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The use of systemic an0- cancer therapy for elderly pa0ents with metasta0c NSCLC. Jared Weiss, MD University of North Carolina 11/14/ PDF

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The use of systemic an0- cancer therapy for elderly pa0ents with metasta0c NSCLC Jared Weiss, MD University of North Carolina 11/14/2014 What is the median age of presenta0on of NSCLC?
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The use of systemic an0- cancer therapy for elderly pa0ents with metasta0c NSCLC Jared Weiss, MD University of North Carolina 11/14/2014 What is the median age of presenta0on of NSCLC? Incidence of NSCLC in the US by age at diagnosis No. of patients 35,000 30,000 25,000 20,000 15,000 10, Median age at diagnosis: 71 84 Age at diagnosis (y) Data from SEER Cancer Statistics Review, Metasta0c Lung Cancer IS a disease of the elderly ¾ of lung cancer is metastaic (stage IV, incurable) at presentaion The median age of presentaion with metastaic lung CA is 71 Therefor, to talk about geriatric lung cancer IS to talk about metastaic lung cancer and To talk about metastaic lung cancer IS to talk about a geriatric populaion. The elderly are untreated badly MispercepIons about expected longevity of the elderly MispercepIons about tolerability of treatments in the elderly MispercepIons about efficacy of treatments in the elderly What is the life expectancy of a 70 year old man? How about a 70 year old woman? 1. Man 2 years, Woman 3 years 2. Man 5 years, Woman 7 years 3. Man 10 years, Woman 12 years 4. Man 12 years, Woman 14 years 5. Man 14 years, Woman 16 years The elderly: In the absence of severe comorbidity, life expectancy is likely driven by the lung cancer Age Male Life Female life expectancy expectancy SSA acturial life table, cited in Weiss, 2013 Tradi0onal view of Quality of Life Chemo causes: Nausea Alopecia FaIgue InfecIons Therefor, maximize quality of life by avoiding chemo. An Alterna0ve View of Quality of Life Symptoms of progressive cancer Side- effects of therapy Cancer growth causes: *Pain *Cough *Shortness of breath *FaIgue *Organ Failure *Thrombosis *Hoarse voice *Nausea *Anorexia Chemo can alleviate cancer suffering. BeNer drugs and bener suppor0ve care means more tolerable ani- cancer therapy. Ways out from Between the Rock (Side effects of treatments) and the Hard Place (Suffering Caused by cancer) Geriatric Assessment Direct data on efficacy and safety of treatments in the elderly Drugs with improved efficacy and decreased toxicity ELVIS: Chemo works in the elderly Vinorelbine 30 mg/m 2 days 1 & 8 every 21 days vs supporive care 1- year Survival 14% vs 32% Favorable QoL Overall ELVIS Group. J Natl Cancer Inst. 1999;91:66-72. Issues in 1 st line chemotherapy Two drugs vs. one Bevacizumab (AvasIn) Molecular opions Elderly- specific chemo? Poor PS paients Timeline for Chemo (Every regimen is different; just basic idea here) Regimen 1: Carboplatin + Imaging Partner drug +/- Biologic X 2-3 cycles (cycle is three weeks in most regimens so 6-9 weeks PR or SD PD Treat to 4-6 cycles Change chemo: Carboplatin + Different partner +/- Biologic Observe with imaging until progression Maintenance chemotherapy: 1. Stop carboplatin 2. Continue partner +/- biologic or Just partner or Just biologic or New drug (pemetrexed or erlotinib) PR: Partial response SD: Stable disease PD: Progressive disease Regimen 2: Partner drug +/- Biologic CALGB 9730: Results by Age Stage IIIB/IV NSCLC N = 561 R A N D O M I Z E Carbopla0n AUC = 6 Paclitaxel 225 mg/m 2 Day 1 every 21 days Paclitaxel 225 mg/m 2 Day 1 every 21 days Chemo Age 70Age 70 Resp Rate Median Survival 1- year Survival Paclitaxel 15% 6.8 mo 33% Carbo/ Paxlitaxel 28% 9.0 mo 38% Chemo Age 70 Resp Rate Median Survival 1- year Survival Paclitaxel 21% 5.8 mo 31% Carbo/ Paxlitaxel 36% 8.0 mo 35% Lilenbaum RC, et al. J Clin Oncol. 