Maintenance Treatment for Advanced NSCLC

Yvonne Summers PhD, FRCP

ESMO Preceptorship Programme

March 2019

Disclosures

• Advisory board and/or lectures for:

– Roche, BMS, Takeda, MSD, Astra Zeneca,

Abbvie, Pfizer

Milestones in the Palliative Systemic Treatment of NSCLC

1990 2000 2010

Platinum based Chemotherapy (MIC, MVP)

Platinum +3rd Generation Agents

EGFR TKIs(unselected patients)

1st line EGFR TKIs(mutated patients)

Pemetrexed in Non-Squamous NSCLC

Maintenance therapies in NSCLC (Pemetrexed, Erlotinib, Docetaxel, Gemcitabine, Bevacizumab)

Ongoing development - Molecular profiling & development of therapies targeting the biological drivers of cancer:

• Overcoming resistance to EGFR TKI’s, next generation ALK inhibitors (ceritinib, alectinib, brigatenib, lorlatinib)

• NTRK, KRAS pathway (MEK, BRAF, MTOR), PI3K pathway, FGFR, ROS1, RET, HER2,etc

2015

Crizotinib(ALK+patients)

Immunotherapy(anti PD-1, PD-L1)

CrizotinibROS 1

What is Maintenance Therapy?

• Patients receive 1st line treatment for NSCLC (platinum doublet chemotherapy)

• Approximately 40% will progress whilst on treatment and may go on to

receive 2nd line treatment immediately

• Approximately 60% will not progress – what happens next?

Wait until Progression (Will patients be fit enough for

treatment at this point?)

Consider for 2nd line treatment

Consider for Maintenance Therapy

Consider for 2nd line treatment

PD PD

0 25 50 75 100

Socinski, et al. JCO 2002

Belani, et al. JCO 2003

Brodowicz, et al. Lung Cancer 2006

von Plessen, et al. Br J Cancer 2006

Barata, et al. WCLC 2007

Park, et al. JCO 2007

Ciuleanu, et al. Lancet 2009

Pirker, et al. Lancet 2009

Scagliotti, et al. JCO 2008

Fidias, et al. JCO 2009

Percentage

The limitations of ‘watch and wait’

• In studies of NSCLC, around 50% of patients did not receive any second-line therapy

What Maintenance Therapy Will We Consider?

• “Continuation” of a first line drug or “switch” to a new drug

• Immediately after initial 1st line (chemo) therapy

• Providing response to initial therapy is stable disease or

better and PS remains good (0-1)

– Pemetrexed, erlotinib, docetaxel, gemcitabine, bevacizumab

• Excluding:

– EGFR and ALK directed therapy

– Immunotherapy

– Continuing therapy after 2nd line chemo eg nintedanib, ramicirumab

Immediate vs Delayed Docetaxel

Stage IIIB/IVNSCLCPS 0-2N=566

Gem Carbox4

ImmediateDocetaxel

x6 N=153

Delayed Docetaxel

X6N=156

SDCRPR

Fidias et al JCO 2009: 27; 591-98

Immediate versus Delayed Docetaxel

2-3% FN

~30% grade 3/4 neutropaenia

PFS 5.7 vs 2.7 mo (p<0.0001)

OS 12.3 vs 9.7 mo (p=0.085)

Patients who actually received docetaxel in delayed arm had same OS

37% in delayed arm never received treatment

OS for those who did not proceed to randomisation was

4.7 months

Fidias et al JCO 2009: 27; 591-98

JMEN - Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in Advanced NSCLC: Study Design

♦ Stage IIIB/IV NSCLC

♦ ECOG PS 0-1

♦ 4 prior cycles of GEM, DOC,

or PAC+CIS or CARB, with

CR, PR, or SD

♦ Randomization factors:

• Sex

• Performance status

• Disease stage

• Best tumor response*

• Non-platinum drug*

• Brain metastases

Double-blind, Placebo-controlled, Multicenter, Phase III Trial

Primary Endpoint=PFS2:1

Randomization

Pemetrexed IV 500 mg/m2 (d1, q21d)+

BSC (N=441)†

Placebo IV (d1, q21d)+BSC (N=222)†

*With regard to induction therapy. †B12, folate, and dexamethasone given in both arms.

