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Current Modalities in the Treatment of Lung Cancer
 

Current Modalities in the Treatment of Lung Cancer

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Christopher Azzoli, M.D., Assistant Member, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center: Current Modalities in the Treatment of Lung Cancer ...

Christopher Azzoli, M.D., Assistant Member, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center: Current Modalities in the Treatment of Lung Cancer

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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    Current Modalities in the Treatment of Lung Cancer Current Modalities in the Treatment of Lung Cancer Presentation Transcript

    • Hackensack University Medical Center John Theurer Cancer CenterNew Frontiers in the Management of Solid and Liquid Tumors Lung Cancer Update 2011 Harry Harper, M.D. Christopher Azzoli, M.D. November 4, 2011
    • Lung Cancer Update, 2011 OVERVIEW• Lung cancer facts and figures• Screening smokers for lung cancer• NSCLC: – Surgery – Chemotherapy + XRT – Chemotherapy• SCLC: – Chemotherapy – Chemotherapy + XRT – Prophylactic cranial irradiation
    • Cancer in the United States, 2011 New Cases DeathsProstate 240,890 Lung 156,940 Breast 230,480 Colorectal 49,380 Lung 221,130 Breast 39,520Colorectal 141,210 Prostate 33,720 Jemal, Cancer Facts & Figures 2011, CA, 2011
    • Stage at Diagnosis: Females 100 Breast Cancer 100 Lung Cancer 90 All Races 90 80 White 80Percent (%) 70 African American 70 60 61 59 60 60 55 55 51 50 50 39 40 33 32 40 30 30 22 22 22 20 20 15 15 12 10 5 4 8 10 0 0 Localized Regional Distant Localized Regional Distant Jemal A et al. CA Cancer J Clin. 2010;60:227-300.
    • September, 2002 – February, 2004 50,000 participants randomized Monitor through 2009 Low-dose fast spiral CT Current, or former heavy 0 1 2 cigarette smoker(>1ppd x 30 years) Randomized Age 55-74 CXRPrimary endpoint: 0 1 2Mortality due to lung cancer Years
    • National Lung Screening Trial24% CT scans “abnormal” (>4mm solid nodule or enlarged nodes)7% of CXR were “abnormal” Lung Lung Lung Lung Total Lung Cancer cancers cancers cancers cancer deaths Deaths Avoided detected detected detected deaths Scan 1 Scan 2 Scan 3CT 270 168 211 427 1877 1 for every Total: 320 screened 649CXR 136 65 78 503 1998 Mammogram: Total: 1 for every 279 HR HR 570 from 0.80 0.93 age 50 NLST, NEJM 2011
    • Estimated American Smokers at Risk CDC sponsored National Health and Nutrition Examination Survey (NHANES) 9,762 Americans polled in 2007-08Criteria Total Smokers Current Former55-74, ≥30 pack 7,425,000 4,027,000 3,398,000years50-79, ≥20 packyears 13,500,000 9,114,000 4,386,00055-74, any 26,627,000 7,738,000 18,889,000smoking history≥50, any smokinghistory 46,481,000 14,729,000 31,752,000≥21, ≥10 years ofsmoking any 77,005,000 39,883,000 37,122,000amount Data Courtesy of Peter Bach
    • “We’re gonna need a bigger boat.”
    • “Don’t smoke cigarettes.”
