Review on activated protocols in advanced non-small cell lung cancer. Rolf Stahel Zürich, Switzerland

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1 Review on activated protocols in advanced non-small cell lung cancer Rolf Stahel Zürich, Switzerland Lucerne,

2 Case report 1 75 y/o man retired, held many jobs from working as driver, attendant at gasoline station to sexton. Plays trombone at the Salvation Army 2/06 follow-up CT one year after TUR-P for benign prostate hyperplasia:?solitary lesion in L lower lobe. 5/06 follow-up CT: 1.5 cm lesion L upper lobe, additional small L pleural based lesions 6/06 thoracoscopic wedge resection L lower lobe and pleural biopsy: Non-small cell lung cancer with carcinomatosis of pleura: referral for palliative chemotherapy

3 Case report 1 Patient assymptomatic, PS 0, no comorbidities Normal hematology and chemistriy CT:

4 Review on activated protocols in advanced non-small cell lung cancer 1. What is non-small cell lung cancer? 2. Questions for the average patient with advanced disease 3. Questions for selected patients with advanced disease

5 Changing distribution of lung cancer histology (U Texas Galvaston) Mary Wahbah, Ann Dign Pathol, 2007

6 EGFR: downstream signaling About 50% of lung adenocarcinoma harbor somatic mutations of six genes that encode proteins in the EGFR signaling pathway Akt PI3K EGFR, HER2 Cell membrane EGFR-TK SOS RAS ATP ATP P GRB2 RAF MAPK STAT MEK Proliferation Invasion Gene transcription cell-cycle progression Nucleus Angiogenesis Metastasis Resistance to apoptosis

7 Two mutually exclusive pathways to lung adenocarcinoma (pooled data from East Asian and western countries) Smokers Tobacco KRAS mutations (14%) Genetic factors? Adenocarcinoma Never Smokers? Carcinogen EGFR mutations (31%) HER2 mutations (4%) BRAF mutations (1%) HER4 mutations (rare) Gazdar, IASLC Workshop 2006

8 RAS mutation and in NSCLC K-ras mutation in 30% of lung adenocarcinoma is associated with smoking and is a poor prognostic factor in resected tumors Rodenhuis, NEJM 1987; Slebos, NEJM 1990 Meta-analysis of 23 studies with mutational data: HR 1.4 (CI ) Mascaux, Br J Cancer 2005 Adjuvant cisplatin/vinorelbine subgroup analysis according to ras mutation: No apparent benefit in pts with ras mutated tumors (however not significant in interaction analysis and not significant in f/u manuscript) Winton, NEJM 2005, TSAO JCO 2007

9 RAS mutation and in NSCLC The presence of KRAS mutation in circulating DNA from patients with non-small cell lung cancer is associated with a poorer outcome Gautschi, Cancer Letters 2007 Lack of sensitivity of K-ras mutated tumors to gefitinib or erlotinib Pao, PLoS 2005

10 EGFR mutations in lung adenocarcinoma RR 0% RR 70% RR > 80% Sharma, Nat Rev Cancer, 2007

11 Review on activated protocols in advanced non-small cell lung cancer 1. What is non-small cell lung cancer? 2. Questions for the average patient with advanced disease (chemotherapy, targeted therapy) 3. Questions for selected patients with advanced disease (chemotherapy, targeted therapy)

12 Case report 2 10/04: 54-y/o lawyer, with history of panic attacks presents at the ER with anxiety and dyspnea attack after air travel. CT-Chest: No evidence of PE, two distinct small noduli 2 cm and 1.5 cm in diameter in R lower lobe,?dignity 11/04: Thoracic surgery: Wedge resection of one lesion reveals adenocarcinoma with broncheoalveolar components. Subsequent resection of R lower lobe and mediastinal lymph node dissection: Pathology: Two lesions, both adenocarcinoma, one with broncheoalveolar component, in R lower lobe, involvement of ipsilateral mediastinal lymph nodes

13 Case report 2 Diagnosis: Adenocarcinoma T4 pn2, M0 stage IIIB, no EGFR mutations 1-4/05: 4 cycles adjuvant chemotherapy (cisplatin/gemcitabine) 1/06 CT control:

14 Case report 2 6/06

15 Case report 2 7/06: Bronchoscopy and fine needle aspiration of subcarinal node: Adenocarcinoma Therapy with erlotinib initiated, patient develops anceniform rash on face and chest 9/06: CT: Progression of pulmonary nodules. Chemotherapy with carboplatin and pemetrexed. No clinical side effects 11/06 3 cycles: stable disease 2/07 6 cycles: stable disease 7/07 12 cycles: stable disease 1/08 18 cycles: stable disease

