The use of systemic anti-cancer therapy for elderly patients with

metastatic NSCLC

Jared Weiss, MDUniversity of North Carolina

11/14/2014

What is the median age of presentation of NSCLC?

1. 402. 503. 604. 705. 806. 90

Incidence of NSCLC in the US by age at diagnosis

0

5000

10,000

15,000

20,000

25,000

30,000

35,000

<50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 >84

Median ageat diagnosis: 71

Age at diagnosis (y)

No

. of p

atie

nts

Data from SEER Cancer Statistics Review, 1975-2001.

The elderly are untreated…badly

• Misperceptions about expected longevity of the elderly

• Misperceptions about tolerability of treatments in the elderly

• Misperceptions 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 years2. Man 5 years, Woman 7 years3. Man 10 years, Woman 12 years4. Man 12 years, Woman 14 years5. Man 14 years, Woman 16 years

The elderly: In the absence of severe comorbidity, life expectancy is likely driven

by the lung cancerAge Male Life

expectancyFemale life expectancy

0 76 81

20 57 62

40 38 42

60 21 24

65 18 20

70 14 16

75 11 13

80 8 10

85 6 7

90 4 5

95 3 3

100 2 2

SSA acturial life table, cited in Weiss, 2013

“Traditional” view of Quality of Life

Chemo causes:• Nausea• Alopecia• Fatigue• Infections

Therefor, maximize quality of life by avoiding chemo.

An Alternative View of Quality of Life

Symptoms ofprogressivecancer

Symptoms ofprogressivecancer

Side-effectsof therapySide-effectsof therapy

Cancer growth causes:

*Pain*Cough*Shortness of breath*Fatigue*Organ Failure*Thrombosis*Hoarse voice*Nausea*Anorexia

Chemo can alleviate cancer suffering.

Better drugs and better supportive care means more tolerable anti-cancer therapy.

Cancer growth causes:

*Pain*Cough*Shortness of breath*Fatigue*Organ Failure*Thrombosis*Hoarse voice*Nausea*Anorexia

Chemo can alleviate cancer suffering.

Better drugs and better supportive care means more tolerable anti-cancer therapy.

ELVIS: Chemo works in the elderlyVinorelbine 30 mg/m2 days 1 & 8 every 21 days vs supportive care

1-year Survival 14% vs 32% Favorable QoL Overall

ELVIS Group. J Natl Cancer Inst. 1999;91:66-72.

Issues in 1st line chemotherapy

• Two drugs vs. one• Bevacizumab (Avastin)• Molecular options• Elderly-specific chemo?• Poor PS patients

Timeline for Chemo (Every regimen is different; just basic idea here)

Regimen 1:Carboplatin +Partner drug +/-Biologic X2-3 cycles(cycle is threeweeks in mostregimens so6-9 weeks

Regimen 1:Carboplatin +Partner drug +/-Biologic X2-3 cycles(cycle is threeweeks in mostregimens so6-9 weeks

ImagingImaging

PR orSDPR orSD

Treat to 4-6cyclesTreat to 4-6cycles

Observe with imaginguntil progressionObserve with imaginguntil progression

Regimen 2:Partner drug +/-Biologic

Regimen 2:Partner drug +/-Biologic

Change chemo:Carboplatin +Different partner +/-Biologic

Change chemo:Carboplatin +Different partner +/-Biologic

PDPD

Maintenance chemotherapy:1. Stop carboplatin2. Continue partner +/- biologic or Just partner or Just biologic or New drug (pemetrexed or erlotinib)

Maintenance chemotherapy:1. Stop carboplatin2. Continue partner +/- biologic or Just partner or Just biologic or New drug (pemetrexed or erlotinib)

PR: Partial responseSD: Stable diseasePD: Progressive disease

Overall Survival and Progression-free survival in IFCT-0501 Trial

Quoix E, et al. Lancet. 2011;378:1079-1088.

PFSOS

HR 0.64 (95% CI 0.52-0.78, p<0.0001)

HR 0.51 (95% CI 0.42-0.62, p<0.0001)

Pemetrexed 500 mg/m2 IV Q3W

+Carboplatin

AUC 5 IV Q3W

Trial Design

RANDOMIZATION

1:1

n=137*

Arm A

Arm B

Eligibility:• Stage IIIB/IV NSCLC

(malignant effusion)• ECOG PS 2• No prior chemotherapy• Stable CNS disease • Measurable disease• Adequate organ function

(including GFR≥ 45 ml/min)• Signed informed consent

Stratification factors:• Stage: IIIB vs IV • Age: ≥70 vs <70 • Wt loss: ≥5% vs <5%

Pemetrexed 500 mg/m2 IV Q3W

Primary endpoint:• Overall Survival

Secondary endpoints:• Progression-free survival• Overall response ate• Safety

5

Pre-medications:• Vitamin B12: 1mg IM Injection • Folic Acid: 350-1,000mcg po daily• Dexamethasone 4mg po BID the day• before, the day of, and the day after

X 4 cycles

Median age: 65 in both groups>70 years: 35.2% in pemetrexed group 36.8% in pemetrexed + carbo group

