Current Progress for Non-Small Cell Lung Cancer Treatment

Transcription

1 Chemotherapy : Mechanisms of Action Current Progress for Non-Small Cell Lung Cancer Treatment Topo inhibitors Alkylators CHR Tubulin active agents Topo I,II Pt Wen-Pin Su, M.D./ Prof. Wu-Chou Su National Cheng-Kung University Hospital Sep. 19, 21 Protein synthesis inhibitors F TS, DHFR RR Antimetabolites Treatment for NON-SMALL CELL LUNG CANCER 1st generation 2nd generation 3rd generation Survival in trials of Supportive Care Versus Support Care Plus Chemotherapy (Only trials using regimens based on Cisplatin) cyclophosphamide doxorubicin cisplatin (low dose) vincristine methotrexate ifosfamide mitomycin C cisplatin (high dose) vinblastine carboplatin vindesine paclitaxel docetaxel gemcitabine vinorelbine Irinotecan BMJ, 1995 First-line chemotherapy options in NSCLC (E1594): comparable efficacy with platinum doublets (Reaching a plateau) Probability of survival NSCLC = non-small cell lung cancer Therapeutic plateau: overall survival <12 months Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Time (months) Schiller, et al. NEJM 22 Cumulative Probability SECOND LINE NSCLC treatment Survival Update TAX 317B Docetaxel 75 mg/m 2 vs BSC T75 BSC75 Median 7.5 vs. 4.6 mos. Log-rank p = 1 1-year 37% vs. 12% Chi-square p = Survival Time (months)

2 Pemetrexed Pemetrexed Mechanism of Action Cell Membrane Folate Carriers (mainly RFC) Pemetrexed FPGS Pemetrexed-Glu n PRPP + Gln dtmp TS DNA Synthesis GARFT 1-CHO-FH 4 IMP DHFR AMP RNA & DNA Synthesis GMP 5, 1-CH 2 -FH 4 FH 4 dump FH 2 % Response Rates [CI=5.9,13.2] [CI=5.7,12.8] CR and PR Stable Disease Pemetrexed (n=264) Docetaxel (n=274) Survival Distribution Phase III ALIMTA vs. Docetaxel in 2 nd -line NSCLC Efficacy End Points: Survival Overall Survival HR.75.5 MST 8.3 mo 1-yr OS: 29.7% Alimta (N=283) Docetaxel (N=288) HR.99 95% CI of HR (2, 1.2*) 5 MST 7.9 mo 1-yr OS: 29.7% * Test of superiority and 1% non-inferiority not statistically significant Hanna et al. J Clin Oncol. 24; 22: Hospitalizations, Transfusions & Growth Factors Pemetrexed Docetaxel (n=265) (n=276) p-value Total hospitalizations 1.5% 13.4% <.1 due to febrile neutropenia Patients with > 1 hosp 6.4% 1.5%.92 due to other drug-related adverse event G-CSF/GM-CSF 2.6% 19.2% <.1 Erythropoietin 6.8% 1.1%.169 Red blood cell 16.6% 11.6%.85 Transfusions Phase III trial of Bevacizumab in NSCLC (E4599): Overall survival Cetuximab in NSCLC treatment FLEX: overall survival RR 35% vs 15% PFS (mo) 6.2 vs 4.5 Adapted from Sandler A, et al. N Engl J Med 26;355: Pirker the Lancet 373:1525, 29