16 Optimal duration of chemotherapy Survival Gem PTX VNR Maintenance with new agents Soon, WCLC 2007

17 Optimal duration of chemotherapy Progression-free suvival Gem VNR Maintenance with new agents Soon, WCLC 2007

18 ALIMTA in 1 st line NSCLC: Study JMEN Stage IIIb/IV NSCLC prior to induction therapy PS 0 or 1 Received 1 of 6 induction regimens x 4 cycles B12/Folate/steriods in both arms R ALIMTA 500 mg/m2 + BSC D1 Cycle = 21 days Primary objective: Overall Survival Superiority design, 2:1 randomization N=660, approx. Double-blind, placebo-controlled Placebo + BSC D1 Cycle = 21 days

19 SATURN: Sequential Tarceva in unresectable NSCLC 1st line maint. Study Period Screening Period Tumour samples (mandatory) EGFR protein expression (IHC) results Tarceva 150mg/day Stage IIIb/IV NSCLC 4 cycles of a first-line standard platinum-based doublet No progression (n=850*) Randomisation with stratification Progression Placebo Planned Recruitment = 1,700 TITAN Until PD, death or unacceptable toxicity Until PD, death or unacceptable toxicity PD = progressive disease Closed to accrual 12/07

20 Randomised trials of first line chemotherapy +/ targeted therapies Target Agent Chemotherapy Outcome EGFR Gefitinib, Erlotinib PC/GP No benefit Erlotinib PC/GP No benefit Cetuximab PC No benefit Cetuximab (1 cell/hpf) GC Survival benefit VEGF Bevacizumab PC Survival benefit Bevacizumab GC PFS benefit VEGFR2 Sorafenib, Vandetinib CP? MMPs AG3340; BMS PC No benefit FT (ras) llonafarnib PC No benefit PKCα ISIS 3521 PC/GP No benefit RXR Bexarotene PC No benefit mtor Sirolimus Various No benefit EGFR = epidermal growth factor receptor; VEGF = vascular endothelial growth factor, MMP = matrix metalloproteniase; FT = farnesyl transferase; PKC = protein kinase C; RXR = retinoid X receptor; mtor = mâmmalian target of rapamycin, PC = paclitaxel/carboplatin, GC =gemcitabine cisplatin

21 AVAiL study: Manegold, 2007

22 AVAiL study: Manegold, 2007

23 ATLAS: Tarceva + Avastin following the new standard of care in first-line treatment 1st line Avastin + Tarceva PD Off study Chemotherapy naïve stage IIIb/IV nonsquamous NSCLC Avastin plus chemotherapy* PD or significant toxicity Off study Non-PD (n 800) Avastin + placebo AVG3671g (phase IIIb) Avastin 15mg/kg every 3 weeks; Tarceva 150mg/day *Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel 1:1 PD Primary endpoint = PFS Status: ongoing planned n=1150 Tarceva

24 Ongoing phase II trials of Avastin and Tarceva as first-line therapy in NSCLC ML19389 Previously untreated stage IIIb/IV nonsquamous NSCLC n=47 (MO18632) n=109 (ML19389) Tarceva 150mg/day + Avastin 15mg/kg every 3 weeks [until toxicity or PD] Gemcitabine + either cisplatin or carboplatin every 3 weeks [x 6 or until PD] MO18632 Primary endpoint: non-progression rate at 6 weeks (MO18632); disease stabilisation at 12 weeks (ML19389) Secondary endpoints: overall response rate, survival, progression-free survival, safety PIs: Drs F Zappa, M Pless (ML19389) Drs AC Dingemans, EF Smit, HJM Groen (MO18632) 24

25 TORCH: sequence of Tarceva and chemotherapy 1st line Previously untreated stage IIIb/IV NSCLC Tarceva 150mg/day Gemcitabine + cisplatin (six cycles) PD PD Gemcitabine + cisplatin (six cycles) Tarceva 150mg/day Assess non-inferiority of 1 st -line Tarceva and 2 nd -line CT, compared with 1 st -line CT and 2 nd -line Tarceva Primary endpoint (ph III) = overall survival Secondary = QoL, PFS, safety, tumour biomarkers Non-selected patients Status: ongoing planned recruitment >900 interim analysis planned (rate of PD) MO19759 (phase II/III): National Cancer Institute of Naples, Italy PIs: C Gridelli, F Ciardiello (Italy) C Butts, R Feld, FA Shepherd (Canada)

26 Review on activated protocols in advanced non-small cell lung cancer 1. What is non-small cell lung cancer? 2. Questions for the average patient with advanced disease (chemotherapy, targeted therapy) 3. Questions for selected patients with advanced disease (chemotherapy, targeted therapy)