Overall Survival—PS2 trial

Lilenbaum, ASCO 2012, Abstr 7506

mOS 9.1 vs. 5.6mHR=0.57 (0.41-0.79)p=.001

Pem + CarboPem alone

Overall Survival, elderly subset from PS2 trial

Lilenbaum, ASCO 2012, Abstr 7506

Stage IIIb/IV NSCLC Stage IIIb/IV NSCLC No prior therapy for No prior therapy for metastatic diseasemetastatic disease

PS 0-1PS 0-1 N N = = 1,0501,050

Albumin-bound paclitaxelAlbumin-bound paclitaxel100 mg/m100 mg/m22 d1, 8, 15 d1, 8, 15Carboplatin AUC 6 d1Carboplatin AUC 6 d121 Day Cycles21 Day Cycles

No PremedicationNo Premedication1:11:1

Paclitaxel 200 mg/mPaclitaxel 200 mg/m22 d1 d1 Carboplatin AUC 6 d1Carboplatin AUC 6 d121 Day Cycles21 Day Cycles

With Premedication of With Premedication of Dexamethasone + AntihistaminesDexamethasone + Antihistamines

Carbo/paclitaxel vs. Carbo/Nab-paclitaxel

Patients had no active brain metastases or ≥ grade 2 neuropathy at baseline

Socinski, et al. 2010 ASCO LBA7511

Socinski, et al. JCO 30:17, 2012

Carbo/paclitaxel vs. Carbo/Nab-paclitaxel

Overall Survival

N/Events Median OS

74/44 19.9 months

82/61 10.4 months

ab-P/C

P/C

* Subgroup analyses exploratory in nature

Socinski et al, ASCO 2011, Abstr 7551

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

NCT01702844

Randomized Phase II First Line Trial

Randomization

Carboplatin AUC 6 D1Nab-paclitaxel 100mg/m2 D1, 8, 15

Carboplatin AUC 6 D1Nab-paclitaxel 100 mg/m2 D1, 8

Inclusion•1st line NSCLC•At least 70 years of age

NCT02151149

CDDP/Pem vs. CDDP/Gem elderly data (Nonsquamous patients)

HR OS (all favor pem):

Subgroup <65: .89 Subgroup >65: .75

Subgroup <70: .83Subgroup >70: .85

Gridelli et al, Clinical Lung Cancer, 13:5, 2012.

JMEN elderly data: Pem vs. placebo

HR OS (all favor pem):

Subgroup <65: .62 Subgroup >65: .87

Subgroup <70: .63Subgroup >70: .81

Gridelli et al, Clinical Lung Cancer, 13:5, 2012.

Treatment Scheme of ECOG 4599

Non-squamous NSCLC

Absence of brain metastasis

ECOG PS 0 or 1

Informed consent

RANDOMIZE

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

Pem vs doce elderly Hanna data: OS

<70 years

>70 years

HR 1.02Pem 7.8mDoce 8m

HR .86Pem 9.5mDoce 7.7m

Weiss et al, JCO 24:27, 2008.

Specific Drugs in Elderly Lung CADrug Excretion My opinion on geri friendlinessCisplatin Mostly urine AWFUL

Carboplatin Mostly urine GOOD; much better than cisplatinPaclitaxel Mostly feces Moderate; better when given weekly

Docetaxel Mostly feces AWFUL; dose reduce from 75mg/m2 to 60mg/m2 when needed

Nab-paclitaxel

Mostly feces VERY GOOD

Gemcitabine Mostly renal GoodPemetrexed Mostly renal VERY GOOD

Weiss, Expert Rev. Anticancer Ther. 12:1, 2012.

6 FEB 2002 11 FEB 2002

2009 Perspective

Mok, NJEM 2009

Crizotinib(n = 173)

Chemotherapy(n = 174)

Events, n (%) 100 (58) 127 (73)

Median, mos 7.7 3.0

HR (95% CI) 0.49 (0.37-0.64)

P value < .0001

Pro

babi

lity

of S

urvi

val W

ithou

t P

rogr

essi

on (

%)

100

80

60

40

20

00 5 10 15 20

25 MosPts at Risk, nCrizotinib

Chemotherapy

Shaw AT, et al. N Engl J Med. 2013;368:2385-2394.

Crizotinib vs Standard Chemotherapy in ALK+ NSCLC (PROFILE 1007): PFS in 2nd or 3rd Line

173174

9349

3815

114

21

00

PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum in Advanced

Untreated NSCLC

Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. Mok T, et al. ASCO 2014. Abstract 8002.

100

80

60

40

0

20

0 5 10 15 20 25 30 35

PF

S (

%)

Crizotinib(n = 171)

Chemotherapy(n = 169)

HR (95% CI) P Value

ORR, % 74 45 < .001

mPFS, mos 10.9 7.0 0.45 (0.35-0.60) < .001

Adv ALK-pos nonsquamous

NSCLC not previously

treated(N = 343)

Crizotinib 250 mg BID

Pemetrexed + Cisplatin orCarboplatin

q3w x 6 cycles

Primary endpoint: PFS

Nivolumab in SqCC Lung

Brahmer, NEJM 2015

Nivolumab in non-SqCC NSCLC

Paz-Ares ASCO 2015

Toxicity of PD1

Brahmer, NEJM 2015

THANK YOU!For more information: www.cancergrace.org

For advocacy: www.lungcancerinitiativenc.org