BSC=Best supportive care; CARB=carboplatin; CIS=cisplatin; CR=complete response; d1, q21d=day 1, dose once

every 21 days; DOC=docetaxel; ECOG=Eastern Cooperative Oncology Group; GEM=gemcitabine;

IV=intravenous; PAC=paclitaxel; PR=partial response; SD=stable disease. Ciuleanu et al. Lancet 2009: 374:1432-40

JMEN: Patient Characteristics

Pemetrexed

n=441

%

Placebo

n=222

%

Median Age (years) 60.6 60.4

Males/Females 73/27 73/27

White/Asian/Other* 63/32/4 67/30/3

Disease Stage IIIB/IV 18/82 21/79

Smoker/Never-smoker

73/26 71/28

ECOG PS 0/1 40/60 38/62

Histology

Nonsquamous 74 70

Adenocarcinoma 50 48

Large cell carcinoma

2 5

Other or indeterminate

21 18

Squamous 26 30

*Other includes Hispanic, African, Aboriginal.

ECOG=Eastern Cooperative Oncology Group; PS=performance status.

Ciuleanu et al. Lancet 2009: 374:1432-40

JMEN: Initial Therapy

Pemetrexed

n=441

%

Placebo

n=222

%

Docetaxel-carboplatin 5 3

Docetaxel-cisplatin 2 2

Paclitaxel-carboplatin 30 27

Paclitaxel-cisplatin 6 9

Gemcitabine-carboplatin 24 22

Gemcitabine-cisplatin 33 38

Best response to induction treatment

CR+PR/SD 47/52* 52/48

*Three patients had progressive disease following induction (protocol violation); one patient was unknown.

CR=complete response; PR=partial response; SD=stable disease.

Ciuleanu et al. Lancet 2009: 374:1432-40

Study Treatment

Pemetrexed

n=441

Placebo

n=222

Number of patients treated 434 222

Median number of cycles (range) 5.0 (1-55) 3.5 (1-46)

Dose reductions (%) 5 1

Discontinuations due to drug-related toxicities (%) 5 1

Patients completing ≥6 cycles (%) 48 27

Patients completing ≥10 cycles (%) 23 9

Mean weekly dose intensity (%) 95.76 --

Median follow-up time (months) 12.0 10.1

Ciuleanu et al. Lancet 2009: 374:1432-40

Drug-related Non-laboratory Toxicities*

Pemetrexed (n=441) Placebo (n=222)

All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%)

Fatigue† 24 5 10 <1

Anorexia 19 2 5 0

Infection 5 2 2 0

Diarrhea 5 <1 3 0

Nausea 19 <1 5 <1

Vomiting 9 <1 1 0

Sensory neuropathy 9 <1 4 0

Mucositis/Stomatitis 7 <1 2 0

Rash 2 <1 <1 0

*Updated safety analysis performed 6 months after initial progression-free survival (PFS) analysis. For the purpose of this table, a cut-off of 5% was used

for inclusion of all events where the investigator considered a possible relationship to pemetrexed.†p<0.05 for grade 3 or 4 rate of fatigue between study arms.

Ciuleanu et al. Lancet 2009: 374:1432-40

JMEN: PFS AND OS

0 3 6 9 12 15 18 21 24 27

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PEM 4.5 months

PLA 2.6 months

Time (months)

Pro

gre

ssio

n-f

ree

Pro

bab

ilit

y

HR=0.44 (95% CI: 0.36-0.55)

p<0.0001

CI=confidence interval; HR=hazard ratio; PEM=pemetrexed; PLA=placebo.

*Based on the ITT population, assessed by investigators (N=663).

Progression-free Survival - Nonsquamous

(Intent-to-treat Population)*

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PEM 15.5 months

PLA 10.3 months

HR=0.70 (95% CI: 0.56-0.88)

p=0.002

Su

rviv

al P

rob

ab

ilit

y Time (months)

CI=confidence interval; HR=hazard ratio; PEM=pemetrexed; PLA=placebo.

Overall Survival - Nonsquamous

(Intent-to-treat Population)*

*Based on the ITT population, assessed by investigators (N=663).