3 Malignant Lung Epithelial Tumors Histology Determines the Choice of Chemotherapy Option Carcinoma (CA) Non-small Cell CA (NSCC) Small Cell CA Typical Carcinoid Atypical Carcinoid Neuroendocrine CA Squamous Cell CA Non-squamous Cell NSCC Adenocarcinoma Other NSCC Large Cell CA Other Large Cell CA Large Cell Neuroendocrine CA IHC in DDx of adenoca and SCC Immunoquery website (accessed 3/2/1): suggested panel = CK 5/6 and TTF-1 AdenoCa SCC CK 5/6 1% positive 99% positive p63 27% 97% 34betaE12 35% 99% CK 7 97% 27% TTF-1 77% 7% CEA-P 86% 44% Immunohistochemistry of Lung Cancer TTF-1 p63 Surfactant Apoproteins HMWCK (CK5-6, 34βE12) Napsin A Desmocollin 3 CK 7 ADENOCARCINOMA SQUAMOUS CELL CARCINOMA Scagliotti 29 ECOG 1594: Efficacies by Histology Log-rank test for comparing OS and PFS distributions among different histology groups Survival in each histology group for different chemotherapy regimen Results: No difference in OS and PFS between the four histology groups No survival difference between the four chemotherapy regimens in each histology group Regardless of histology types, OS and PFS were similar in chemonaive NSCLC patients treated with standard platiumbased doublets involving paclitaxel, docetaxel, or gemcitabine! WCLC 29 Hoang et al, Abstract # PD6.4.1 WCLC 29 Hoang et al, Abstract # PD6.4.1 Percent Surviving 1 5 Results of Pemetrexed Overall Survival (SCC versus non-scc) Patients Randomized to Pemetrexed Squamous: Median = 6.2 Non-squamous: Median = 9.2 Overall Survival (months) p=1 Percent Surviving 1 5 Patients Randomized to Docetaxel Squamous: Median = 7.4 WCLC 27 Peterson P et al., Abstract # P2-328 Non-squamous: Median = 8.2 Overall Survival (months)

4 Higher Thymidilate Synthase (TS) Expression in Squamous Cell Carcinoma Ceppi P et al. Cancer 26;17: Overall Survival: Non-Squamous (AdenoCa or Large Cell Ca) Histology Determines the Choice of Chemotherapy Option- Adenocarcinoma/ large cell carcinoma Pemetrexed (1st line paid by 健 保, good ECOG patients) Further Maintenance treatment? J Clin Oncol. 28 Jul 2;26(21): Pemetrexed/BSC vs Placebo/BSC in NSCLC: Study Design Progression-free Survival by Histology (SCC versus non-scc) Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS -1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response non-platinum drug brain mets 2:1 Randomization Pemetrexed 5 mg/m 2 (d1,q21d) + BSC (N=441)* Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B 12, folate, and dexamethasone given in both arms HR=7 (95% CI:.37-) P <1.9.7 Pemetrexed 4.4 mos Placebo 1.8 mos Progression-free Probability Non-squamous (n=481) Time (months) Placebo 2.5 mos Squamous (n=182) HR=3 (95% CI: ) P =96 Pemetrexed 2.4 mos Time (months) Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 28; Chicago, IL. Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 28; Chicago, IL.

5 Genetic Change in lung cancer --- Adenocarcinoma (AD), SCC (SQ) and SCLC Genetic change resulting from histology also determines the choice of cancer treatment Histology guided treatment: Inhibition of the EGF-EGFR signaling pathway OSI-774 Erlotinib Tarceva EGFR HER1 RAS RAF PI3-K py K K SOS py GRB2 MEK py PTEN AKT STAT MAPK ZD1839 Iressa g BR.21: Erlotinib versus placebo Overall Survival Erlotinib Placebo *HR.71, p <1 31% Proliferation / maturation Survival / apoptosis Gene transcription Cell-cycle progression G2 M S G1 Angiogenesis Metastasis Baselga % 1 2 Survival distribution function Is there a survival benefit with erlotinib in current/ex-smokers? Current/ex-smokers HR=.9 (.7 ), p=.141* Erlotinib (n=358) Placebo (n=187) Time (months) Treatment interaction test p= 2 (significant) *Log-rank test Never smokers HR=2 (8 4), p<1 Placebo (n=42) Erlotinib (n=14) Time (months) Neversmokers EGFR mt k ras mt neither Ever-smokers EGFR mt k ras mt neither Adenocarcinoma Estimated Genomic Probabilities East Asia West (Japan, Korea, Taiwan, HK) (USA, Australia) 6 studies 2 studies n = 814 n = 116 7% 1% 29% 29% 17% 54% 37% % 63% 8% 41% 51% Shigematsu, Sakema, Takema, Bae, Tam

