Treatment of PS 2 Patients with Advanced NSCLC:

Transcription

1 Treatment of PS 2 Patients with Advanced NSCLC: Current State of the Art Corey J Langer MD, FACP Director, Thoracic Oncology Abramson Cancer Center Professor of Medicine University of Pennsylvania Philadelpia, PA Corey.langer@uphs.upenn.edu PS2 Patients with NSCLC: What We Know 1. Heterogeneous group of patients 2. A large proportion of the NSCLC population (30% 40%) 3. Frequently excluded from clinical trials When included, frequently combined with the elderly, although each represents different populations 4. Generally tolerate therapy poorly 5. PS 2: associated with poorer survival 1

2 PS2 Patients with NSCLC: What We Don t Know 1. How to accurately assess PS2 patients 2. The influence of co-morbidities vs disease burden on PS and treatment outcome 3. Best therapy Chemo vs BSC Doublets versus monotherapy Targeted agents Assessment of PS Significant discordance between assessment of performance status by physician versus patients Agreement between patients and physicians occurred in only 43% of the 3272 patients studied Physicians overestimated PS by 38% Cella et al, BIOQOL/Q-SCORE Database,

3 Impact of PS on Outcome ECOG 1581 Performance Objective Median Toxic Status Response (%) Survival (wks) Deaths (%) Ruckdeschel JC, Finkelstein DM, Ettinger DS et al. A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin Oncol 4: 14-22, ECOG Recursive Partitioning Analysis Terminal Nodes Median Survival (mos) Intact Appetite (n) Diminished Appetite (n) PS0 Female (111) 8.54 (15) Male 9.86 (219) 6.74 (50) PS1 Female 7.77 (214) 6.95 (102) Male 6.70 (421) 5.08 (224) PS2 Female 5.31 (24) 2.30 (27) Male 4.30 (64) 3.43 (100) Jiroutek M, et al. Proc Am Soc Clin Oncol. 1998;17:

4 ECOG Recursive Partitioning Analysis Terminal Nodes Median Survival (mos) Intact Appetite (n) Diminished Appetite (n) PS0 Female (111) 8.54 (15) Male 9.86 (219) 6.74 (50) PS1 Female 7.77 (214) 6.95 (102) Male 6.70 (421) 5.08 (224) PS2 Female 5.31 (24) 2.30 (27) Male 4.30 (64) 3.43 (100) Jiroutek M, et al. Proc Am Soc Clin Oncol. 1998;17:1774. BMJ Meta-analysis Cisplatin-based Therapy BMJ 1995;311:

5 Retrospective Analyses of the Role of Chemotherapy in PS 2 Patients with Advanced NSCLC Survival benefit with single agent vinorelbine in PS 2 subset of ELVIS trial (26 weeks vs. 8 weeks with BSC) Conflicting data on the possible superiority of platinumbased doublets vs. single agents CALGB 9730*: survival 4.7 mos vs. 2.4 mos with carboplatin/paclitaxel and paclitaxel respectively Le Chevalier:** no difference in survival between platinum-vinca i combination vs. vinorelbine alone *Lilenbaum R J Clin Oncol, 2005; 23: **Le Chevalier T J Clin Oncol,1994;12: CALGB 9730: PS 2 Subset Analysis Total PS 2 P CbP P CbP All N OR (%) MST (mos) 1-yr OS%* yr OS% NA NA *Wilcoxon =.1014; Log rank P =.0123; SS (<.0001) vs PS 0-1 Lilenbaum RC, et al. JCO

6 1.0 CALGB 9730: Survival by treatment and PS Probability P / PS 0-1 P / PS 2 CP / PS 0-1 CP / PS 2 N MS 1YS 2YS % 12% % 0% % 10% % 9% Months Advancing Age Declining PS E5592 ELVIS IFCT 6