Ciuleanu et al. Lancet 2009: 374:1432-40

Histology GroupsMedian OS (months)

PEM PLAp-value

(HR)

Overall population 13.4 10.60.012

(0.79)

Nonsquamous* (n=481) 15.5 10.30.002

(0.70)

Adenocarcinoma (n=328)

16.8 11.50.026

(0.73)

Large cell (n=20)

8.4 7.90.964

(0.98)

Other (n=133)

11.3 7.70.025

(0.61)

Squamous (n=182) 9.9 10.80.678

(1.07)

JMEN: Efficacy by Histology

*Nonsquamous histology included patients with adenocarcinoma, large cell carcinoma, and other/unknown histology (that is, all patients without a diagnosis

of predominantly squamous cell carcinoma).

HR=hazard ratio; OS=overall survival; PEM=pemetrexed; PFS=progression-free survival; PLA=placebo.

There was a statistically significant treatment-by-histology interaction with OS (p=0·033).

Ciuleanu et al. Lancet 2009: 374:1432-40

Copyright © American Society of Clinical Oncology

Scagliotti, G. V. et al. J Clin Oncol; 26:3543-3551 2008

Overall Survival and progression-free survival (PFS) curves for the entire population, patients with nonsquamous histology (adenocarcinoma plus large

cell), and patients with squamous histology

PARAMOUNT: Study Design

Induction Therapy4 cycles, q21d

Continuation Maintenance Therapyq21d until PD

Pemetrexed + BSC

Placebo + BSC

Pemetrexed+ Cisplatin

CR/PR/SDper

RECIST

R2:1

Stratified for:

• PS (0 vs 1)

• Disease stage (IIIB vs IV) prior to induction

• Response to induction (CR/PR vs SD)

♦ Randomized, placebo-controlled, double-blind phase III study ♦ Pemetrexed 500 mg/m2; Cisplatin 75 mg/m2

♦ Folic acid and vitamin B12 administered to both arms

• Previously untreated

• PS 0/1

• Stage IIIB-IV

NS-NSCLC

Pas-Ares et al. Lancet 2012: 13:247-55

PARAMOUNT: Initial Patient Disposition

939 Pts Enrolled

539 Pts Randomized(2:1 Randomization)

Pemetrexed ArmN=359

Placebo ArmN=180

83 Pts Failed Screening

Induction Phase

Maintenance Phase

1022 Patients (Pts) Screened

400 Pts Not Randomized217 Progressive Disease62 Adverse Event (AE)56 Death

29 Study Disease15 AE11 Drug-related AE1 Procedure-related AE

65 Other Reasons548 Patients Eligible for Maint

8 Discontinued Pt Decision 1 Discontinued Phys Decision

Pas-Ares et al. Lancet 2012: 13:247-55

PARAMOUNT: Patient Characteristics

*Protocol violations.

Pemetrexed(N=359)

Placebo(N=180)

Age

Median Age, yrs 61 62

< 65 yrs, % 66 62

Male, % 56 62

Caucasian, % 94 95

Smoker, %

Ever Smoker 76 80

Never Smoker 23 19

ECOG PS, %

0 32 33

1 68 66

2/3* 0.3 1

Pas-Ares et al. Lancet 2012: 13:247-55

PARAMOUNT: Disease Characteristics

Pemetrexed(N=359)

%

Placebo(N=180)

%

Disease stage IV* 91 90

Histology

Adenocarcinoma 86 89

Large cell 7 7

Other Nonsquamous 7 4

Induction Response

CR/PR 44 42

SD 53 53

PD/Unknown† 3 6

* TNM Staging System for Lung Cancer, 5th edition. † Protocol violations.

PARAMOUNT PFS from randomisation

0 3 6 9 12 15 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

PFS: Reassessed at Time of Final OS

PemetrexedPlacebo

Unadjusted HR: 0.60 (0.50-0.73)

Su

rviv

al

Pro

bab

ilit

y

Time (Months)

Patients at Risk

Pem +BSC 359 215 139 97 67 47 32 22 16 10 5 0

Plac + BSC 180 75 33 16 9 7 6 4 2 0 0 0

mPFS 4.4 vs 2.8 months

PARAMOUNT final OS from randomisation

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

0 3 6 9 12 15 18 21 24 27 30 33 36

Time from randomisation (Months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al p

rob

ab

ilit

y

Log-rank P=0.0195Unadjusted HR: 0.78(95% CI: 0.64–0.96)

Pemetrexed

Placebo

Pemetrexed Placebo

Median OS (mo) 13.9 11.0

(95% CI) (12.8–16.0) (10.0–12.5)

