Dr Ross Soo, MB BS, PhD, FRACP

Department Haematology-Oncology, National University Hospital

National University Cancer Institute, Singapore

National University Health System

ESMO Preceptorship Programme, Non-small cell lung cancer, Singapore, 20-21 November 2019

Systemic therapy for non-oncogene addicted NSCLC

Disclosures

• Advisory Board: Astra-Zeneca, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan

• Research grant: Astra-Zeneca, Boehringer Ingelheim

Systemic therapy in non-driver addicted NSCLC:

• First-line treatment of NSCLC without actionable oncogenic driver, with contraindications to use of immunotherapy

• 1st line management of non-squamous NSCLC

• Maintenance

• Anti-angiogenic agents

• EGFR inhibitors

• 1st line management of squamous NSCLC

General approach

• The treatment strategy should consider the histology, molecular pathology, age, PS, comorbidities and the patient’s preferences

• Systemic therapy should be offered to all stage IV patients with PS 0–2

In the beginning…line chemotherapy is better than BSC

NSCLC Meta-Analyses Collaborative Group. JCO 2008

2,714 patients,16 RCTs

Chemotherapy improves OS vs BSC: HR 0.77

One-year OS: 29% from 20%

ESMO guidelines:

Chemotherapy with platinum doublets should be considered in

all stage IV NSCLC patients without an actionable oncogenic

driver, without major comorbidities and

PS 0–2

Platinum-based doublets are the recommended chemotherapy

option in all stage IV NSCLC patients with no contraindications

to platinum compounds

Planchard ESMO guidelines 2019

• Which chemotherapy?• Platinum doublet with 3rd generation drugs (paclitaxel, gemcitabine, docetaxel,

vinorelbine) have comparable efficacy

• Cisplatin or carboplatin?• Cisplatin:

• higher ORR but paclitaxel or gemcitabine + a platinum agent in both arms had equivalent response.

• more nausea or vomiting

• Carboplatin: more thrombocytopenia and neurotoxicity

• Six cycles or fewer?• Six cycles: longer PFS, higher toxicity• Recommendation: 4 cycles +/- maintenance (I, A) and maximum of 6 cycles (I, B)

nab-Paclitaxel and Carboplatin : higher ORR, less neurotoxicity

Socinski JCO 2012

ESMO Guidelines:

Nab-paclitaxel combination can be considered an option in advanced NSCLC

patients, particularly in patients with:

1. greater risk of neurotoxicity

2. preexisting hypersensitivity to paclitaxel

3. or contraindications to standard paclitaxel premedication

1L treatment of advanced non-Squamous NSCLC without driver oncogenes (NSCC)

• Pemetrexed-based chemotherapy is preferred to gemcitabine- or docetaxel-based combinations in patients with non-squamous tumours

• Pemetrexed is restricted to NSCC in any line of treatment line

• Carboplatin and pemetrexed can be an option in patients with a contraindication to cisplatin

Planchard Ann Oncol 2018

Pemetrexed platinum and gemcitabine platinum have differential efficacy based on histology: JMDB

Cisplatin/ Pem superior in non-SCC Cisplatin/gemcitabine superior in SCC

OS in Nonsquamous NSCLC

Median (95% CI)

11.8 (10.4-13.2)

10.4 (9.6-11.2)

Adjusted HR (95% CI)

0.81 (0.70-0.94) P = .005

OS in Squamous NSCLC

Median (95% CI)

9.4 (8.4-10.2)

10.8 (9.5-12.1)

Adjusted HR (95% CI)

1.23 (1.00-1.51) P = 0.05

Scagliotti J Clin Oncol 2008

Survival Time (Mos) in All Patients

Su

rviv

al P

rob

ab

ility

0

0.2

0.6

1.0

0.4

0.8 CP

CG

0 6 12 18 24 30

Median (95% CI)

10.3 (9.8-11.2)

10.3 (9.6-10.9)

Adjusted HR (95% CI)