7 ECOG 5592: Elderly Data RANDOMIZATION cddp 75 mg/m 2 & Etoposide 100 mg/m 2 d 1-3 Paclitaxel l 135 mg/m 2 /24 o d2 Paclitaxel 250 mg/m 2 /24 o d 2 + G-CSF BREAKDOWN by Elderly ( 70) v Young (<70) Elderly: cardiovascular (p=0.009) + resp (p=0.044) comorbidities Age N RR(%) TTP (mo) MS (mo) 1 YS (%) 2YS (%) < P value Log rank leukopenia (p=0.0001) and neuropsych tox (0.0025) in 70 yrs No difference baseline QoL, TOI, or over time CONCLUSION: PS trumps age; Fit elderly merit/benefit from Tx...Langer et al., J Natl Cancer Inst. 94(3): , 2002 Retrospective Analyses of Platinumbased Doublets in Elderly(> 70) Patients with Advanced NSCLC Several subset analyses conducted assessing outcome in patients > age 70 SWOG 9509/ carbo/paclitaxel vs. cis/vinorelbine (Kelly 2001) ECOG 5592 cisplatin/etoposide vs. cisplatin/paclitaxel (Langer 2002) CALGB 9730 carbo/paclitaxel (Lilenbaum 2002) ECOG 1594 four platinum doublets (Langer 2003) TAX 326 cis/docetaxel vs. cis/vinorebine vs. carbo/docetaxel (Fossella 2003) No differences in survival Trend for greater toxicity in some studies, particularly myelosuppression Trend for improved tolerance of carboplatin vs. cisplatin Major potential limitation these elderly subsets likely not representative of the general elderly population 7

8 Weekly paclitaxel combined with monthly carboplatin versus single agent therapy in patients aged 70 to 89 : IFCT-0501 randomized phase III study in advanced non- small cell lung cancer Elisabeth Quoix, JP Oster, V Westeel, E Pichon, G Zalcman, L Baudrin, A Lavolé, J Dauba, MP Lebitasy & B Milleron on behalf of the French Intergroup (IFCT) Study scheme NSCLC Stage III-IV Age years PS 0-2 n = 451 R A N D O M Vinorelbine or Gemcitabine* Carboplatin + paclitaxel l Erlotinib** 150 mg/d Stratification by centre, PS 0-1 vs. 2, age 80 vs. >80 and stage III vs. IV *Choice of the center at the beginning of the study ** In case of PD or excessive toxicity 8

9 Inclusion criteria Age With Stage III (not amenable to RT) or Stage IV NSCLC PS 0-2 No prior treatment except surgery or palliative radiation therapy At least 3 weeks after must have elapsed after radiation therapy or major surgery. Adequate hematological, renal and hepatic function Life expectancy of at least 12 weeks Signed informed consent Geographically near enough for follow-up Patients characteristics (1) Single agent (n= 226) G (n = 164) V (n = 62) All Doublet (n= 225) Gender Male 129 (78.7%) 43 (69.4%) 172 (76.1%) 161 (71.6%) Median age Range PS Stage IIIA-B IV Histology Squamous Adeno Other (70.1%) 49 (29.9%) 35 (21.3%) 129 (78.7%) 54 (32.9%) 85 (51.8%) 25 (15.2%) (80.6%) 12 (19.4%) 7(11.3%) 55 (88.7%) 20 (32.3%) 30 (48.4%) 12 (19.4%) (73%) 61 (27%) 42 (18.6%) 184 (81.4%) 74 (32.7%) 115 (50.9%) 37 (16.4%) (72.9%) 61 (27.1%) 46 (20.4%) 179 (79.6%) 77 (34.2%) 114 (50.7%) 34 (15.1%) p Never smokers 33 (20.2%) 17 (27.4%) 50 (22.2%) 44 (19.6%)

10 Patients characteristics (1) Single agent (n= 226) G (n = 164) V (n = 62) All Doublet (n= 225) Gender Male 129 (78.7%) 43 (69.4%) 172 (76.1%) 161 (71.6%) Median age Range PS Stage IIIA-B IV Histology Squamous Adeno Other (70.1%) 49 (29.9%) 35 (21.3%) 129 (78.7%) 54 (32.9%) 85 (51.8%) 25 (15.2%) (80.6%) 12 (19.4%) 7(11.3%) 55 (88.7%) 20 (32.3%) 30 (48.4%) 12 (19.4%) (73%) 61 (27%) 42 (18.6%) 184 (81.4%) 74 (32.7%) 115 (50.9%) 37 (16.4%) (72.9%) 61 (27.1%) 46 (20.4%) 179 (79.6%) 77 (34.2%) 114 (50.7%) 34 (15.1%) p Never smokers 33 (20.2%) 17 (27.4%) 50 (22.2%) 44 (19.6%) 0.49 PFS (ITT) P F S p r o b a b i l I t y Single Single Doublet Doublet Median : 6.1 months (95% CI ) 1-year PFS : 15.4% (95% CI ) Median : 3.0 months (95% CI ) 1-year PFS : 2.3% (95% CI ) p <10-6 Months Single Doublet