    • NSCLC IIIBStaging IIIA LYMPH NODES II I
    • Majorchange:7th-EditionTNMStagingJuly, 2009 IIA Node-negative tumors >5cm are now stage II
    • Best Treatment for NSCLC: SURGERY Surgically resected patients, 1990 – 2000 Overall Survival with SurgeryOverall Survival 8988 / 15952 : TOTAL 1 3 5 7 9 Goldstraw, et al. J Thorac Oncol. 2007;2:706-714
    • Benefit of Adjuvant Cisplatin+VinorelbineLACE, N=4584Pignon , JCO 2008;26 HR 0.92 N=1371 5Y risk 36% HR 0.83 N=1616 5Y risk 61% HR 0.83 N=1247 5Y risk 74%
    • Benefit of Adjuvant Cisplatin+Vinorelbine LACE, N=4584 Number Needed to Treat Pignon , JCO 2008;26 to Save 1 Life 1 / absolute risk reductionStage IB HR 0.92 N=1371 5Y risk 36% 1 / 3% = 33 patients HR 0.83Stage II N=1616 5Y risk 61% 1 / 10% = 10 patientsStage III N=1247 HR 0.83 5Y risk 74% 1 / 13% = 8 patients
    • Best Treatment for Unresectable/Inoperable NSCLC: RADIATION THERAPYUnresectable Stage III (N2-N3) NSCLC: MST 3YS Febrile G3-4 (mos) (%) Illness EsophagitisXRT only (>6000 rads) 11 m < 10% 3% 3%Cisplatin-based chemo, then XRT 15 m 10-20 8% 5%“SEQUENTIAL”Cisplatin-based chemo plus XRT 17 m 20-30 15% 30%“CONCURRENT”REFERENCES:1. Dillman, NEJM 19902. RTOG 94-10, Curran, JNCI, 20113. Chemo before chemo+RT (induction) is toxic, does not improve overall survival (CALGB 39801)4. Docetaxel after chemo+RT (consolidation) is toxic, does not improve overall survival (HOG 01-24)
    • Important clinical trials in unresectable stage IIIB NSCLC Cisplatin + Pemetrexed x 3 R Pemetrexed x 4 A Concurrent XRT to 6600cGy N D N=600 O M Dealer’s choice x 4: I Cisplatin + Etoposide x 3 Etoposide Z E Concurrent XRT to 6600cGy Vinorelbine PaclitaxelUS NIH, 2011.
    • Best treatment for stage IV NSCLC: DRUG THERAPYSurvival No Cytotoxic Chemo + Target Chemo chemo anti- EGFR angio mutation genesisMST (mo) 4 8 12 301-year (%) 10 20 50 902-year (%) 0 3 10 30 • Improving length of life • Improving quality of life
    • “Cytotoxic” Chemotherapy for Stage IV NSCLC n=1725 Cisplatin 75 mg/m2 Day 1 plus Pemetrexed 500 mg/m2 Day 1 Stage IV NSCLC R One cycle = 3 weeks, stop at 6 cycles Record Cisplatin 75 mg/m2 Day 1 plus histology Gemcitabine 1,250 mg/m2 Days 1, 8 Results Pem/Cis Gem/Cis HR No. patients 862 863 Median survival (mos) 10.3 10.3 0.94 Adenocarcinoma (847) 12.6 10.9 Large cell (153) 10.4 6.7 SqCC (473) 9.4 10.8 1.23Scagliotti et al, 2008.
    • “Continuation Maintenance” Chemotherapy Four cycles of pemetrexed (500 mg/m2, Day 1) + cisplatin (75 mg/m2, Day 1)* n=900 CR, PR, or SD and ECOG PS of 0 or 1 Pemetrexed 500 mg/m2 Placebo + BSC* + BSC* (D1, q21d) (D1, q21d) until disease 2:1 until disease progression randomization progression N=372 pts N=186 pts PFS HR=.62, OS results pendingPaz-Ares et al, 2011Paz-Ares et al, 2011.
    • Biologic/Molecular Targets for New Drugs Tumor cell bevacizumab VEGF Endothelial cell MetMab cetuximab figitumumab VEGF PDGF IGFR VEGFR EGFR PDGFR MET Sorafenib Gefitinib CC CC Sunitinib P P Erlotinib P P Axitinib P P Sorafenib ARQ197 P P Vandetanib P P Pazopanib Sunitinib XL-184 EML4-ALK AxitinibCrizotinib Motesanib Crizotinib Vandetanib Pazopanib P P XL-184 Motesanib Pi3K Pi3K Raf Raf Akt Akt MEK MEK mTOR mTOR ERK ERK Gene Transcription Gene Transcription Angiogenesis Proliferation Metastasis Adhesion Angiogenesis Survival
    • Target Angiogenesis: Bevacizumab SQUAMOUS HISTOLOGY EXCLUDED (for squamous histology, rate of hemoptysis 30% in phase 2 testing PFS OS 100 CbP 100 CbP CbP + Bevacizumab CbP + Bevacizumab Patients Surviving (%) Patients With PFS (%) 80 80 p < .001; HR = 0.66 p = .003; HR = 0.79 Median PFS: 6.2 mos vs. Median OS: 12.3 mos vs. 60 4.5 mos 60 10.3 mos 6-Mos PFS: 55% vs. 33% 1-Yr OS: 51% vs. 44% 1-Yr PFS: 15% vs. 6% 2-Yr OS: 23% vs. 15% 40 40 20 20 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Time (mos) Time (mos) RR: 15% for CbP Vs. 35% for CbP + BevacizumabSandler et al, NEJM 2006.
