non-small-cell lung cancer Quimioterapia adjuvante para câncer de pulmão não pequenas

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1 Adjuvant chemotherapy for non-small-cell lung cancer Quimioterapia adjuvante para câncer de pulmão não pequenas células Daniel B. Costa, MD, PhD, MMSc Division i i of Hematology/Oncology l Beth Israel Deaconess Medical Center Harvard Medical School

2 Disclosure slide Consulting fees from: -Pfizer -Roche -AstraZeneca

3 Major types of primary lung cancers Neuro-endocrine tumors (carcinoid) < 5 % Non-small cell lung cancers (NSCLC) 80% Small cell lung cancer (SCLC) 15 %

4 Etiology of non-small cell lung cancer (NSCLC) Smoking - Nicotine-based cigarettes carry carcinogens such as benzo[a]pyrene and nitrosamine Asbestos Radon Radiation therapy - Genetic predisposition - _ genes related to smoking addiction and effects of nicotine (CHRNA3( and CHRNA5) _variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers _ genes related to the metabolism of carcinogens (GST) _ genes related with cellular differentiation and suppression of malignant transformation

5 Major histologies in NSCLC squamous cell carcinoma adenocarcinoma

6 1. Adjuvant systemic cisplatin-based chemotherapy in completely l resected stages IB- IIIA non-small cell lung cancer 2. Novel approaches to improve upon adjuvant chemotherapy - biomarkers for patient and chemotherapy selection - VEGF-targeted (angiogenesis) therapies (registration trial by ECOG: E1505) - selection of specific patients/tumors that can be targeted with novel therapies (EGFR TKIs and ALK TKIs)

7 Staging system (TNM) for NSCLC non-small-cell lung cancer (NSCLC) lung cancer in the 1980s and 1990s: all NSCLCs are the all NSCLCs are the same

8 Staging system (TNM) and survival: NSCLC Stage 5yr survival yr survival IA 61% >75-80% IB 38% 64% IIA 34% IIB 24% 39% IIIA 13% 26% IIIB 5% <10% IV 1% <3% Adapted from Mountain, CF, Chest 1997; 11:1710 and Pisters KMW, J Clin Oncol 2008.

9 Staging system (TNM) for NSCLC and evidencebased therapeutic decisions

10 Standard-of-care therapies by stage for NSCLC Stage I: lobectomy (surgery) radiotherapy (non-surgical cases) Stage II: lobectomy (surgery) + adjuvant cisplatindoublet (chemotherapy) Stage III: concurrent cisplatin-doublet i (chemotherapy) + radiotherapy (XRT) or adjuvant chemotherapy Stage IV: palliative therapy. 1 st line cis or carboplatin- doublet; 2 nd -3 rd line docetaxel (chemo), pemetrexed (chemo), erlotinib (EGFR TKI), crizotinib (ALK TKI)

11 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: historical perspective (1) - From the 1950s to 1990s, surgery alone was the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC); - Lack of surgical resection, even in stage I NSCLC, pertained a poor prognosis. Long term survival of non-treated stage I patients was below 10% at 5 years; - However, even with complete surgical resection the 5-year survival rates of stage IB to IIIA NSCLC continued to be disappointing; To improve survival clinicians examined the use of -To improve survival, clinicians examined the use of chemotherapy and radiation in the pre and post-operative setting

12 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: C historical perspective e (2) Adjuvant chemotherapy in other completely resected solid malignancies Type of cancer 5-Year Survival 5-Year Survival (surgery plus (node positive) (surgery alone) adjuvant chemotherapy) Breast cancer ~ 60-70% ~ 75-80% Colon cancer ~ 55-65% ~ 75-80%

13 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: historical perspective (3) - First trials of f adjuvant chemotherapy started in 1970s; - First trials of cisplatin-based adjuvant chemotherapy in the 1980s; - Small trials (<150 patients), poor design, flawed staging, number of patients too small to detect benefit; - In 1995, meta-analysis of 52 small randomized trials showed a possible 5% benefit at 5 years for cisplatin-based chemotherapy after complete surgical resection of stages IB-IIIA NSCLC; Renewed interest in the role of adjuvant chemotherapy in the 1990s - Renewed interest in the role of adjuvant chemotherapy in the 1990s and 2000s

14 Systemic chemotherapy for stage IV NSCLC ECOG 1594 (defined standard of care in late 1990s/early 2000s) chemotherapy combinations ECOG1594 (2002) - response rate (RR) 17-23% - progression-free survival (PFS) 3.5 mths - median overall survival (OS) 8 mths Schiller JH., et al. N Engl J Med Jan 10;346(2):92-8.