Censoring (%) 28.7 21.7

Survival rate (%, 95% CI)

1-year 58 (53–63) 45 (38–53)

2-year 32 (27–37) 21 (15–28)

Pas-Ares et al. Lancet 2012: 13:247-55

PARAMOUNT: Post-discontinuation Therapy

Pemetrexed (N=359)

%*

Placebo (N=180)

%*Patients Receiving Post

Discontinuation Therapy64 72

Erlotinib 40 43

Docetaxel† 32 43

Gemcitabine 10 8

Vinorelbine 8 6

Investigational drug 6 4

Carboplatin 5 4

Paclitaxel 3 3

Pemetrexed 2 4

Cisplatin 1 2*Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown. †Only docetaxel usage differed significantly between arms (P=0.013).

What questions JMEN and PARAMOUNT do not answer

• How does 6 cycles of cisplatin pemetrexed

compare to 4 plus maintenance?

• Is there a benefit to continuing pemetrexed

maintenance after carboplatin pemetrexed?

• Norwegian lung cancer study group – 1st line pemetrexed carboplatin vs gemcitabine carboplatin* – n=427, 4 cycles, PS 0-2, 1EP HRQoL– No difference in HRQoL– OS 7.3 vs 7.0 months

*Groeberg et al, JCO 27:3217-3224, 2009

Pemetrexed Maintenance: Audit of practice

• Retrospective audit from April 2014 - April 2016. • N = 32, PS 0-1, 80%/20% PR/SD to Cisplatin Pemetrexed• Patients received a median of 6 cycles of Pemetrexed (range 1 to 25 cycles), with 14 patients (43.8%) still

on treatment at the time of data analysis.• Majority of patients (n=15/18, 83.3%) discontinued treatment due to progression, and 3 patients stopped

due to Grade 3/4 toxicities• Most did not require dose reduction (n=28/32, 87.5%), and 7 patients (21.9%) required 1 to 2 dose delays. • Of the 18 patients who progressed, 44.4% proceeded to have second line systemic therapies

Median PFS 4.2 monthsN=18

Median OS 14.9 monthsN=32

Lim et al. Lung Cancer 2016:S0169-5502(17)

SATURN a double-blind, randomised, phase III study of maintenance erlotinib versus placebo following non-

progression with 1st-line platinum-based chemotherapy in patients with advanced NSCLC

Stratification factors:

• EGFR IHC (positive vs negative vsindeterminate)

• Stage (IIIB vs IV)

• ECOG PS (0 vs 1)

• CT regimen (cis/gem vs carbo/doc vs others)

• Smoking history (current vs former vs never)

• Region

1:1

Chemonaïve advanced

NSCLCn=1,949

Non-PDn=889

4 cycles of 1st-line

platinum-based doublet*

Placebo PD

Erlotinib150mg/day

PD

Mandatory tumour sampling

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

carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

EGFR = epidermal growth factor receptor; IHC = immunohistochemistry

Co-primary endpoints:

� PFS in all patients

� PFS in patients with EGFR IHC+ tumours

Secondary endpoints:

� Overall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)

Cappuzzo et al. Lancet Oncol. 2010 Jun;11(6):521-9

SATURN – OS and PFS

Overall Survival

Progression Free Survival

SATURN: PFS and OS in EGFR mutation group with SD on 1st line chemotherapy

Erlotinib (n=15)

Placebo (n=15)

HR=0.48 (0.14–1.62) Log-rank p=0.2285

22.1

Su

rviv

al

rate

(%

)

100

80

60

40

20

0

Time (months)

OS

Su

rviv

al

rate

(%

)

100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

Erlotinib (n=15)

Placebo (n=15)

HR=0.03 (0.00–0.21) Log-rank p<0.0001

11.2 3.1

PFS

Data are not mature; 67% of patients with EGFR mutation+ disease in the placebo arm received a

0 3 6 9 12 15 18 21 24 27 30 33 36

Cappuzzo F et al Lancet Oncology. 2010;11(6):521-529

IUNO: randomised double-blind placebo controlled trial of maintenance erlotinibcompared to erlotinib on progression

(in patients without EGFR mutations)

