maintenance therapy for advanced nsclc · bevacizumab pemetrexed cisplatin q3w previously untreated...

Maintenance Therapy for Advanced NSCLC

Suresh S. Ramalingam, MDProfessor of Hematology and Medical Oncology

Assistant Dean for Cancer ResearchEmory University School of Medicine

Deputy Director, Winship Cancer Institute

Disclosures

• Scientific advisory board meetings

– Astra Zeneca, Amgen, Abbvie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Genentech, Merck, Novartis.

Timing of Second-Line Therapy in Advanced NSCLC: the Dawn of “Maintenance”

Platinum-based doublet

4 cycles

(Bevacizumab—ATLAS)Delayed second-line therapy

• Docetaxel (Fidias)

• MD Choice (JMEN)

• MD Choice (SATURN)

• MD Choice (ATLAS)

Immediate second-line therapy

• Docetaxel (Fidias)

• Pemetrexed (Ciuleanu)

• Erlotinib (SATURN)

• Erlotinib (ATLAS)Chemotherapy-

naïvestage IIIB/IV

NSCLC

Is this “maintenance,” “sequential,” “prolonged duration,” or just earlier use of effective second-line therapy?

Stable or responding disease

RANDOMIZE

ECOG 4599: Chemo +/- Bevacizumab in NS-NSCLC (1st-Line)

Sandler et al , NEJM 2006

Induction

Pem + cisplatin d1, q21d x 4

CR, PRSD

2:1

Patient eligibility:- Nonsquamous NSCLC- No prior systemic therapy

Continuation maintenance (until PD)

Pemetrexed + BSC d1, q21d (n = 359)

Continuation maintenance (until PD)

Placebo + BSC d1, q21d (n = 180)

R

PARAMOUNT Phase III Study of Pemetrexed Continuation—Maintenance

• Randomized, placebo-controlled, double-blind, phase III

• Pemetrexed: 500 mg/m2, cisplatin, 75 mg/m2• Folic acid, vitamin B12 administered in both arms• Stratification

– PS (0 vs. 2)– Stage (IIIB vs. IV) prior to induction– Response to induction (CR/PR vs. SD)

Paz-Ares LG et al. J Clin Oncol. 2013;31:2895-2902.

SD = stable disease.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Surv

ival

pro

bab

ility

Unadjusted HR = 0.60 (0.50–0.73)

PemetrexedPlacebo

Time (months)

PFS: reassessed at time of final OS

18 21 24 27 30 33

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Surv

ival

pro

bab

ility

Unadjusted HR = 0.62 (0.49–0.79)

PemetrexedPlacebo

Time (months)

PFS: primary efficacy endpoint

PARAMOUNT: PFS From Randomization


PARAMOUNT: Final Overall Survival from Randomization


Patients at risk

Pem + BSC 359 333 272 235 200 166 138 105 79 43 15 2 0

Placebo + BSC 180 169 131 103 78 65 49 35 23 12 8 3 0

Time from randomization (months)0 3 6 9 12 15 18 21 24 27 30 33 36

Surv

ival

pro

bab

ility

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pem Placebo

OS median (mos.)(95% CI)

13.9(12.8–16.0)

11(10.0–12.5)

28.7 21.7

Survival rate (%) (95% CI)

1-year 58 (53–63) 45 (38–53)

2-year 32 (27–37) 21 (15–28)

HR = 0.78; P=0.0195

JMEN: Phase III Trial of Maintenance Pemetrexed in Advanced NSCLC

Ciuleanu T et al. Lancet. 2009;374:1432-1440.

Primary endpoint: PFS

2:1

B12, folate, and dexamethasone are given

in both arms.