0.94 (0.84-1.05)CP vs CG

Intention to treat (all histologies):

no difference between CP and GC

Nonsquamous NSCLC Squamous NSCLC

Paclitaxel + carboplatin +

bevacizumab x6 cycles

q3w

Paclitaxel + carboplatin

q3w x6 cycles

Stage 4, NSCLC

Treatment naïve

ECOG PS=0-1

N=878

OS

Safety

Addition of bevacizumab to chemotherapy: ECOG 4599

Sandler NEJM 2006

Bevacizumab until PD,

intolerable toxicity

ECOG4599: addition bevacizumab to carboplatin/ paclitaxel improves OS

Carboplatin / paclitaxel + bevacizumab

Carboplatin / paclitaxel

0

20

40

60

80

100O

ve

rall

su

rviv

al

(%)

0 4236302418126

HR (95% CI) = 0.79 (0.67, 0.92), p=0.003

OS= 12.3 vs 10.3 months

Time (months)

Sandler NEJM 2006

PFS: 6.2m vs 4.5m

ORR: 35% vs 15%

Bevacizumab may be offered in the absence of contraindications

in eligible patients with advanced NSCC (bevacizumab should be

given until progression) [I, A]

Other issues with bevacizumab

• Can I combine it with another chemotherapy other than paclitaxel?

• Is CNS mets a contraindication?

Other issues with bevacizumab

• Can I combine it with another chemotherapy?• Bevacizumab might therefore be considered with platinum-based regimens

beyond paclitaxel/carboplatin in the absence of contraindications [II, B].

• Is CNS mets a contraindication?• Treatment with bevacizumab has also shown encouraging efficacy and

acceptable safety in patients with NSCC and asymptomatic, untreated brain metastases

• EMA removed label restriction on March 25, 2009, to allow patients with untreated CNS metastases to receive bevacizumab

Maintenance therapy

• Factors to be considered:

• Histology

• Residual toxicity after 1L chemotherapy

• Response to platinum doublet

• Performance status

• Patient preference

• Types of maintenance:

• Continuation maintenance :

• use of an agent that was included in 1L treatment

• Switch maintenance:

• introduction of a new agent after four cycles of platinum-based chemotherapy

Continuation maintenance therapy: pemetrexed after x4 cycles cisplatin/ pemetrexed (PARAMOUNT)

Paz-Ares Lancet Oncol 2012, JCO 2013

Improvement in PFS Improvement in OS

ESMO guidelines:

Continuing pemetrexed following completion of 4 cycles of first-line

cisplatin/pemetrexed ChT is, therefore, recommended in patients with

NSCC, in the absence of progression after first-line ChT and upon

recovery from toxicities from the previous treatment [I, A].

Switch maintenance therapy: pemetrexed after x4 cycles platinum based chemotherapy (JMEN).

OS and PFS more pronounced in non-squamous subset

PFS benefit in non-squamous OS benefit in non-squamous

Ciuleanu Lancet 2009

IUNO: 1L maintenance vs 2L erlotinib in NSCLC without EGFR mutations.

Cicenas Lung Cancer 2016

Switch maintenance

Study Induction Maintenance PFS (HR, p value) OS (HR)

Fidias Carboplatin/

gemcitabine x4

Docetaxel

Observation

5.7m (p<0.001)

2.7m

12.3m (p=0.09)

9.7m

SATURN Platinum doublet x4 Erlotinib

Placebo

12.3w (0.71, p<0.001)

11.1w

12.0m (0.81, p=0.0088)

11m

IFCT-GFPC

0502

Cisplatin/

gemcitabine x4

Gemcitabine

Erlotinib

Observation

3.8m

2.9m

1.9m (0.69, p=0.003)

12.1m (0.89, p=0.39)

11.4m (0.87, p=0.3)

10.7m

Fidias JCO 2009, Cappuzzo Lancet Oncol 2010, Perol JCO 2012

ESMO guidelines:

NSCC and PS 0–1, pemetrexed switch maintenance should be

considered in patients with disease control after x4 non-

pemetrexed containing platinum-based chemotherapy

Maintenance treatment with erlotinib is only recommended for

NSCC patients with an EGFR-sensitising mutation [III, B].

How about maintenance EGFR TKIs in unselected patients?