    • Bevacizumab with other Drugs SQUAMOUS HISTOLOGY EXCLUDED 1.0 PFS 1.0 PFS Possibility of PFS (%) 0.8 CG + Placebo 0.8 CG + Placebo CG + Bevacizumab CG + Bevacizumab 7.5 mg/kg 15 mg/kg 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 Time (mos) Time (mos) End Point CG + Placebo CG + Bev (7.5 mg/kg) CG + Bev (15 mg/kg) 0.75 (0.62–0.91); 0.82 (0.68–0.98); PFS, HR (95% CI) NA p = .0026 p = .0301 Median PFS (mos) 6.1 6.7 6.5 RR (%) 20 34 (p < .0001) 30 (p < .017) Median Survival (mos) 13.6 13.4 HR, p value 13.1 (0.92, p = .3664) (1.02, p = .8420)Reck et al, 2010, 2009.
    • Ongoing BevacizumabTrials Determination of Eligibility Primary Endpoint: OS Arm A - 450 Patients Arm B - 450 Patients Pemetrexed Paclitaxel 500 mg/m2 iv q21d 200 mg/m2 iv q21d Induction Therapy: Carboplatin Carboplatin up to four 21-day cycles AUC 6 iv q21d AUC 6 iv q21d Bevacizumab Bevacizumab Patients with CR, PR, or SD 15 mg/kg iv q21d 15 mg/kg iv q21d After induction therapy Continue on to maintenance therapy Pemetrexed Bevacizumab Maintenance Therapy: until PD or treatment discontinuation 500 mg/m2 iv q21d 15 mg/kg iv q21d Bevacizumab Patients with PD: 15 mg/kg iv q21d follow up q90d until death Patients without PD: follow up q6w until PD; thereafter, follow up q90d until death Post discontinuation follow upPatel et al, 2009.
    • Testing Bevacizumab for Early-stage NSCLC: ECOG 1505 Eligibility • Resected IB (>4cm) – IIIA R Chemotherapy* x 4 cycles • ≥ lobectomy A • Adequate MLND sampling N • All pts: level 7 D O • Left: level 5 or 6 M • Right: level 4 I Chemotherapy* x 4 cycles + • No previous chemotherapy Z bevacizumab x 1 year • No planned XRT E • No CVA / TIA / ATE N = 1500 Primary endpoint: overall survival• Cisplatin and vinorelbine• Cisplatin and docetaxel Secondary endpoints: disease-free survival, safety• Cisplatin and gemcitabine [bleeding and arterial thromboembolic events]• Cisplatin and pemetrexed No molecular markers being studied prospectively Accrual has been slow. Results anticipated in 2016.
    • Angiogenesis: Targeted Agents on the Horizon Agent Description Reference Sorafenib Multi-kinase inhibitor including VEGFR Spigel et al, 2010 Sunitinib Multi-kinase inhibitor including VEGFR Govindan et al, 2010 Axitinib Multi-kinase inhibitor including VEGFR Kelly et al, 2010 BIBF 1120 Multi-kinase inhibitor including VEGFR, PDGFR, FGFR Reck, 2010 (intedanib) Cediranib Multi-kinase inhibitor including VEGFR Mitchell et al, 2010 Vandetanib Multi-kinase inhibitor including EGFR and VEGFR Morabito et al, 2010 HuMV833 Antibody to VEGF-A Jayson et al, 2002 IMCL 1121b Antibody to VEGFR2 Spratlin et al, 2010 (ramucirumab) IMC-18F1 Antibody to VEGFR1 Schwartz et al, 2010 VEGF Trap Antibody to VEGF-A Leighl et al, 2010 (aflibercept)VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor;FGFR = fibroblast growth factor receptor.