27 First line cisplatin/pemetrexed vs cisplatin/gemcitabine in NSCLC Randomized phase III, non-inferiority design, 1725 pts, histology predefined subgroupanalysis Adenocarcinoma and large cell carcinoma (1000 pts, 58% of study population) Probability without Event Median (95% CI) CP 11.8 (10.4, 13.2) CG 10.4 (9.6, 11.2) CP vs CG Adjusted HR (95% CI) 0.81 ( ) Survival Time (months) in Non-Squamous Patients Patients at Risk CP CG Significant superior survival for cisplatin/pemetrexed in non-squamous cell carcinoma (higher thymidylate synthesis levels in squamous cell carcinoma) 0 0 Scagliotti, WCLC 2007

28 Randomized Phase 2 - IGF-1R antibody (CP751,871) in Untreated Advanced NSCLC Arm A 48pts 2:1 randomization Maximum 17 doses of study drug Day wk intervals If no response or progressive disease after 2 (two) courses physician allowed to add CP 751,871 or give as single agent. ARM B 25pts Karp, ASCO 2007 = Taxol 200mg/m2 = CarboPlat AUC = 6 = CP751,871 Antibody

29 Response rate (RR) by histology Patients TCI (44% adenocarcinoma) TC (40% adenocarcinoma) TOTAL (N = 73) Adenocarcinoma (n = 31) Non-adenocarcinoma (n = 42) 22/48 (46%) 8/25 (32%) 8/21 (38%) 3/10 (30%) 14/27 (52%) 5/15 (33%) 46% RR satisfied criterion (> 40%) to proceed further TCI RR higher than TC across the parameters of age, stage, and smoking class groups 71% responses in Squamous Histology Karp, ASCO 2007

30 Prospektive ERCC1-Studie (GILT) 1:2 R Control CDDP/Doce ORR 39% MS 9.8 N 141 A N D O RT-PCR: ERCC1 low ERCC1 high CDDP/Doce Gem/Doce 53% % (P=0.02) 47% ERCC1 mrna predicts response but not survival (?docetaxel best 2nd agent, significant influence of 2nd line treatment) Cobo, JCO 2007

31 BRCA1 BRCA1 deficiency confers resistance to paclitaxel and vinorelbine and sensitivity to cisplatin A differential predictor between platinum and antimicrotubule drugs: Low BRCA1 sensitivity to cisplatin High BRCA1 sensitivity to taxanes 57 pts receiving neoadjuvant cis/gem Taron, Hum Mol Genet 2004

32 BRCA1 Expression Customization (BREC) Study design CONTROL Docetaxel/Cis Advanced chemonaïve NSCLC 1 : 3 Q 1 BRCA1 Gem/Cis Stratification: Histology ECOG BRCA1 expression quartiles EXPERIMENTAL Q 2 & 3 BRCA1 Docetaxel/Cis Q 4 BRCA1 Docetaxel GILT Study: Basis for planned 2 nd randomized trial of customized CT based on BRCA1 mrna expression by quartiles, instead of high/low dichotomy, could further improve customization

33 Clinical predictors vs EGFR mutation in (first-line) gefitinib treated (Asian) patients Clinical predictors: female, adenocarcinoma, never smokers Han, Lung Cancer 2006

34 Case report 1 6/06 thoracoscopic wedge resection L lower lobe and pleural biopsy: Non-small cell lung cancer with carcinomatosis of pleura: referral for palliative chemotherapy Histology: adenocarcinoma Smoking history: Never smoker EGFR mutation analysis: deletion in exon 19 (dell747-e749, A750P) Treatment in SAKK trial 19/05: Single arm erlotinib/bevaczumab combination, chemotherapy with platin/gemcitabine upon progression

35 Case report 1 7/06: erlotinib and bevacizumab (SAKK 19/05)

36 EURTAC-SLCG: STATISTICS R A N D O M I Z A T I O N N= ARM A N=65 73 ARM B N=65 73 Erlotinib 150 mg/d/vo Benefit TTP 7 m Cis 75/Gem 1250 Cis 75/ Doc 75 Carbo5/Gem 1000 Carbo6/Doc 75 Benefit TTP 4 m C R O S S O V E R TARGET POPULATION N=1500 pts σ status Met cis/ gem Unmet cis/doc

37 MET amplification leads to gefitinib resistance in lung cancer by activating ErbB3 signaling Concurrent inhibition of MET by PHA und EGFR suppresses growth of MET amplified, EGFR mutant adenocarcinoma cell line Engelman, Science 2007

38 Targeted approach to lung adenocarcinoma Mitsudomi, Cancer Sci 2007