6 Personalized Anti-cancer Treatment in NSCLC Customizing Cisplatin Based on ERCC1 mrna Expression in NSCLC Randomization model RR = 37.6% vs 47.5% (p=.3) RR for low vs hi = 53.2% vs 47.2% Cobo, M. et al. J Clin Oncol; 25: Case Report Case Report Dramatic Response to Day 55 yo woman No smoking history s/p RLL and LUL lobectomies for lung adenocarcinoma 2 years later, recurrence with bilateral pulm nodules Resistance to multi-chemotherapy Response to erlotinib 2 months EGFR Mutations Associated with Sensitivity to /Erlotinib in lung adenocarcinoma EGF ligand binding Tyrosine kinase autophos EGFR mutations and response to TKI TM K DFG Y Y Y Y GXGXXG K DFG L L Exon: LREA G719A/C deletion L858R L861Q Sensitive mutations Deletion in exon 19 or point mutation in exon 21 (L858R), L861Q, G719A/C/S Resistance mutations Insertion mutations in exon 2 and activating mutations in KRAS Intrinsic resistance T79 M mutation and amplification or overexpression of the MET gene 2nd resistance Lynch et al 4; Paez et al 4; Pao et al 4 Yamamoto H, Lung cancer, 29

7 EGFR-TKI Response rate EGFR Response & Mutation efficacy in mutant EGFR in 1st setting N Response Rate* Disease Control Rate* Time to Treatment Failure (M) Overall Survival (M) Any mutation % 87.3% del 2 95.% 95.% , L858R % 95.7% 9. NR EGFR Mutation rate 19del or L858R % 95.3% other mutations % 58.3% Wild type 35 2% 68.6% Not performed % 93.8% 5.6 NR ALL % 82.1% Mitsudomi T. Int J Clin Oncol 26 * Independent review using RECIST NR: not reached Yang CH et al. JCO 28 IPASS Study design (in Pan-Asian Area) in 1st line lung adenocarcinoma (from Randomized phase III study) Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light ex-smokers* Life expectancy 12 weeks PS -2 Measurable stage IIIB / IV disease Non-inferior (25 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (2 mg / m 2 ) q3 weeks # superiority Endpoints Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <1 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 1 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Mok et al. NEJM 361:947-57, 29 Objective response rate in EGFR mutation positive and negative patients Progression-free survival in EGFR mutation positive and negative patients Overall response rate (%) 71.2% 47.3% Carboplatin / paclitaxel EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.6), p=1 EGFR M- odds ratio (95% CI) = 4 (1, 7), p=13 1.1% 23.5% (n=132) (n=129) (n=91) (n=85) Probability of progression-free survival At risk : C / P EGFR mutation positive (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 8 (.36, 4) p<1 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.%) Treatment by subgroup interaction test, p<1 Probability of progression-free survival EGFR mutation negative (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.5, 3.98) p<1 No. events gefitinib, 88 (96.7%) No. events C / P, 7 (82.4%) Odds ratio >1 implies greater chance of response on gefitinib Mok et al. NEJM 361:947-57, 29 ITT population Cox analysis with covariates Mok et al. NEJM 361:947-57, 29