RANDOMIZE

Pemetrexed 500 mg/m2 q3 weeksBest supportive care

N = 441

Placebo q3 weeks

Best supportive careN = 222

Stage IIIB/IV NSCLCPS 0/1

4 prior cycles of gemcitabine, docetaxel, or

paclitaxel plus cisplatin, or carboplatin

with CR, PR, or SD

JMEN Efficacy: Maintenance Pemetrexed vs. Placebo

Ciuleanu T et al. Lancet. 2009;374:1432-1440.

Histology Pemetrexed Placebo P-value

Median PFS, months

All

Nonsquamous (n = 482)

Adenocarcinoma (n = 329)

Large cell (n = 20)

Other (n = 133)

Squamous (n = 181)

4.0

4.4

4.6

4.5

4.1

2.4

2.0

1.8

2.7

1.5

1.6

2.5

<0.0001

<0.0001

<0.0001

0.1040

0.0002

0.8960

Median OS, months

All

Nonsquamous (n = 482)

Adenocarcinoma (n = 329)

Large cell (n = 20)

Other (n = 133)

Squamous (n = 181)

13.4

15.5

16.8

8.4

11.3

9.9

10.6

10.3

11.5

7.9

7.7

10.8

0.012

0.002

0.026

0.964

0.025

0.678

Erlotinib 150 mg/day

Placebo

PD

PD

Treatment-naïve advanced NSCLC

N = 1949

Stratification factors: • EGFR IHC (+ vs. – vs. int)• Stage IIIB vs. IV• ECOG PS 0 vs. 1• CT regimen• Smoking history• Region

Primary endpoint: PFS in all and EGFR IHC+ patients

Secondary endpoints: OS in all and IHC +/– patients, biomarker analysis, safety, QoL, time to symptomatic progression

1:1

4 cycles of first-line

platinum-based

doublet*

Non-PDN = 889

Maintenance Therapy in NSCLC:The SATURN Study

Cappuzzo F et al. Lancet Oncol. 2010;11:521-529.

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/ vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/ paclitaxel.

R

QoL = quality of life.

About 50% of all tumors were able to be sequenced for EGFR mutation.

Time (weeks)

Pat

ien

ts w

ith

ou

t p

rogr

ess

ion

(%

)

Pat

ien

ts w

ith

ou

t p

rogr

ess

ion

(%

)

PFS: wild-type EGFR PFS: mutated EGFR

HR = 0.78 (0.63–0.96)P=0.0185

HR = 0.10 (0.04–0.25) P<0.0001

0

20

40

60

80

100

0 8 16 24 32 40 48 56 640

20

40

60

80

100

Erlotinib (N = 22)

Placebo (N = 27)

Erlotinib (N = 199)

Placebo (N = 189)

Time (weeks)

0 8 16 24 32 40 48 56 64

SATURN: PFS by EGFR Mutation Status

Cappuzzo F et al. Lancet Oncol. 2010;11:521-529.

IFCT Trial

Advanced NSCLC

18-70 yrs

PS0/1

N=834

CR/PR/SD

with cis/gem

Gemcitabine

N=154

Erlotinib

N=155

Observation

N=155

Perol M et al. J Clin Oncol. 2012;30(28):3516-3524.

IFCT Trial: PFS

Gemcitabine maintenance versus observation Erlotinib maintenance versus observation


IFCT Trial: Overall Survival

Gemcitabine maintenance versus observation Erlotinib maintenance versus observation


Salvage Therapy in IFCT


Survival for Patients Actually Receiving Docetaxel on Immediate and Delayed Arms

Fidias PM et al. J Clin Oncol. 2009;27:591-598.