1:1

Chemonaïveadvanced

NSCLC

Non-PDN=643

4 cycles of 1st-line

platinum-based doublet*

Placebo Erlotinib

ErlotinibChemo/

BSC

EGFR-activatingmutation in exon 19

or L858R NOT present

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel

cisplatin/vinorelbine; carboplatin/gemcitabine;

carboplatin/docetaxel, carboplatin/paclitaxe, cisplatin /pemetrexed,

carboplatin/pemetrexed

EGFR = epidermal growth factor receptor

Primary endpoint:

� Overall Survival (OS)

Secondary endpoints:

� PFS

� RR

� DCR

Cicenas et al J.Lungcan.201610.007s

IUNO – OS and PFS

• Maintenance erlotinib did not improve OS or PFS in patients without an EGFR activating mutation

• mOS 9.7 vs 9.5 months HR=1.02, 95% CI 0.85-1.22, p=0.82

• PFS HR 0.94, 95% CI 0.80-1.11, p=0.48

• Erlotinib is not recommended for 1st line maintenance treatment in patients without an EGFR activating mutation

Cicenas et al J.Lungcan.201610.007

Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC

0502 phase III study

Perol et al. JCO 30: 3516-3524, 2012

Study aim

Two primary objectives – to determine whether maintenance

gemcitabine (Gem) is better than observation and whether sequential

erlotinib is better than observation. Primary endpoint: PFS from

randomisation by independent panel review. Secondary endpoints: OS,

safety of maintenance treatment, symptom control.

Study population

•Stage IIIB/IV NSCLC

•PS 0-1, 18-70 years, brain metastases allowed

•No evidence of disease progression after 4 cycles of Gem-Cis induction CT

•Stratification based on gender, histology (adenocarcinoma vs other),

smoking status, centre and response vs stabilisation to induction CT

Pemetrexed

administered

as 2nd line

treatment in

all 3 arms

Perol et al. JCO 30: 3516-3524, 2012

IFCT-GFPC 0502 phase III study

Patient characteristics

Observation

(n=155)

Gemcitabine

(n=154)

Erlotinib

(n=155)

Median age, years 59.8 57.9 56.4

Male/Female, % 73/27 73/27 73/27

ECOG PS 0/1 at inclusion, % 50/50 47/53 52/48

ECOG PS 0/1/2 at randomisation, % 44/53/3 40/54/6 38/56/6

Stage IIIB/IV, % 9/91 9/91 7/93

Brain metastases, % 0.6 3.2 1.3

Ever/never smoker, % 62/38 62/38 62/38

Adenocarcinoma/ squamous/other,

%

67/19/14 66/22/12 63/17/20

Response to induction CT: OR/SD, % 53/47 53/47 53/47

Perol et al. JCO 30: 3516-3524, 2012

Drug-related adverse events

Observation

(n=155)

Gemcitabine

(n=154)

Erlotinib

(n=155)

≥1 drug-related grade 3/4 AE, % 2.6 27.9 15.5

Grade 3/4 AE .

Anaemia, % 0.6 2.6 1.3

Neutropenia, % 0.6 20.8 0.6

Thrombopenia, % 0 6.5 0

Rash, % 0 0 9.0

Diarrhoea, % 0 0.6 0.6

Anorexia, % 0.6 0.6 1.3

Asthenia, % 0 1.3 2.6

Drug-related deaths 0 2* 0

*1 death due to bacterial pneumonia, 1 death caused by pneumonia and renal failure.

Perol et al. JCO 30: 3516-3524, 2012

Results: PFS by independent review –Gemcitabine vs Observation

Obs

(n=152)

Gem

(n=149)

Median PFS, months 1.9 3.8

PFS at 3 months, % 30.3 55.0

PFS at 6 months, % 8.6 22.1

1.0

0.8

0.6

0.4

0.2

0.0

HR=0.56 (0.44-0.73)

Log-rank test, p<0.001

Observation

Gemcitabine

0 5 10 15 20 25 30 35 40

Time (months)

Pro

ba

bil

ity

Perol et al. JCO 30: 3516-3524, 2012

Results: PFS by independent review –

Erlotinib vs ObservationObs

(n=152)

Erl

(n=153)

Median PFS, months 1.9 2.9

PFS at 3 months, % 30.3 35.3

PFS at 6 months, % 8.6 16.3

1.0

0.8

0.6

0.4

0.2

0.0

HR=0.69 (0.54-0.88)

Log-rank test, p=0.003

Observation

Erlotinib

0 5 10 15 20 25 30 35 40

Time (months)