2004;23: IFCT Trial of Pla0num- Doublet Chemo for Advanced NSCLC in Pa0ents Advanced NSCLC Stage III or IV Age PS 0-2 N = 451 R A N D O M I Z E Carbopla0n day 1 paclitaxel days 1, 8, 15 Every 28 days Vinorelbine or Gemcitabine days 1 & 8 Every 21 days Erlo0nib daily Erlo0nib daily Primary Endpoint: Overall survival Terminated early by Data Safety Monitoring Board Quoix EA, et al. ASCO Abstract 2. Overall Survival and Progression- free survival in IFCT Trial OS PFS HR 0.64 (95% CI , p 0.0001) HR 0.51 (95% CI , p 0.0001) Quoix E, et al. Lancet. 2011;378: Trial Design Eligibility: Stage IIIB/IV NSCLC (malignant effusion) ECOG PS 2 No prior chemotherapy Stable CNS disease Measurable disease Adequate organ func0on (including n=137* GFR 45 ml/min) Signed informed consent Primary endpoint: Overall Survival 1:1 R A N D O M I Z A T I O N Stra0fica0on factors: Stage: IIIB vs IV Age: 70 vs 70 Wt loss: 5% vs 5% Secondary endpoints: Progression- free survival Overall response ate Safety Median age: 65 in both groups 70 years: 35.2% in pemetrexed group 36.8% in pemetrexed + carbo group Arm A Arm B Pemetrexed 500 mg/m2 IV Q3W Pemetrexed 500 mg/m2 IV Q3W + Carbopla0n AUC 5 IV Q3W Pre- medicaions: Vitamin B12: 1mg IM InjecIon Folic Acid: 350-1,000mcg po daily Dexamethasone 4mg po BID the day before, the day of, and the day aper X 4 cycles 5 Overall Survival PS2 trial mos 9.1 vs. 5.6m HR=0.57 ( ) p=.001 Pem + Carbo Pem alone Lilenbaum, ASCO 2012, Abstr 7506 Overall Survival, elderly subset from PS2 trial Lilenbaum, ASCO 2012, Abstr 7506 Lung CancerS Old view Evolving view Adeno- carcinoma EGFR Others MET EML4- ALK ROS1 kras BRAF Non- small cell Lung Cancer Large- cell carcinoma Squamous- cell carcinoma BRAF MET TITF- 1 PIK3CA Carbo/paclitaxel vs. Carbo/Nab- paclitaxel Stage IIIb/IV NSCLC No prior therapy for metastatic disease PS 0-1 N = 1,050 PaIents had no acive brain metastases or grade 2 neuropathy at baseline 1:1 Albumin- bound paclitaxel 100 mg/m 2 d1, 8, 15 Carbopla0n AUC 6 d1 21 Day Cycles No Premedica0on Paclitaxel 200 mg/m 2 d1 Carbopla0n AUC 6 d1 21 Day Cycles With Premedica0on of Dexamethasone + An0histamines Socinski, et al ASCO LBA7511 Carbo/paclitaxel vs. Carbo/Nab- paclitaxel Socinski, et al. JCO 30:17, 2012 Overall Survival ab-p/c P/C N/Events Median OS 74/ months 82/ months * Subgroup analyses exploratory in nature Socinski et al, ASCO 2011, Abstr 7551 Gridelli et al, Clinical Lung Cancer, 13:5, CDDP/Pem vs. CDDP/Gem elderly data (Nonsquamous patients) Toxicity Age 65 Years n 815 (67.2%) Pem Cis (n 390) Gem Cis (n 425) Age 65 Years n 398 (32.8%) Pem Cis (n 215) Gem Cis (n 183) Thrombocytopenia 11 (2.8) 34 (8.0) 11 (5.1) 32 (17.5) Neutropenia 45 (11.5) 107 (25.2) 45 (20.9) 49 (26.8) Anemia 23 (5.9) 43 (10.1) 7 (3.3) 19 (10.4) Leukopenia 15 (3.8) 34 (8.0) 11 (5.1) 12 (6.6) Diarrhea Without Colostomy 6 (1.5) 5 (1.2) 1 (0.5) 4 (2.2) Fatigue 26 (6.7) 15 (3.5) 14 (6.5) 12 (6.6) Febrile Neutropenia 2 (0.5) 12 (2.8) 6 (2.8) 8 (4.4) Nausea 32 (8.2) 17 (4.0) 17 (7.9) 10 (5.5) Vomiting 27 (6.9) 29 (6.8) 11 (5.1) 9 (4.9) HR OS (all