15 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: historical perspective (4) Late 1990s and early 2000s: Four (4) large randomized d trials comparing placebo vs platinum-based chemotherapy in resected stages IB to IIIA NSCLC were launched in the late 1990s and early 2000s Trials: IALT (Europe), ANITA (Europe), JBR.10 (Canada-USA), CALGB 9623 (USA) Best studied chemotherapy doublet: cisplatin/vinorelbine

16 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: IALT trial results (2004; resected stages I-III) - Chemotherapy associated with higher survival rate than observation (44.5% vs. 40.4% 4% at 5 years); HR 0.86 (95% CI, ; P<0.03) Adapted from The International Adjuvant Lung Cancer Trial Collaborative Group N Engl J Med 2004; 350:

17 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: JBR.10 trial results (2005; resected stages IB-II) chemotherapy: 50 mg/m2 of cisplatin on days 1 and 8 every 4 weeks for 4 cycles and 25 mg/m2 of vinorelbine weekly for 16 weeks - 5-year survival rates were: 69% for cisplatin/ vinorelbine 54% for observation, (p=0.03) Adapted from Winton et al. N Engl J Med 2005; 352:2589.

18 Role of post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: CALBG9633 trial results (2006; resected stage IB 6 th TNM) chemotherapy: carboplatin 6 AUC and paclitaxel 200 mg/m2 D1 21-day cycle x 4 T 4cm T < 4cm Adapted from Strauss et al. JCO November 1, 2008 vol. 26 no

19 Summary of key trials of adjuvant platinum-based chemotherapy vs placebo in completely resected NSCLC: all favor chemotherapy for stages II and IIIA Ti Trial Stages Overall benefit Stage IB Stage II Stage IIIA (hazard ratio) IALT I-III 0.86 (0.76 to 0.95 (0.74 to 0.93 (0.72 to 0.79 (0.66 to ,867pts 0.98) 1.23) 120) 1.20) 0.95) JBR ANITA 2006 CALBG IB-IIA 482pts IB-IIIA 829pts IB 344pts 0.69 (0.52 to 0.91) 0.80 (0.66 to 0.96) 0.80 (0.60 to 1.07) 0.79 (0.77 to 1.95) 1.10 (0.76 to 1.57) 0.80 (0.60 to 1.07) 0.59 (0.42 to 0.85) 0.71 (0.49 to 1.03) 0.69 (0.53 to 0.90) LACE meta- I-IIIA IIIA 0.89(0.82 to analysis 4,584pts 0.96) 0.93 (0.78 to 1.10) 083(073t 0.83 (0.73 to 083(073t 0.83 (0.73 to 0.95) 0.95) Adapted from Pignon et al. JCO July 20, 2008 vol. 26 no

20 Summary of key trials of adjuvant platinum-based chemotherapy vs placebo in completely resected NSCLC: Lung Adjuvant Cisplatin Evaluation (LACE) Adapted from Pignon et al. JCO July 20, 2008 vol. 26 no

21 Decision Aid Tool for Resected Stage II NSCLC

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23 2007 Recommendations for Adjuvant Treatment of Stages I-IIIA IIIA NSCLC: Adjuvant Radiotherapy Stages IA/B and IIA/B: Adjuvant radiation is not recommended. Stage IIIA: Adjuvant radiation therapy is not recommended for routine use because of the lack of prospective, randomized clinical trial data evaluating its efficacy. A clinical trial is underway to determine the advisability of its routine use. Recommendations apply only to completely resected tumors.