8 Progression-free survival by mutation status for high EGFR-gene-copy number patients Personalized treatment for NSCLC according to EGFR mutation status Probability of progression-free survival High EGFR-gene-copy number, mutation positive (n=96) Carboplatin/paclitaxel (n=94) HR (95% CI) = 8 (.34, 7) No. events gefitinib, 7 (72.9%) No. events C/P, 79 (84.%) Probability of progression-free survival High EGFR-gene-copy number, mutation negative (n=26) Carboplatin/paclitaxel (n=29) HR (95% CI) = 3.85 (2.9, 7.9) No. events gefitinib, 26 (1%) No. events C/P, 24 (82.8%) At risk : C/P Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; Post-hoc analysis in ITT population Fukuoka et al. ASCO 29 Mutation: positive: EGFR-TKI negative: chemotherapy Mok et al N Engl J Med 29 Recently reported Phase III studies of gefitinib as first-line treatment for NSCLC in selected populations EGFR mutation is important for personalized advanced lung cancer - Prospective randomized phase III study (NEJ2 and First Signal study) - Maintenance NSCLC treatment with erlotinib (Saturn) NEJ2 (Japan) Patients Chemo-naïve EGFR M+ PS 1 First-SIGNAL (Korea) (Another IPASS) Patients Chemo-naïve Adenocarcinoma Never smokers ECOG PS 2 Eastern Cooperative Oncology Group * Maximum 9 cycles 25 mg/day (n=98) Carboplatin AUC 6 & paclitaxel 2 mg/m 2 3- weekly (n=1) 25 mg/day (n=159; M+ 26) Endpoints Primary PFS (superiority) Secondary OS, ORR, QoL, disease-related symptoms safety and tolerability Endpoints Primary OS Secondary PFS, ORR, QoL, Gemcitabine disease-related symptoms (125 mg/m 2 ) & safety and tolerability cisplatin (8 mg/m 2 ) 3-weekly* (n=15; M+ 16) Maemondo M et al. NEJM 362:238-8, 21 Lee et al WCLC 29 PFS and OS Cross-over study design Probability of PFS PFS and ORR with first-line gefitinib versus doublet chemotherapy in EGFR M+ Asian patients across three Phase III studies HR (95% CI) = 8 (.36, 4) p<1 Probability of PFS HR (95% CI) =.36 (5,.51) p<1 Probability of PFS HR (95% CI) = 13 (.38, 1.221) p= IPASS p< Days NEJ2 p< First-SIGNAL p=2 3.5 versus 23.6 months ORR % ORR % ORR % Maemondo M et al. NEJM 362:238-8, 21 (n=132) (n=98) (n=26) C / P (n=129) C / P (n=1) G / C (n=16) Mok et al N Engl J Med 29; Lee et al WCLC 29; Maemondo M et al. NEJM 362:238-8, 21

9 Lung cancer maintenance treatment with erlotinib (SATURN trial) ( 任 何 histology) Chemonaïve advanced NSCLC n=1,949 Mandatory tumor sampling Stratification factors: 4 cycles of 1st-line platinumbased doublet* EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS ( vs 1) CT regimen (cis( cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Non-PD n=889 Co-primary endpoints: Erlotinib 15mg/day 1:1 Placebo *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel Cappuzzo F et al. Lancet Oncology 21 11:521-9 PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: PD PD OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC tumors; biomarker analyses; safety; time to symptom progression; QoL PFS probability PFS*: all patients (ITT) HR=.71 (2 2) Log-rank p<1 Erlotinib Time (weeks) Placebo PFS at 12 wks (%) 53 4 PFS at 24 wks (%) Erlotinib (n=437) Placebo (n=447) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks PFS according to EGFR mutation status EGFR mutation is a predictive biomarker for TKI usage in lung adenocarcinoma PFS probability EGFR mutation+ HR=.1 (4 5) Log-rank p<1 Erlotinib (n=22) Placebo (n=27) EGFR wild-type HR=.78 (3.96) Log-rank p=185 Erlotinib (n=199) Placebo (n=189) Test Marker Register Stratify (EGFR mutation) Marker+ Assign one cancer treatment (as TKI) Time (weeks) Time (weeks) Interaction p<1 Marker- Assign another treatment (as C/T) Cappuzzo F et al. Lancet Oncology 21 11:521-9 Case Report Mutations in the ERBB Pathway in NSCLC Ligand Ligand-binding domain Exon 19 del Erlotinib Day 4 months 25 months 55 yo woman No smoking history s/p RLL and LUL lobectomies for lung adenocarcinoma 2 years later, recurrence with bilateral pulm nodules Resistance to multi-chemotherapy Response to erlotinib Acquire resistance to erlotinib T79M no MET BIBW = both EGFR and HER2 PTEN 2 1 PI3K AKT mtor K Survival K Grb-2 SOS STAT 3/5 RAS 3 RAF 4 MEK MAPK Proliferation