12.5 12.5

0

2

4

6

8

10

12

14

Immediate

Delayed

N 145 98

MST

(m

on

ths)

RANDOMIZE

Bevacizumab pemetrexedcisplatin q3w

Previously untreated stage IIIB/IV nonsquamous

NSCLC

Bevacizumab (7.5mg/kg) q3w

Bevacizumab(7.5mg/kg) +

pemetrexed q3w

PD

PD

4 cycles of induction therapy (n = 373)

Maintenance therapy (n = 244)

1:1

Criteria: CR/PR/SD (RECIST)

Primary endpoint: PFSSecondary endpoints: OS, safety

• Open-label, randomized, multicenter, phase III study

• Stratified by gender, smoking status (never smoker vs. past/current smoker), and disease control after 4 cycles

AVAPERL: Phase III Study of Bevacizumab Maintenance ± Pemetrexed After Bevacizumab First-

Line Therapy in NSCLC

Barlesi F et al. J Clin Oncol. 2013;31:3004-3011.

Bev

maintenance

(n = 125)

Bev + Pem

maintenance

(n = 128)

Hazard

ratio P-value

Median PFS 6.6 mo 10.2 mo 0.50 <0.001

Median OS 15.7 mo 19.2 0.75 0.23

Best ORR 50% 55.5% — 0.88

Median DOR 5.7 mo 9.2 mo 0.53 0.006

Median duration of

disease control 4.9 mo 7.8 mo 0.52 <0.001

AVAPERL: Efficacy of Maintenance Bevacizumab With or Without Pemetrexed in Nonsquamous NSCLC

Barlesi F et al. J Clin Oncol. 2013;31:3004-3011.

All patients received cisplatin/pemetrexed/bevacizumab as first-line treatment.

ECOG 5508: Bevacizumab vs. Pemetrexed vs. Bevacizumab + Pemetrexed Maintenance

First-Line Advanced NSCLC

ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT01107626.

Advanced NSCLC nonsquamous

No prior treatment

CarboplatinPaclitaxel

Bevacizumabq3wk

× 4 cycles

RANDOMIZATION

Bevacizumabq3wk

Pemetrexedq3wk

Bevacizumab + Pemetrexed

q3wk

Response or stable disease

N = 1515

Primary endpoint: OSSecondary endpoints: PFS, ORR, toxicity

Opened August 2010Sponsor: ECOGPI: S. Ramalingam

Percent Eligibility for Therapy Beyond First-Line Chemotherapy Upon Progression

0 25 50 75 100

Patients Receiving Second-Line Therapy (%)

Fidias et al, 2009

Scagliotti et al, 2008

Pirker et al, 2008

Ciuleanu et al, 2008

Park et al, 2007

Barata et al, 2007

von Plessen et al, 2006

Brodowicz et al, 2006

Belani et al, 2003

Socinski et al, 2002

Gridelli et al, 2010

Advantages of Maintenance Therapy

• All patients with advanced NSCLC experience progression despite extent of response to first line therapy

• Maintenance therapy has the potential to delay progression and potentially improve survival

• Patients are in a better overall condition to tolerate additional therapy than in the second line setting

• Ability to administer a mechanistically distinct agent after first line therapy

What is an Ideal Maintenance Therapy Agent?

• Efficacious (PFS & Survival)

• Tolerated well

• Ability to administer easily in the outpatient setting

• No cumulative toxicity

• Affordable

Potential Candidates for Maintenance Therapy

• Heavy disease burden

• Symptomatic disease

• Good performance status (0/1)

• Good tolerance of prior chemotherapy

• EGFR mutation or ALK translocation

Immunotherapy as Maintenance

• PD-1/PDL-1 inhibitors are given until progression

• Optimal duration of therapy?

• When given in combination with chemo, CPI are continued as maintenance

– Does the maintenance phase add to the benefit

Key Questions

• Role of maintenance therapy in patients that receive first-line immunotherapy

• How does immunotherapy compare to chemotherapy in maintenance setting

• Combination of chemo-immuno maintenance therapy?

Conclusions

• Maintenance therapy improves survival in advanced NSCLC

• Decision to administer maintenance therapy should be made based on

– Symptom burden

– Disease burden

– Patient preference

– Tolerance of prior therapy

– Genotype

maintenance therapy for advanced nsclc · bevacizumab pemetrexed cisplatin q3w previously untreated...

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