24 Post-operative (adjuvant) cytotoxic chemotherapy for NSCLC: choice of chemotherapy use of f modern platinum-doublet t schemes Cisplatin D1/Vinorelbine D1, D8 of 21 day cycle X 4 (adenocarcinoma/squamous cell carcinoma) side-effects: Nausea and vomiting (20-30%) Neutropenia (70%), neutropenic fever and severe infection Neuropathy (10%), nephrotoxicity (5%), hair loss uncommon (<10%) Cisplatin D1/Gemcitabine D1, D8 of 21 day cycle X 4 (adenocarcinoma/squamous cell carcinoma) side-effects: Nausea and vomiting (20-30%) Neutropenia (50%), thrombocytopenia (40%), Rash (15%) Neuropathy (10%), nephrotoxicity (5%), hair loss uncommon (<20%) Cisplatin D1/Docetaxel D1 of 21 day cycle X 4 (adenocarcinoma/squamous cell carcinoma) side-effects: Nausea and vomiting (20-30%) Neutropenia (70%), anemia (40%), myalgias (20%) Neuropathy (20%), nephrotoxicity (5%), hair loss common (>99%) Cisplatin D1/Pemetrexed D1 of 21 day cycle X 4 (adenocarcinoma) side-effects: Nausea and vomiting (20-30%) Neutropenia (10%), anemia (20%) Neuropathy (10%), nephrotoxicity (5%), hair loss uncommon (<5%)

25 How to provide adjuvant platinum-based chemotherapy for resected NSCLC: (proposed flow chart from Harvard-affiliated hospitals) NSCLC (complete surgical resection - R0) 7 th TNM stage: Stage IA/IB < 4cm post-operative surveillance (consider clinical trial) * consider carboplatin when cisplatin contraindicated Stage IB > 4cm offer platinum-based* chemotherapy Stage II Stage IIIA -adenocarcinoma: cisplatin/pemetrexed p -squamous cell carcinoma: cisplatin/vinorelbine cisplatin/gemcitabine cisplatin/docetaxel + (consider clinical trial)

26 1. Adjuvant systemic cisplatin-based chemotherapy in completely l resected stages IB- IIIA non-small cell lung cancer 2. Novel approaches to improve upon adjuvant chemotherapy - biomarkers for patient and chemotherapy selection - VEGF-targeted (angiogenesis) therapies (registration trial by ECOG: E1505) - selection of specific patients/tumors that can be targeted with novel therapies (EGFR TKIs and ALK TKIs)

27 Potential predictive biomarkers for cytotoxic chemotherapies approved for NSCLC (ongoing clinical studies) chemotherapy mechanism of action tumor biomarker cisplatin docetaxel DNA crosslink anti-mitotic microtubule ERCC1, BRCA1 BRCA1 gemcitabine anti-metabolite pyrimidine idi analog RRM1 anti-metabolite TS Gazdar A. N Engl J Med. 2007;356(8):771-3 pemetrexed multi-target (thymidilate Besse B. et al. J Clin Oncol 2013 folate antagonist synthase) Rossel R. et al. PLoS One. 2009;4(5):e5133

28 IALT- ERCC1 as a predictive and prognostic marker IALT-Bio (designed d to examine tumor markers within the main study) ERCC1 IHC is not reproducible (no clinical use for IHC to select patients) Adapted from Olaussen et al. N Engl J Med Sep Adapted from Friboulet et al. N Engl J Med;368:

29 Potential predictive biomarkers for cytotoxic chemotherapies for NSCLC using mrna expression profiles (ongoing clinical studies)

30 Rationale for targeting VEGF in adjuvant studies of NSCLC ECOG 4599 (approved bevacizumab in 2005 for advanced non-squamous histology) - Monoclonal antibody against VEGF. Bevacizumab (Avastin ) -- recombinant humanized monoclonal Ab (human IgG1 + antigen-binding from a murine Ab) -- Bevacizumab may enhance chemotherapeutic options due to normalization of tumor vasculature -- Bevacizumab improves outcomes in stage IV colon cancer, NSCLC and renal cell carcinoma chemotherapy + bevacizumab vs - RR 35% - PFS 6.2 mths - OS 12 mths chemotherapy - RR 15% ECOG 4599 (2005) - PFS 4.5 mths - OS 10.3 mths Sandler A. et al. N Engl J Med Dec 14;355(24):

31 Does bevacizumab add to the survival advantage of standard adjuvant chemotherapy in resected NSCLC? ECOG 1505 cisplatin-based chemotherapy x 4 Resected NSCLC (cisplatin-gemcitabine) any histology (cisplatin-docetaxel) t l) 6thTNM (cisplatin-vinorelbine) stage IB (> 4cm) (cisplatin-pemetrexed) pemetrexed) stage II (N1 nodes) stage IIIA (N2 nodes) cisplatin-based chemotherapy Randomized phase III trial x 4 target: 1500 pts + primary end-point: overall bevacizumab b 15 mg/kg q 3wks survival up to 1 year (awaiting results)

32 Does immunotherapy (MAGE-A3 vaccine) improve outcomes of adjuvant therapy in NSCLC? MAGRIT phase III clinical trial The large Phase III study involving more than lung cancer patients found that the experimental therapy did not help The large Phase III study, involving more than 2,000 lung cancer patients, found that the experimental therapy did not help patients live longer without their disease recurring.