11 Overall survival (ITT) S U R V I V A L Single MST = 10.3 months Doublet (95% CI year survival 45.1% (95% CI ) Single agent MST = 6.2 months (95% CI ) 1-year survival 26.9% (95% CI ) p= Doublet Months Single Doublet Multivariate analysis of survival (Cox model) N=407 (patients without any missing data) Stepwise variable selection procedure, entry level=0.20, stay level=0.05 Variables Hazard ratio [95% CI] p Arm B [ ] A PS Smoking history No Yes Histology [ ] [ ] ADC [ ] Squamous [ ] Other 1 ADL 6 <6 Weight loss 5% > 5% [ ] [ ]

12 Exploratory Sub-group analysis N HR 95% LCL 95% UCL p All (B:A) PS 0/ PS Age 80 yr Age > 80 yr Adenocarcinoma Other histology Smokers Never smokers Weight loss < 5 % Weight loss 5 % ADL = ADL < MMS MMS < Favors doublet OS The univariate hazard ratio was derived from a Cox model with a single treatment covariate Conclusions Carboplatin-based doublet resulted in a doubling of median PFS from 3 to 6.1 months, an improvement of median OS from months to 10.3 and of 1-year survival rate from 27% to 45%. Carbo-based doublet had a beneficial effect on survival in most of the subgroups tested [including PS 2], even those with lower prognosis Manageable (acceptable) toxicity New paradigm for elderly patients with advanced NSCLC: monthly carboplatin + weekly paclitaxel 12

13 Rationale of the study (4) Erlotinib:Placebo PS 0-1 PS 2-3 Male Female <65 years >65 years Adenoca Squamous Other Histology Weight loss <5% Weight loss 5-10% Weight loss >10% Never smoker Smoker 1 prior regimen 2+ prior regimens Erlotinib in 2 nd and 3rd line almost as effective vs placebo in PS 2-3 as in PS Hazard Ratio F. Shepherd N Engl J Med 2005;353: PS 2 Specific Trials through 2006 ECOG 1599 STELLAR 3 STELLAR 4 OSI: Erlotinib; CbP 13

14 PS 2 Specific Trials through 2006 ECOG 1599: first dedicated, PS-2 specific randomized d phase II, cooperative group trial STELLAR 3: first PS-2 specific, randomized phase III trial in NSCLC STELLAR 4: second PS-2 specific, randomized phase III trial in NSCLC OSI: Erlotinib; CbP: first trial to test EGFr TKI in PS 2 pts upfront ECOG 1599: Dose-Attenuated CbP or GC in PS2 Advanced NSCLC R A N D O M I Z E Carboplatin AUC 6 q3wk Paclitaxel 200 mg/m 2 q3wk Gemcitabine 1 g/m 2 days 1, 8 q3wk Cisplatin 60 mg/m 2 q3wk Tester, Langer et al. ASCO 2004, JCO 07 14

15 ECOG 1599: Outcomes of Doublet Therapy in PS2 Patients N = 102 Arm GC PCb CR (%) 2 0 PR (%) SD (%) MS (mo) PFS (mo) y OS (%) Tester, Langer et al. ASCO 2004, JCO 07 Recent Clinical Trials With PS2 Patients: Survival Best No. of Single Supportive Doublet Patients Care Agent Gridelli CALGB HeCOG ECOG ECOG Chemotherapy prolongs survival. Gridelli. Ann Oncol. 2004;15:

16 New Agents Cytotoxics (with improved toxicity profiles) Targeted agents (often non-toxic or minimally toxic) STELLAR 3: Trial Design Chemotherapy- e naïve PS2 patients with advanced NSCLC Stratified by: Stage Sex History of brain mets Geographic region R A N D O M I Z E PPX 210 mg/m 2 Carboplatin (AUC 6) q3w N = 199 Paclitaxel 225 mg/m 2 Carboplatin (AUC 6) q3w N=201 Langer et al ASCO 05 16