Pro

ba

bil

ity

Perol et al. JCO 30: 3516-3524, 2012

Results: Overall Survival

1.0

0.8

0.6

0.4

0.2

0.0

Gemcitabine vs observation

HR=0.89 (0.69-1.15) p=0.39

Erlotinib vs observation

HR=0.87 (0.68-1.13) p=0.30

Observation median 10.8 mo

Gemcitabine median 12.1 mo

Erlotinib median 11.4 mo

0 5 10 15 20 25 30 35 40

Time (months)

Pro

ba

bil

ity

Perol et al. JCO 30: 3516-3524, 2012

AVAPERL RESULTS

Bevacizumab + Pemetrexed

N=125

BevacizumabN=128

p-value

PFS

(median, months)

7.4 3.7p<0.0001

HR 0.57

OS

(median, months)

15.7 13.2P=0.29

HR 0.87

Berlesi et al. JCO 31:3004-3011, 2013, Ann Oncol 2014; 5; 1044-52

• Maintenance pemetrexed in combination with bevacizumab is associated

with improvement in PFS for patients who have had first line treatment with

Cisplatin+Pemetrexed and Bevacizumab

• Should the control arm been pemetrexed alone as there is more single

agent activity associated with this agent?

Patel et al. JCO 31: 4349-4357, 2013

PointBreak: PFS and OS in patients

who went onto receive maintenance

Patel et al. JCO 31: 4349-4357, 2013

Summary of Maintenance Trials

Trial PFS (months) OS (months)

Fidias (Docetaxel) 5.7 vs 2.7 p<0.001 12.3 vs 9.7 p=0.0853*

JMEN (Pemetrexed) 4.5 vs 2.6 HR 0.44 15.5 vs 10.3 HR 0.70

PARAMOUNT

(Pemetrexed)

4.4 vs 2.8 HR 0.62 13.9 vs 11.0 HR 0.78

SATURN (Erlotinib) 3.0 vs 2.8 HR 0.71 12 vs 11 HR 0.81

IUNO (Erlotinib, EGFR

wt)

3.0 vs 2.8 HR 0.94* 9.7 vs 9.5 HR1.02*

Perol (Gemcitabine) 3.8 vs 1.9 HR 0.56 12.1 vs 10.8 HR 0.89*

AVAPERL (Beva+Pem

vs Beva)

7.4 vs 3.7 HR 0.57 15.7 vs 13.2 HR 0.87*

POINTBREAK (PemCBeva vs PacCBeva)

6.0 vs 5.6 HR 0.83(8.6 vs 6.9 in those who got to

maintenance)

12.6 vs 13.4 HR1.00*(17.7 vs 15.7 in those who

got to maintenance)

* Not statistically significant

Guidelines for Maintenance TreatmentGuideline Recommendation

ESMO 2018 PS 0-1, after 4 cycles platinum

doubletGemcitabine continuationPemetrexed for NS-NSCLC with

SD/PR, switch or continuation+/- bevacizumab if given before

ASCO 2017 Pemetrexed for NS-NSCLC with

SD/PR, switch or continuation

Chemotherapy switch for all histologies

Bevcizumab (not with pem)

(Erlotinib not reviewed in 2017)

NCCN 2018 (2019) NS-NSCLC:

Pemetrexed switch

Pemetrexed, gemcitabine,

bevacizumab +/- pemetrexed continuationSq-NSCLC: gemcitabine continuationdocetaxel switch

Summary

• Rapidly changing therapeutic environment with PD-L1 expression

now changing first line therapy – (patients now receiving PD-1/PD-

L1 inhibitors + chemo for up to 2 years)

• Maintenance treatment is an option for patients of good PS (0-1)

after 4 cycles of platinum doublet chemotherapy with stable

disease or better

• Needs discussion with patient:

o some patients want a break from treatment

o Increased toxicity burden, increased frequency of follow up

visits

• Clinically meaningful improvements in PFS and OS

• Options include:

o Pemetrexed switch or continuation for NS – NSCLC – most

robust data (££)

o Less robust evidence for gemcitabine (£)

o Evidence for docetaxel but toxicity is a barrier (£)

o Erlotinib no longer an option for patients without EGFR

activating mutations

o Continuation bevacizumab +/- pemetrexed (£££)

Questions?