Study Induction Maintenance PFS (HR, p value) OS (HR)

SATURN Platinum doublet x4 Erlotinib

Placebo

12.3w (0.71, p<0.001)

11.1w

12.0m (0.81, p=0.0088)

11m

WJTOG Platinum doublet x3

Platinum doublet x6

Gefitinib

Observation

4.6m (0.68 p<0.001)

4.3m

13.7m (p=ns)

12.9m

INFORM Platinum doublet x4 Gefitinib

Placebo

4.8m (0.69, p=0.003)

2.6m

18.7m (p=ns)

16.9m

Cappuzzo Lancet Oncol 2010, Takeda JCO 2010, Zhang Lancet Oncol 2012

1L treatment of advanced Squamous NSCLC

• Platinum-based doublets with a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended in advanced SCC patients without major comorbidities and PS 0–2

Planchard Ann Oncol 2018

Planchard Ann Oncol 2018

ECOG PS 2: carboplatin+ pemetrexed

• platinum-based (preferably carboplatin) doublets should be considered in eligible PS 2 patients [I, A].

• Pemetrexed 500 mg/m2 vs carboplatin AUC 5 + pemetrexed 500 mg/m2 x4 cycles

OS: 9.3m vs 5.3m

HR: 0.62, 95% CI, 0.46 to 0.83

Zukin JCO 2013

Poor PS

• Single-agent ChT with gemcitabine, vinorelbine, docetaxel [I, B] or pemetrexed (restricted to NSCC) [II, B] is an alternative treatment option

• MILES: VNR/ gemcitabine no better OS than gemcitabine or vinorelbine but more AEs

ELVIS JNCI 1999, Gridelli JNCI 2003

ELVIS study, n=191

ECOG PS 2+

• Chemotherapy prolongs survival and improves QoL in NSCLC patients with PS 2 when compared with BSC [I, A]

• Increased toxicities

Bronte CROH 2015

Elderly: IFCT-0501

• Age: 70–89 years

• WHO PS status: 0–2

• Carboplatin AUC 6 day 1 + paclitaxel 90 mg/m2 day 1, 8, 15 q4w x4 cycles vs vinorelbine 25 mg/m2 day 1, 8 or gemcitabine 1150 mg/m2 day 1, 8 q3w x5 cycles

• Longer PFS and higher ORR at 6w (27% vs 10%)

• More G3–4 neutropenia, febrile neutropenia, thrombopenia, anaemia and sensory neuropathy

Quoix Lancet 2011

10.3m vs 6.2m

How about using 1st line EGFR TKIs in unselected patients?

Gridelli JCO Lung Cancer 2012

In unselected patients, 1st line erlotinib followed by

chemotherapy is inferior to 1st line chemotherapy

followed by erlotinib

Squamous cell NSCLC

• Platinum-based doublets with the addition of a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended in advanced SCC patients without major comorbidities and PS 0–2 [I, A]

Phase III 1st line Gem/ CDDP +/- necitumumab in SCC (SQUIRE)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Months

OS

(%

)

OS

Cisplatin/gemcitabine + necitumumab

Cisplatin/gemcitabine

Pts censored, n (%)

Median OS, mos (95% CI)

Stratified P value (log rank)

Stratified HR (95% CI)

127 (23)

11.5 (10.4-12.6)

.01

0.84 (0.74-0.96)

Cisplatin/ Gemcitabine +

Necitumumab

Cisplatin/ Gemcitabine

106 (19)

9.9 (8.9-11.1)

ORR: 31.2% vs 28.8% (NS)

DCR: 81.8% vs 77.0% (P = .04)

PFS HR: 0.85 (P = .02)

Exploratory EGFR H-score analysis: NS

Thatcher Lancet Oncol 2015

ESMO guidelines:

the addition of necitumumab to cisplatin

and gemcitabine has not been adopted as a standard…and

its use should be carefully evaluated

2nd line therapy

Docetaxel standard 2nd line therapy until recently• Combination chemo has no OS benefit

over single-agent.