17 STELLAR 3: Overall Survival Prob bability of Survival (Intent-to-Treat) PPX/Carboplatin Paclitaxel/ Carboplatin N Median N 1 Median yr 18 1 yr mo18 mo 2 yrs 2 yrs PPX/Carboplatin mo % 7.8 mo 20% 31% 20% 13% 13% Paclitaxel/Carboplatin mo 31% 11% 11% Paclitaxel mo 31% 11% 11% HR=0.97 Log-rank P value= Time From Randomization (Days) 7 11 STELLAR 4: Trial Design Eligibility Requirements: Chemotherapy-naïve Advanced NSCLC PS2 Stratified by: Stage Sex History of brain metastasis Geographic region R A N D O M I Z E PPX 175 mg/m 2 every 3 weeks (N=191) Gemcitabine 1000 mg/m 2 days 1, 8, and 15 every 28 days or Vinorelbine 30 mg/m 2 days 1, 8, and 15 every 21 days (N=190) 80% power to detect 1.5-month difference (4-5.5); hazard ratio (HR)=

18 1.0 Pr robability of Survival STELLAR 4: Overall Survival PPX vs. Gemcitabine/Vinorelbine (Intent-to-Treat) PPX Gemcitabine/ Vinorelbine N Median 1 yr 18 mo 24 mo PPX mo 26% 15% 15% Gemcitabine/ mo 26% 13% 10% Vinorelbine HR=0.95 Log-rank P value= Time From Randomization (Days) 5 Multivariate Analysis: STELLAR 3 and 4 Factor Chi Square P value Albumin < 3.5 vs > < Extrathoracic Tumor (excluding CNS mets) 19.9 < Number of Comorbidities > 2 Smoking Hx

19 Multivariate Analysis: STELLAR 3 and 4 Factor Chi Square P value Albumin < 3.5 vs > < Extrathoracic Tumor (excluding CNS mets) 19.9 < Number of Comorbidities > 2 Smoking Hx Potential Stratifications for Future Trials Erlotinib vs. Chemotherapy in PS2 Patients Stratified by: Center Age (< 70 vs > 70) Extent of Disease (Stage IIIB vs IV) R A N D O M I Z E Erlotinib El ib 150 mg daily Carboplatin AUC 6 + Paclitaxel l 200 mg/m 2 Optional Cross-over to Erlotinib 1:1 Day 1 q 21 days x 4 cycles Lilenbaum et al ASCO 06, J Clin Oncol 26: ,

20 Overall Survival Lilenbaum et al ASCO 06, J Clin Oncol 26: , 2008 PS 2 Specific Trials: ASCO 2007 US Oncology: Obasaju et al SWOG 0341: CALGB 30402: Japan: Hesketh et al Lilenbaum et al Inoue et al 20

21 Randomized Phase III, US Oncology Trial in PS 2 NSCLC R A N D O M I Z E Gemcitabine 1000 mg/m2 d Carboplatin AUC 5 d 1 Gemcitabine 1000 mg/m2 d pts targeted; 6 cycles of Tx projected 1 Endpoint: median survival Obasaju et al ASCO 07, A-7533 Randomized Phase II Trial of Gemcitabine or Gemcitabine/Carboplatin in PS 2, Adv NSCLC Arm Gem Gem/Carbo No (Eval) 85 (81) 85 (79) Mean # cycles % Pts with dose omissions 22% 35% % Pts with dose reductions 35% 57% RDI - Gem 91% 71% RDI - Carbo N/A 90% G 3/4 Neutropenia 10% 27% G 3/4 Thrombocytopenia 2% 22% G 3/4 Anemia 2% 6% 21

22 Randomized Phase II Trial of Gemcitabine or Gemcitabine/Carboplatin in PS 2, Adv NSCLC Arm Gem Gem/Carbo No (Eval) 85 (81) 85 (79) OR % 11.5% 36% PFS (mo) MS (mo) yrOS N/A N/A Mean change in FACT-L Mean change in TOI Obasaju et al ASCO 07, A-7533 CALGB PHASE II TRIAL PS 2 PATIENTS * 1 st Line PS 2 IIIB/IV NSCLC R A N D O M I Z A T I O N DOCETAXEL 30mg/m 2 /d1,8,15 q28 + CETUXIMAB 400mg-250mg/m 2 /wk X 4 cycles DOCETAXEL 30mg/m 2 /d1,8,15 q28 + BORTEZOMIB 1.6mg/m 2 /d1,8,15 q28 MAINTENANCE UNTIL PD MAINTENANCE UNTIL PD PI : R. Lilenbaum, ASCO 07, A-7595 *Trial completed