33 Lung adenocarcinomas in 2014: a disease of oncogenes (EGFR, KRAS mutations; ALK and ROS1 translocations) EGFR mutations (~15%) ROS1 translocations (~6%) other/ unknown other/unknown KRAS mutations (~25%) ALK translocations ti (~20%) EGFR mutations (~50%) ALK translocations ROS1 (~5%) translocations (~2%) KRAS All lung adenocarcinomas Never smokers with lung adenocarcinomas

34 KRAS mutations: are not clinically-useful as a predictive or prognostic marker in the adjuvant setting Goldberg et al Lancet Oncology 2013 Jan;14(1):3-5. Cuffe et al J Thor Oncol 2012 Jun;7(6):963

35 Epidermal growth factor receptor (EGFR) pathway in epithelial malignancies: EGFR tyrosine kinase inhibitors (TKIs) in clinical practice gefitinib AstraZeneca erlotinib OSI Pharmaceuticals Genentech - Roche Side-effect profile in humans: 1) Skin rash ~50-80% pts 2) Diarrhea ~ 20-50% pts 3) Anorexia ~ 10-15% pts 4) Interstitial Lung Disease <1-5% Ciardiello F, et al. N Engl J Med 2008; 358:

36 EGFR TKIs as first line therapy for EGFR mutated NSCLC: Gefitinib (NEJ 002) and erlotinib (EURTAC) vs chemotherapy N-lobe exon 19 deletions T790 C-helix G719 P-loop exon 20 insertions L858 L861 NEJ 002 erlotinib l ti ib activation loop C-lobe Adapted from Yasuda, Kobayashi, Costa DB. Lancet Oncology 2012; 13(1):e23-31 EURT TAC Maemondo M., et al. N Engl J Med Jun 24;362(25): Rossel R., et al. Lancet Oncol Mar;13(3):

37 Ongoing clinical trials for use of EGFR TKIs (gefitinib and erlotinib) for EGFR L858R or exon 19 deletions mutated NSCLCs as adjuvant chemotherapy ASCO 2014 Presentation: Median follow-up of 3y 2y-DFS from enrollment is 90% (97% stage 1, 73% stage 2, 92% stage 3). 24 pts have recurred, only 2 during erlotinib treatment and the others after stopping erlotinib ib (median time to recurrence 11.7m after stopping erlotinib). 46% of recurrences were at a single site, 17% CNS only. 63% (n=15) of recurring pts underwent repeat biopsy, with only 1 pt having T790M detected. 71% (n=17) of recurrent pts were retreated t with erlotinib ibwith 75% still on erlotinib (range 2-42+m). ASt Study of fel Erlotinib ib(t (Tarceva) After Surgery With or Without t Adjuvant Chemotherapy in Non-Small Cell Lung Carcinoma (NSCLC) Patients Who Have Epidermal Growth Factor Receptor (EGFR) Positive Tumors (RADIANT) Phase III trial (n>1000), , 2013 expect results soon ( ) 2015)

38 Retrospective studies for use of EGFR TKIs (gefitinib and erlotinib) for EGFR L858R or exon 19 deletions mutated NSCLCs as adjuvant chemotherapy (data is inconclusive) Janjigian et al J Thor Oncol 2011 Mar;6(3):569

39 How to provide adjuvant platinum-based chemotherapy for resected NSCLC: (proposed flow chart from Harvard-affiliated hospitals) NSCLC (complete surgical resection - R0) 7 th TNM stage: Stage IA/IB < 4cm post-operative surveillance (consider clinical trial) * consider carboplatin when cisplatin contraindicated Stage IB > 4cm offer platinum-based* chemotherapy Stage II Stage IIIA (in 2014: role of tumor markers are unclear) -adenocarcinoma: cisplatin/pemetrexed p -squamous cell carcinoma: cisplatin/vinorelbine cisplatin/gemcitabine cisplatin/docetaxel + (consider clinical trial)