favor pem): Subgroup 65:.89 Subgroup 65:.75 Subgroup 70:.83 Subgroup 70:.85 Gridelli et al, Clinical Lung Cancer, 13:5, JMEN elderly data: Pem vs. placebo Toxicity Age 65 Years n 319 (67%) Pem (n 217) Placebo (n 102) Age 65 Years n 157 (33%) Pem (n 103) Placebo (n 54) Neutropenia 6 (2.7) 0 3 (2.9) 0 Anemia 4 (1.8) 0 4 (3.8) 0 Fatigue 6 (2.7) 0 7 (6.7) 1 (1.9) Neuropathy: Sensory 1 (0.5) 0 2 (1.9) 0 Constipation 1 (0.5) (1.9) Distention/Bloating, Abdominal 1 (0.5) (1.9) HR OS (all favor pem): Subgroup 65:.62 Subgroup 65:.87 Subgroup 70:.63 Subgroup 70:.81 Treatment Scheme of ECOG 4599 Non-squamous NSCLC Absence of brain metastasis ECOG PS 0 or 1 Informed consent R A N D O M I Z E Carboplatin (AUC 6) Paclitaxel 200 mg/m2 Bevacizumab 15 mg/kg* Carboplatin (AUC 6) Paclitaxel 200 mg/m2 * Bevacizumab continued as monotherapy for CR/PR/SD after 6 cycles Ramalingam, JCO 26:1, 2008 Efficacy of bevacizumab in Elderly in E4599 (carbo/paclitaxel +/- bev) PFS OS mpfs 4.5PC, 5.9m PCB, HR.76, p.063 mos 12.1 PC, 11.3 PCB, HR.87 Ramalingam, JCO 26:1, 2008 BR.21 (erlotinib vs. placebo in 2 nd line): overall survival HR=0.70 ( ) Stratified log-rank p 0.001 Percentage Erlotinib Placebo At risk Time (months) Erlotinib Placebo Shepherd F, et al. N Engl J Med 2005. BR.21 elderly subset OS Elderly PFS Elderly Toxicity: Greater for older patients compared to younger patients. QOL: Favors erlotinib in elderly and to similar extent as younger patients. Whearley- Price, JCO, 26:14, 2008 Pem vs doce elderly Hanna data: OS 70 years HR 1.02 Pem 7.8m Doce 8m 70 years HR.86 Pem 9.5m Doce 7.7m Weiss et al, JCO 24:27, 2008. The Less Func0onal Elderly PS2 Renal dsyfuncion HepaIc dysfuncion Toxicity G3/4 Toxicity (%) P CP Anemia 3.9 p= Thrombocytopenia Neutropenia 1.0 p= Febrile Neutropenia 2.9 p= Nausea/Emesis Diarhea 2 1 Dyspnea Grade 5 Events 0 p= * * Renal failure; Sepsis; Pneumonia, and Thrombocytopenia Lilenbaum, ASCO 2012, Abstr 7506 Specific Drugs in Elderly Lung CA Drug ExcreIon My opinion on geri friendliness Cispla0n Mostly urine AWFUL Carbopla0n Mostly urine GOOD Paclitaxel Mostly feces Moderate Docetaxel Mostly feces AWFUL Nab- Mostly feces paclitaxel Gemcitabine Mostly renal Pemetrexed Mostly renal VERY GOOD Good VERY GOOD Weiss, Expert Rev. AnIcancer Ther. 12:1, 2012. Promising Clinical Trials for the Elderly ABI NSCLC- 005 LCCC1210 Immunotherapy Ongoing Second Line Phase II trial (LCCC1210) Inclusion: At least 70 years of age Prior non-taxane doublet 1 targeted agent allowed if mutation + PS0-2 Adequate end-organ fxn (relatively liberal criteria) Sites: UNC Cleveland Clinic Upitt Highlands Oncology Rex Hospital Fox Chase Swedish Cancer Institute Bon Secours (pending) NCT NCT Randomized Phase II First Line Trial Carboplatin AUC 6 D1 Nab-paclitaxel 100mg/m 2 D1, 8, 15 Randomization Inclusion 1 st line NSCLC At least 70 years of age Carboplatin AUC 6 D1 Nab-paclitaxel 100 mg/m 2 D1, 8 What we re actually doing in the US: SEER/Medicare Database First Line No chemotherapy 75% (n = 15,786) Chemotherapy 26% (n = 5499) PlaInum, other 19% Doublet, no plainum PlaInum, taxane 48% 6% Single agents 23% Other 5% Survival Survival Chemotherapy SupporIve care HR P Mos Since Diagnosis Mos Since Diagnosis PlaInum- doublet therapy Single Agent HR Mos Since Diagnosis Davidoff AJ, et al. J Clin Oncol. 2010;28: High response rate to MK in 2L PDL1+ paients Garon, ASCO 2014 THANK YOU! For more information: For advocacy:
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