23 CALGB PHASE II TRIAL PS 2 PATIENTS * 64 patients accrued 7/05 thru 9/06 5 ineligible 3 never received protocol Tx Majority had adenoca, 13% CNS mets Median age: 70 (range, 35-88) 65% male PI : R. Lilenbaum, ASCO 07, A-7595 CALGB PHASE II TRIAL PS 2 PATIENTS * Arm Doc + Bort Doc + C225 No OR% PFS (mo) mo PFS% MS (mo) Gr 3/4 Heme 18% 18% Gr 3/4 non-heme 36% 44% Conclusion: No obvious advantage to the addition of Bortezomib or C225 to Docetaxel in this setting: Similar RR% and MS vs Doc alone; Increased toxicity PI : R. Lilenbaum, ASCO 07, A

24 SWOG 0341: RP2 Original proposal Erlotinib* R Erlotinib/Carbo/Paclitaxel * EGFR (+) IHC or FISH SWOG 0341: Erlotinib in PS 2 NSCLC Morphed into a straight phase II trial unselected on basis of EGFR 82 enrollees Demographics: 53% female; median age 74; 91% current, former smokers; 88% stage IV/recurrent Toxicity: 7% gr 4 (fatigue [3]; dyspnea [2]); 1 possible TRD (ILD) Response rate: 8% (including 1 CR); DCR: 43% PFS: 2.1 mo MS: 5.0 mo; 1 yr OS: 22% Hesketh et al, ASCO 07, A-7536, J Thorac Oncol 3: ,

25 Studies Evaluating EGFR TKI in Pts with Compromised PS Trial Lilenbaum Hesketh Inoue* PS Mutation Status Unselected Unselected All (+) Mut (+) 0% NA 100% No OR% PFS (mo) MS (mo) Akira Inoue, Kunihiko Kobayashi, Kazuhiro Usui, Makoto Maemondo, Shoji Okinaga, Iwao Mikami, Masahiro Ando, Koichi Yamazaki, Yasuo Saijo, Akihiko Gemma, Hitoshi Miyazawa, Tomoaki Tanaka, Kenji Ikebuchi, Toshihiro Nukiwa, Satoshi Morita, and Koichi Hagiwara First-Line Gefitinib for Patients With Advanced Non Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy JCO : SWOG PROSPECTIVE STUDY PS 2 pts: Proteomic positive ERLOTINIB CT+ERLOTINIB N=27 as of 2/11 25

26 Prediction of Clinical Outcome in Non-Small-Cell Lung Cancer (NSCLC) Patients treated with EGFR-TKIs using Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-ToF MS) of Serum. Benjamin Solomon, Vanesa Gregorc, Fumiko Taguchi, Heinrich Roder, Kazuo Kasahara, Makoto Nishio, Mark W. Duncan, Fred R. Hirsch, Paul A. Bunn Jr., David P. Carbone Universities of Colorado/Vanderbilt and BIODESIX. Taguchi et al. JNCI. June 2007 Blinded validation in E3503 Patients treated with erlotinib (n = 96 patients with available plasma or serum) p = 0.54 Taguchi et al. JNCI

27 TOPPs Trial Randomized Phase II Trial in PS 2 pts with Chemotherapy-naïve, Non-squamous cell Advanced NSCLC Final accrual: 194 pts R A N D O M I Z E Pemetrexed 500 mg/m2 Q 3 wks Pemetrexed 500 mg/m2 Q 3 wks Carboplatin AUC 5 Q 3 wks Pemetrexed 500 mg/m2 Q 3 wks Carboplatin AUC 5 Q 3 wks Bevacizumab 15 mg/kg Q 3 wks Management of PS 2 Patients With Advanced NSCLC (1) PS 2 patients represent a sizable percentage of our practice. Expanding number of PS 2 specific trials; but a relative paucity of evidence-based, prospective data are available Treatment practices vary considerably Prognosis remains poor Reliable and reproducible scales for assessing PS and relationship with co-morbidities are prime research goals Combination chemotherapy may have its greatest impact on patients with PS 2 who are symptomatic from their cancer, whereas single agents may be best in those with co-morbidities STELLAR trials, though (-), have enriched the literature and identified a number of prognostic variables that should be used as stratification factors in future studies: serum albumin, extrathoracic involvement, co-morbidities, smoking hx 27

28 Management of PS 2 Patients With Advanced NSCLC (2) The use of targeted agents in PS 2 patients should be carefully individualized Marker identification is even more crucial in this population To date, empiric addition of targeted agents to standard chemotherapy in this setting has NOT provided benefit Dedicated studies in PS 2 patients are still needed Excellent setting for exploring newer, less toxic regimens Focus on QoL, Co-morbidity indices, PROs Phase III of combination vs constituent single agents 28