J Clin Oncol. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.

  12. 12-02 12-00 Patient with EGFR mutation deletion exon 19

  13. Newly diagnosed 3-16-07 3 months of erlotinib 6-18-07 Patient with L858 EGFR mutation

  14. EGFR T790M: Frequently Found inTumor Cells From Patients With Acquired Resistance to EGFR TKIs Pao W, et al. PLoS Med. 2005;2:e73; Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501.

  15. T790M blocks erlotinib binding and leads to a resistant phenotype Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008

  16. IPASS: Phase III Trial of Gefitinib vs Carboplatin/Paclitaxel in Selected PatientsWith Advanced NSCLC Never or light ex-smoker* with adenocarcinoma histology PS 0-2 Stage IIIB or IV chemotherapy-naïve NSCLC N=1217 Gefitinib (250 mg/day) Offered carboplatin/paclitaxel on progression R A N D O M I Z E Carboplatin (AUC 5 or 6) + Paclitaxel (200 mg/m2) 3 times weekly up to 6 cycles Primary endpoint: PFS (noninferiority) Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerability Exploratory: biomarkers – EGFR mutation, gene copy number, and protein expression *Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15 years ago and smoked ≤10 pack-years. Mok. N Engl J Med. 2009;361:947.

  17. IPASS: PFS by EGFR Mutation Status Within Treatment Arms Gefitinib EGFR M+ (N=132)Gefitinib EGFR M– (N=91)Carboplatin/paclitaxel EGFR M+ (N=129) Carboplatin/paclitaxel EGFR M– (N=85) 1.0 0.8 Gefitinib, HR=0.19; P<0.0001Carboplatin/paclitaxel, HR=0.78; P=0.1103 Probability of PFS 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Time From Randomization (Months) HR <1 implies a lower risk of progression in the M+ group compared with the M– group. M=mutation. Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO. 2008 (abstr LBA2).

  18. IPASS: PFS and OS by EGFR Mutation Status OS (2010) PFS (2008) Probability of Survival 1.0 Probability of Progression-Free Survival 1.0 Gefitinib EGFR M+ Gefitinib EGFR M- C/P EGFR M+ 0.8 0.8 C/P EGFR M- Mutation + 0.6 0.6 0.4 0.4 0.2 Mutation - 0.2 0.0 0.0 40 48 4 52 8 16 28 12 20 32 36 44 0 24 4 8 16 20 12 24 0 Mos Mos Reproduced with permission from Fukuoka. J Clin Oncol. 2011;29(21):2866. Reproduced with permission from Yang. ESMO. 2010 (LBA2).

  19. EURTAC: Phase III Study of Erlotinib vs Chemotherapy in Patients with EGFR Mutations • Eligibility: • Chemo naїve • Stage IIIB/IV NSCLC • EGFRexon 19 deletion or exon 21 L858R mutation • ECOG PS 0-2 • (n=174) R A N D O M I Z E Erlotinib 150 mg/day PD Platinum-based doublet chemotherapy q3w × 4 cycles* PD *Cisplatin/docetaxel, cisplatin/gemcitabine, carboplatin/docetaxel, or carboplatin/gemcitabine. • Primary endpoint: PFS • Secondary endpoints: ORR, OS, site of progression, safety, and QOL • Stratification: mutation type and ECOG PS Rosell. ASCO. 2011 (abstr 7503).

  20. Response and PFS in ITT Rosell et al. ASCO 2011 Abstract 7503

  21. OS in ITT Rosell et al. ASCO 2011 Abstract 7503

  22. Summary EURTAC • EURTAC is the first Caucasian front-line EGFR TKI vs chemotherapy study performed in EGFR-mutation positive patients. • The PFS (HR 0.37) was consistent with prior studies and favored the erlotinib arm with no new safety signals. • OS remains immature with high level of crossover.

  23. [TITLE] Yang et al. ASCO 2012 Abstract LBA7500

  24. Phase III Lung LUX-3 Trial 1269 screened, 452 EGFR mutation (+) => 345 randomized Yang et al. ASCO 2012 Abstract LBA7500

  25. [TITLE] Yang et al. ASCO 2012 Abstract LBA7500

  26. ORR favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

  27. PFS favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

  28. PFS Independent Review Subgroup Analysis Yang et al. ASCO 2012 Abstract LBA7500

  29. PFS Common Mutants (Del 19/L858R) Yang et al. ASCO 2012 Abstract LBA7500

  30. QOL: EORTC QLQ C-30 Yang et al. ASCO 2012 Abstract LBA7500

  31. Summary LUNG LUX-3 • Front-line afatinib improved QOL, RR, DCR, and median PFS over cisplatin-pemetrexed in both the overall EGFR mutation population and in the common EGFR mutation (del19/L858) patients. • Subgroup analysis showed benefit across most of the subgroups. • No new safety signals with diarrhea and rash as the most frequent AEs. • On July 12, 2013, the FDA approved afatinib for front-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) as detected by an FDA-approved test. Yang et al. ASCO 2012 Abstract LBA7500

  32. Front-line EGFR TKI • EGFR TKI monotherapy in NSCLC patients with sensitive EGFR mutations improves PFS over chemotherapy. • However, EGFR TKI monotherapy should not be given to patients without EGFR mutations, i.e. EGFR wild-type (WT). EGFR WT patients need front-line chemotherapy. • It is unclear which EGFR TKI should be used front-line. • It is unclear whether EGFR TKI + chemo or chemo then maintenance erlotinib would improve survival for EGFR mutation patients. • CALGB 30406 frontline study (ASCO 2010) • FAST - ACT (intercalating EGFR TKI with chemo) – await results. There are concerns over combining erlotinib-chemo as erlotinib arrests the cancer cells in the G1 checkpoint and chemo usually works best in the mitotic phase. • SATURN – showed that EGFR mutation patients had significant survival improvement with maintenance erlotinib after 4 cycles of chemo.