    • Target EGFR: Cetuximab R Stage IV NSCLC A CT + cetuximab N EGFR expression D cetuximab until PD O by IHC M I CT N=1,688 Z Median 1-year ITT (n=1125) E OS survival ▬ CT + cetuximab 11.3 mo 47% (n=557) Overall survival (%)RETROSPECTIVE SUBGROUP ▬ CT 10.1 mo 42% ANALYSIS: (n=568)• HR = 0.80 in the 354 patients HR=0.871, p=0.044 with the highest EGFR IHC score• HR = 1.05 in patients with lower EGFR IHC score MonthsPirker et al, 2009, and 2011
    • The Biggest Discovery:EGFR Activating Mutations 5 days on gefitinib Pao, Nature Reviews Cancer 10, 760-774
    • Stage IV 1st-line EGFR TKI for EGFR mutationStudy Drugs ORR PFS OSIPASS gefitinib 71% N=261 HR 1.00Yang, ESMO vs. HR 0.48 P=0.9902010 carbo + paclitaxel 47% P<.0001First-SIGNAL gefitinib 85% N=42 HR 0.82Lee, IASLC vs. HR 0.62 P=.6482009 cis + gemcitabine 37% P=.084WJTOG 3405 gefitinib 62% N=172Tsurutani vs. HR 0.49 Not reportedESMO 2009 cis + docetaxel 32% P<.001NEJ 002 gefitinib 74% N=228 HR NSMaemondo vs. HR 0.30 P=0.31NEJM 2010 carbo + paclitaxel 31% P<.001OPTIMAL erlotinib 83% N=154Zhou, ESMO vs. HR 0.16 Not reported2010 carbo + gemcitabine 36% P<.0001
    • EGFR mutation is Prognostic of Survival in Early-stage NSCLC 1.0 Probability of OS 0.8 0.6 0.4 No EGFR mutation: Median OS = 6.3yr (95%CI: 5.6 - 7.8) EGFR mutation: Median OS = 6.9yr (95%CI: 6.3 - NA) 0.2 p (adj for stage) < 0.001 No EGFR mutation 0.0 EGFR mutation Data courtesy 0 1 2 3 4 5 6 7 8 Years After Surgery Sandra No. At Risk D’Angelo No EGFR mutation 896 778 517 293 160 104 65 26 10 MSKCC EGFR mutation 222 204 133 91 55 33 18 7 4
    • Testing erlotinib for early-stage NSCLC with EGFR mutation NCI Personalized Adjuvant Trial “PAT” Resected NSCLC R Erlotinib for 2 years A Tested positive for N D EGFR activating/ O M sensitizing mutation I Z Placebo for 2 years N=400 EUS NIH, 2011.
    • ALK gene translocation drives 3% of NSCLC Vysis LSI ALK dual color break apart probe Break-apart FISH assay of tumor cells from a patient with rearrangement of the gene encoding ALK Kwak et al, 2010.
    • Phase II studies of crizotinib for patients with stage IV NSCLC and ALK translocation• Study A (N = 136 patients), ORR 50%, median duration 10 months• Study B (N = 119 patients), ORR 61%, median duration 12 months• 94% had received prior systemic treatment for NSCLC• No differences in ORR by performance status, the number of prior chemotherapeutic regimens, or the percentage of cells found to have the ALK gene rearrangement were noted. FDA Approval Announcement, 8/26/2011
    • First-line crizotinib for patients with ALK Translocation Randomized Study of Crizotinib vs Pem/Cis or Pem/Carbo in Untreated Patients with Non-squamous Carcinoma of the Lung With EML4-ALK Mutation Crizotinib 250 mg PO BID Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5, q 21 days 1º endpoint: To demonstrate that crizotinib is superior to first-line chemotherapy 2º endpoint: ORR, OS, Duration of Response SafetyUS NIH, 2011.
    • Novel Agents Under Phase III Investigation: Currently Recruiting Trials Agent Mechanism of Action Study ID Primary Completion Date Tivantinib (ARQ c-Met inhibitor NCT01244191 May 2013 197) Tivantinib (ARQ c-Met inhibitor NCT01395758 June 2012 197) Iniparib PARP inhibitor NCT01082549 (ECLIPSE) March 2013 PF-02341066 ALK inhibitor NCT00932893 June 2012 Afatinib EGFR/HER2 inhibitor NCT01121393 (LUX-Lung 6) May 2012 Afatinib EGFR/HER2 inhibitor NCT01085136 (LUX-Lung 5) March 2012 Talactoferrin Immunostimulant NCT00706862 (FORTIS-C) March 2013 Ipilimumab Anti-CTLA4 Antibody NCT01285609 August 2014 Ramucirumab VEGFR-2 inhibitor NCT01168973 June 2014 Necitumumab EGFR inhibitor NCT00981058 (SQUIRE) May 2013 Vargatef Multikinase inhibitor NCT00806819 (LUME-Lung 2) May 2013 MetMab Met inhibitor Recruitment will begin later this year (2011)US NIH, 2011.