10 Drug Contact Residues Are Commonly Affected (T79M, T854A) Mutation in other genes 92% 4% 4% Adapted from Yun et al 7; Cancer Metastasis Rev : Yamamoto H, Lung cancer, 29 Squam 21: Lung Adenoca- Multiple Molecular Subsets Molecularly Tailored Therapy Large Small Adeno Mutations associated with drug sensitivity G719X, exon 19 del, L858R, L861Q Mutations associated with 1ry drug resistance exon 2 dup Mutations associated with 2ry drug resistance L747S, D761Y, T854A, T79M, MET amplification ALK fusion BRAF PIK3CA MEK1 HER2 EGFR Unknown KRAS PDGFR amp Mutation Prediction EGFR exon 19 del/l858r Sens to EGFR TKIs KRAS EGFR T79M/D761Y/T854A MET amplification MEK1 HER2 BRAF ALK fusions PDGFRα amplification PIK3CA ROS generation Res to EGFR TKIs Res to EGFR TKIs; sens to new TKIs. Sens to MET TKIs Sens to MEK inhibitors Sens to HER2 TKIs Sens to BRAF inhibitors Sens to ALK inhibitors (PF ) Sens to PDGFR inhibitors PIK3CA inhibitors Sens to ROS inhibitors. EML4-ALK Fusion Oncogene Fusion results from a small inversion within chromosome 2p Expression of a chimeric TK in which the N- terminal half of echinoderm microtubuleassociated protein-like 4 (EML4) is fused to the intracellular kinase domain of anaplastic lymphoma kinase (ALK) Potent oncogenic activity EML4-ALK Fusion Oncogene Clinical Characteristics Male Younger Never/light smokers Adenocarcinoma Histologically distinct (signet ring cells) Associated with resistance to EGFR TKIs Promising activity of the MET/ALK-inhibitor PF Shaw JCO 27:4247, 29 Shaw WLC,29 #A6.4

11 TTP and OS of EML4-ALK+ patients Compared with EGFR mut and WT Tumours ALK+ N=19 WT/WT N=91 EGFR mut N=31 p-value EGFR 5 mos 6 mos 16 mos p=.4 TKI Chemo mos ND Tumor Responses to PF for NSCLC Evaluable Patients with ALK Fusions Kwak et al PASCO 9 Overall Response Rate = 59 % (17/29) (95%CI: 39%-76%) Disease Control Rate: 83% (24/29) (95%CI: 64-94%) Median Duration of Treatment = 18 weeks OS 2 mos 16 mos 31 mos p=.468/.152 Shaw JCO 27:4247, 29 In high prevalence of EGFR mutation,. ( 但 仍 有 困 境, methology, QC,..) Perform EGFR mutation test before EGFR-TKI If (+), TKI is better than chemotherapy in PFS If (-), chemotherapy is more favored in PFS (no TKI) Selecting patients for chemotherapy Good performance status patients Known resistance to EGFR-TKI such as high T79M of EGFR, ras mutation, cmet ampl., HER2 mutation etc.? No endemic area for EGFR mutation EGFR wild type EGFR unknown Horn, L. et al. J Clin Oncol; 27: This puzzle may not happen 1 健 保 PS-1 健 保 EGFR mutation status 健 保 健 保? CT EGFR-TKI Further treatment BSC 2 3 EGFR mutation status CT? CT EGFR-TKI Further treatment BSC