  33. Outline: NSCLC Epidemiology Histology Molecular Profiling Background IPASS EURTAC LUX LUNG 3 EGFR mutants EML 4 ALK, ROS 1 Crizotinib Upcoming agents

  34. EML4-ALK Fusion Gene • ALK – anaplastic lymphoma kinase • EML 4 – echinoderm microtubule associated protein like 4 • Found Primarily in adenocarcinoma patients who are never- or light former smokers, EGFR and KRAS WT, and younger • All adenocarcinomas: 9% EML4-ALK • If EGFR WT, Caucasian never-smoker, adenocarcinoma: ~10-20% EML4-ALK • EML4-ALK-positive tumors are a distinct entity among lung adenocarcinomas and usually do not respond to EGFR TKIs. • EML 4 ALK is a negative prognostic factor • ALK (+) NSCLC treated with 2nd/3rd line crizotinib have longer OS than those who are not treated with crizotinib. Koivunen et al. CCR 14 (13): 2008; Shaw et al. ASCO 2011 Abstract 7507; Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506

  35. Phase II crizotinib in ALK-positive NSCLC Crino et al. ASCO 2011 Abstract 7514

  36. Tumor response Best response ORR 51.1% SD 34% DCR week 6 85% week 12 74% PD 7.5% Crizotinib was FDA approved for use in pre-treated EML4 ALK patients. Crino et al. ASCO 2011 Abstract 7514

  37. ALK Inhibitor Efficacy in EML4-ALK NSCLC Baseline 2 months of PF-02341066 Kwak EL. J Clin Oncol 2009;27(suppl):Abstract 3509

  38. Crizotinib – ASCO 2010 Plenary • Treatment with crizotinib resulted in impressive clinical activity in patients with ALK-positive advanced NSCLC • ORR: 57% • DCR at 8 weeks: 87% • PFS probability at 6 months: 72% • Crizotinib was well tolerated • Most frequent AEs: mild/moderate GI events and mild visual disturbances • For patients with ALK-positive NSCLC, crizotinib may offer a potential new standard of care.

  39. ROS1 is an oncogene homologous to ALK and LTK within the Insulin Receptor Superfamily v-ros initially discovered as the oncogene in the avian sarcoma RNA tumor virus, UR2 Expression restricted to epithelial cells Normally expressed in kidney, small intestine, lungs, heart and male reproductive organs Orphan receptor with no known ligands Bergethon et al. J Clin Oncol. 2012;30(8):863-870, Doebele. IASLC Targeted Therapy 2012

  40. Screening for ROS1 gene fusions reveals ~1% incidence in NSCLC • RT-PCR (Li et al. PLoS One 2011) • 2/202 (1%) East Asian Never Smokers with adenocarcinoma • assaying for SLC34A2- or CD74-ROS1 fusions • 2/2 CD74-ROS1 • FISH (Bergethon et al. JCO 2012) • 18/1073 (1.7%) • 6/18 confirmed by RT-PCR • 5 CD74-ROS1 • 1 SLC34A2-ROS1 • FISH (Davies et al., accepted AACR 2012) • 5/428 (1.2%) surgically resected • 5/5 confirmed by RT-PCR • 2 CD74-ROS1 • 2 SLC34A2-ROS1 • 1 SDC4-ROS1 • 1/48 patients screened at U. of Colorado • SDC4-ROS1 Doebele. IASLC Targeted Therapy 2012

  41. Clinical tumor responses in ROS1+ NSCLC treated with crizotinib pre-crizotinib post-crizotinib (12 weeks) pre-crizotinib post-crizotinib (56 days) Bergethon et al. JCO 2012 Davies et al. AACR 2012 Doebele IASLC Targeted Therapy 2012

  42. ROS1 • ROS1 gene fusions involved in multiple cancer types • Incidence across multiple studies in NSCLC is approximately 1% • ROS1 mutant patients are younger and more likely to be never smokers with higher grade adenocarcinoma histology • Clinical responses are seen in ROS1 mutant patients with crizotinib • Ongoing clinical trial for ROS1 NSCLC patients using crizotinib Bergethon et al. J Clin Oncol. 2012;30(8):863-870, Doebele. IASLC Targeted Therapy 2012

  43. 2nd generation ALK inhibitors

  44. Tsao Algorithm: Histology and Molecular Profiling NSCLC PATIENT SCC Non-SCC Neuroendocrine Adenocarcinoma Avoid pemetrexed or bevacizumab Platinum-etoposide; Switch Maintenance: pemetrexed, erlotinib EGFR mutation EGFR wild-type Consider 2nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) EML 4 ALK or ROS1 EGFR TKI 1st or 2nd line Maintenance (IPASS, BR.21, SATURN) crizotinib Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

  45. Potential Future of NSCLC - Molecular Profiling Adenocarcinoma PI3K mutant KRAS mutant EGFR mutation EGFR TKI EML 4 ALK or ROS1 mutant PI3K inhibitor Met inhibition Resistance – rebiopsy T790M – irreversible EGFR TKI MET upregulation – Met inhibitor Met + crizotinib BRAF mutation MEK inhibitor combination Resistance – rebiopsy Novel agent BRAF inhibitor Resistance – rebiopsy Hsp90 inhibitor novel agent targeting ALK resistance mutation Resistance – rebiopsy Novel agent Resistance – rebiopsy Novel Agent Resistance – rebiopsy Novel agent Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

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