    • Problem: With so many new drugs, andtargets, how do we know we are givingthe right drug to the right patient?Solution: Test! Don’t guess!
    • Lung Cancer Mutation Consortium Incidence of Single Driver Mutations At least 1 mutation was found in 54% (280/516) of tumors completely tested (CI 50%–59%) 97% of Mutations Mutually ExclusiveKris et al, ASCO 2011.
    • Lung Cancer Mutation Consortium Targeted Clinical Trials Target Agent(s) EGFR Erlotinib + OSI 906 Erlotinib + MM 121 KRAS Tivantinib + Erlotinib GSK1120212 MET Amplification MetMAB EML4-ALK Crizotinib NRAS GSK1120212 MEK1 GSK1120212 BRAF (V600E) GSK2118434 BRAF (not V600E) GSK1120212 HER2 Afatinib PIK3CA BKM120Kris et al, ASCO 2011.
    • Real progress for patients with stage IV NSCLCSurvival No Cytotoxic Chemo+ EGFR Chemo chemo bev TKI for EGFR mutantMST (mo) 4 8 12 301-year (%) 10 20 50 902-year (%) 0 3 10 30 • Improving length of life • Improving quality of life
    • SMALL CELL LUNG CANCER Limited Extensive Stage StageSurgery rarely an option.No molecular markers discovered yet.No new drugs for 20 years!
    • Twice Daily Thoracic Radiotherapy for Limited Stage SCLC Turrisi et al, NEJM, 1999• 417 patients with limited stage SCLC• 4 cycles etoposide + cisplatin with concurrent once vs. twice daily RT to 45 Gy starting with first cycle 2-year survival 41 vs. 47% 5-year survival 16 vs. 26% p = 0.04
    • Prophylactic Cranial Irradiation Auperin et al, NEJM, 1999 Death Brain Mets• 7 randomized trials, 987 pts with CR• 5% increase in survival at 3 yrs• Higher dose improved local recurrence but no effect on survival 16% ↓ risk 54% ↓ risk
    • PCI in Extensive SCLC286 patients with extensive SCLC and response after 4-6 cycles of chemotherapywere randomized to PCI or no PCI Median survival: 6.7 vs 5.4 mo 1 yr survival: 27% vs 13% Slotman et al, NEJM 2007
    • For Extensive Stage: Cisplatin + Etoposide 1.0 0.9 Irinotecan + cis (n = 221) 0.8 Etoposide + cis (n = 110) 0.7Probability 0.6 0.5 P = 0.6226 0.4 0.3 0.2 0.1 0 0 10 20 30 40 Months IP: median 9.3 mo (0.1-32.6) 1yr 35.4%, 2yr 8.0% EP: median 10.2 mo (0.3-44.6) 1yr 36.7%, 2yr 7.9% Hanna, J Clin Oncol 24:2038, 2006
    • “2nd-line” Chemo for Extensive SCLC Topotecan CAV Response Rate 24% 18% Med Survival 6 mo 6 mo Grade 4 (% pts) Neutropenia 70% 72% Anemia 3% 2% Platelets 29% 5% Transfusions RBCs 52% 27% Plts 20% 2% Greater proportion had improved dyspnea, anorexia, hoarseness and fatigue with topotecan von Pawel, JCO, 17:658, 1999
    • “2nd-line” Chemo for Extensive SCLC:• Rechallenge with 1st regimen if time to relapse > 6 months• Topotecan n=637• CAV amrubicin 40 mg/m2 IV on days 1-3 vs.• Irinotecan topotecan 1.5 mg/m2 IV on days 1-5• Paclitaxel HR 0.82, p=NS• Docetaxel primary refractory subgroup, HR 0.77, p=.047• Gemcitabine• Vinorelbine• Amrubicin: active, but failed to significantly improve survival vs. topotecan in phase 3 study Jotte R, J Clin Oncol 29: 2011;29(15s):(abstract 7000),453s
    • Lung Cancer Update, 2011 REVIEW• Lung cancer facts and figures• Screening smokers for lung cancer Newest stories:• NSCLC: Screening saves lives ! – Surgery – Chemotherapy + XRT The era of personalized – Chemotherapy medicine has arrived !• SCLC: EGFR, ALK … – Chemotherapy – Chemotherapy + XRT – Prophylactic cranial irradiation
    • OLDEST STORY:“Don’t smoke cigarettes.”