• Docetaxel: • Improvement in OS vs BSC • Similar efficacy, but more favourable

tolerability for weekly docetaxel schedule

• Pemetrexed:• Comparable OS to docetaxel• Lower rates of neutropenia, alopecia and GI

toxicity

• Docetaxel + antiangiogenic therapy• LUME Lung 1• REVEL• ULTIMATE

• Immune checkpoint inhibitors

Pemetrexed not inferior to docetaxel for OS

Shepherd JCO 2000, Hanna JCO 2004

Docetaxel

75 mg/m2

(n=55)

BSC

(n=49)

Median OS (months) 7.5 4.6

Log-rank p-value 0.01

Ove

rall

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

Survival time (months)

3 6 9 12 15 18 210

Docetaxel better OS vs BSC

2nd line therapy: docetaxel +/- nintedanib(LUME LUNG 1) n=1314

100

80

60

40

20

0

322 302 263 230 203 180 163 149 131 113 96 87 72 59 46 36 25 22 10336 312 269 219 184 159 139 119 101 88 73 62 55 46 33 29 15 13 7

52.7%

44.7% 25.7%

19.1%

No. at risk:Nintedanib

Placebo

Time (months)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70–0.99)

p value 0.0359

Pro

bab

ility

of

surv

ival

(%

)

Reck Lancet Oncol 2014

2nd line therapy: docetaxel +/- nintedanib(LUME LUNG 1) (ADC, n=658)

Time Since Start of 1st-line Therapy <9 mo PD as best response to first-line chemotherapy

Reck Lancet Oncol 2014

ESMO guidelines:

Docetaxel + nintedanib is a treatment option

for patients with adenocarcinoma progressing

after previous chemotherapy or

immunotherapy

2nd line therapy: docetaxel + ramucirumab (REVEL) (n=1253)

Garon Lancet Oncol 2014

ESMO guidelines:

Docetaxel + ramucirumab is treatment option

for patients with NSCLC progressing after

previous chemotherapy or immunotherapy,

with PS 0–2

2nd line therapy: weekly paclitaxel + bevacizumab vs docetaxel (ULTIMATE)

docetaxel wPB

ORR 5.5% 22.5%

Cortot WCLC 2016

Improved PFSNo OS benefit

Is 2nd line EGFR TKIs effective in WT EGFR NSCLC?

Lee JAMA 2014

ESMO Guidelines

Erlotinib represents a potential second/third-line treatment

option in particular for patients not suitable for immunotherapy

or 2L chemotherapy in unknown EGFR status or EGFR WT NSCLC

2L SCC: afatinib vs erlotinib (LUX Lung 8)Afatinib (n=398)

Erlotinib(n=397)

Patients died 307 (77.1%) 325 (81.9%)

Median OS, months

(95% CI)

7.92

(7.19, 8.74)

6.77

(5.85, 7.79)

HR, p-value 0.808 (0.691, 0.946)

p= 0.0077

Soria Lancet Oncol 2015

ESMO Guidelines

In patients with advanced SCC with PS 0–2 unfit

for chemotherapy or immunotherapy, afatinib

is a potential option with unknown EGFR status

or EGFR WT patients

Prior IO: overcoming resistance with chemotherapy

+/- anti-angiogenic agent

Schvartsman Lung Cancer 2017, Park JTO 2018, Grohe Future Oncol 2019, Corral Clin Trans Oncol 2019, Capelletto WCLC 2019, Molife Future Oncol 2019

Author N Prior Treatment Treatment ORR PFS

Schvartsman 28 Platinum chemo, PD-1/ PD-L1 inhibitor Single agent chemotherapy 39% 4.7m

Park 24

49

PD-1/ PD-L1 inhibitor Platinum doublet

monotherapy

66.7%

46.9%

4.5m

3.8m

Grohe 22 Platinum chemo, pembro/ nivo Nintedanib + docetaxel 58% 5.5m

Corral 11 Platinum chemo, PD-1/ PD-L1 inhibitor Nintedanib + docetaxel 36.5% NR

Capelletto 16 Chemo, PD-1/ PD-L1 inhibitor Nintedanib + docetaxel NR 5.84m

Molife 265 Chemo, PD-1/ PD-L1 inhibitor Ramucirumab + chemo NR 26.5m (OS)

Conclusions

• Non-squamous NSCLC:

• Doublet chemotherapy ± bevacizumab

• Carboplatin based doublet, monotherapy

• Maintenance erlotinib not recommended for WT EGFR

• Squamous NSCLC

• Platinum-based doublets with a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) for PS 0-2

• Identifying biomarkers in oncogene WT NSCLC

Thank you for your attention

� Contact: ross_soo@nuhs.edu.sg