Hablemos de mantenimiento

Después de la RC: ¿cómo y hasta cuando?

Rosario García Campelo

Servicio de Oncología Médica

Hospital Universitario A Coruña, INIBIC

LA TAREA DE LA MEJOR NARRATIVA ES RELAJAR AL INQUIETO E INQUIETAR AL

RELAJADO

David Foster Wallace

The message…

The message…

Good things come from good science

Rapid

development of

molecular

targeting agents

Rapid

development of

molecular

targeting agents

Availability of IO

Rapid

development of

molecular

targeting agents

Availability of IOClinical application of

plasma and tissue

based genomic

testing

Treatment Duration in Oncology

Early Stage goal: Treat to Achieve Cure• Limited duration

Stage IV goals: Extend OS, reduce burden/symptoms/ QoL• Duration often limited by toxicity• Maintenance therapy and targeted TKIs changed paradigm• What about IO? Is the same concept?

Ongoing Phase 3 Adjuvant Studies in Early Stage NSCLC

• ANVIL- ECOG-ACRIN – Adjuvant nivolumab versus observation

• BR 31- CCTG – Adjuvant durvalumab versus placebo

• PEARLS – EORTC – Adjuvant pembrolizumab versus placebo

• IMpower 010 – Adjuvant atezolizumab versus observation

8

Open questions regarding IO and TKI in early-locally

advanced disease

• Duration of treatment: one year….enough, too short, too long?

• Is duration of treatment the same for all tumor types?

• The dose…lower than in stage IV?

• Toxicity…the same in early than in advanced disease?

Stav I et al. Med Oncol 2018

WHAT DO PATIENTS AND WE WANT?

TO BE CURE…

To relieve a person of the symptoms of a

disease of condition

To eliminate a diseaseor condition with

medical treatment

SURVIVAL ≠

CURE

What did we need in advanded disease to prolong

treatments?

3 strong arguments

What did we need in advanded disease to prolong

treatments?

3 strong arguments

▪ Active drugs

What did we need in advanded disease to prolong

treatments?

3 strong arguments

▪ Active drugs

▪ Drug with few cumulative toxicities

What did we need in advanded disease to prolong

treatments?

3 strong arguments

▪ Active drugs

▪ Drug with few cumulative toxicities

▪ Scientific evidence…

Would you stop 1st line treatment after 4 cycles of

therapy in a metastatic breast, CCR or prostate cancer

patient without progression or significant toxicity?

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

2 YEARS SURVIVAL RATE NSCLC (non-squamous)

0%

5%

10%

15%

20%

25%

30%

35%

40%

ECOG1594 JMBD ECOG4599 PARAMOUNT AVAPERL

11%

19%23%

32%

39%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al.

Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi

et al. Ann Oncol 2014

EL EFECTO DIFERENCIAL DE LA

QUIMIOTERAPIA Y LAS TERAPIAS DIRIGIDAS

EL EFECTO DIFERENCIAL DE LA

QUIMIOTERAPIA Y LAS TERAPIAS DIRIGIDAS

QUIMIOTERAPIA

EL EFECTO DIFERENCIAL DE LA

QUIMIOTERAPIA Y LAS TERAPIAS DIRIGIDAS

QUIMIOTERAPIA

TERAPIAS DIRIGIDAS

Finally we can talk about long term survivors in

advanced melanoma

Presented By Christian Blank at 2018 ASCO Annual Meeting

January 2014…PS 3, EVA 8

• 51 years old female

• HBP, Obesity

• Ex-smoker: 8 Pack/year

• January 2014: LungAdenocarcinoma pT1bN0M1b

• PS 3

• Exon 21 L858R mut

• Clinical trial: afatinib

TKIs in NSCLC…how long should we treat?

January 2014…PS 3, EVA 8

November 2018…PS 0, EVA 0

• 51 years old female

• HBP, Obesity

• Ex-smoker: 8 Pack/year

• January 2014: LungAdenocarcinoma pT1bN0M1b

• PS 3

• Exon 21 L858R mut

• Clinical trial: afatinib

TKIs in NSCLC…how long should we treat?

How many of you would stop EGFR TKI right now?

Rational to sustain TKI inhibition: Disease Flare-Up

Chaft J.E, CCR 2011

• Flare after EGFR TKI cessation in 23% (n=14/61) leading to

hospitalization or death

• The median time to disease flare after TKI discontinuation was 8 days

(range 3–21).

What do patients want?

Patient preference

Blinman et al. Lung Cancer 2010

Sadfer T, NEJM 2018

Gilligan J Clin Oncol 2018

INNOVATION CHANGES THE GAME…

The classic approach…

Disease

Take pill

Killsomething

The classic approach…

Disease

Take pill

Killsomething

The classic approach…

Disease

Take pill

Killsomething

Disease

Geneticalteration

Targetedtherapy

The classic approach…

The new approach….

Disease

Take pill

Kill something

Disease

Genetic alteration

Targeted therapy

The new approach….

Disease

Take pill

Kill something

Disease

Genetic alteration

Targeted therapy

Organ/Disease

Microenviroment

Inmune System

UNIQUE ACTIVITY PATTERNS…

Ascierto AL, Frontiers in Oncol 2015

61 years old male

Active smoker 50 paq/year

May 2014: Stage IV squamous Cell Lung Cancer

cT4NxM1b (bilateral adrenal metastasis)

1st line: Platinum-Gem 6 cycles :PD

January 2015:

2nd line Docetaxel: severe acute infusion reaction

PS 1-2

June 2015: Clinical trial IO

THE PATIENT

CTLA-4, cytotoxic T-lymphocyte associated protein 4; PD-L1, programmed death

ligand 1

02/11/2018

PR after 24 minutes of anti PD-1 infusion….and more than 3 years without active treatment……

02/11/2018

PR after 24 minutes of anti PD-1 infusion….and more than 3 years without active treatment……

3 years after stopping IO…

Why would you want to stop ICI?

Why would you want to stop ICI?

• Do we have enough evidence for prolonged treatment?

Why would you want to stop ICI?

• Do we have enough evidence for prolonged treatment?

• Is the treatment working? PR, CR, SD…

Why would you want to stop ICI?

• Do we have enough evidence for prolonged treatment?

• Is the treatment working? PR, CR, SD…

• Patient choice (remember…the name of the dog)

– Inconvenience

– Toxicity (>gr 3), prolonged low grade toxicity

Why would you want to stop ICI?

• Do we have enough evidence for prolonged treatment?

• Is the treatment working? PR, CR, SD…

• Patient choice (remember…the name of the dog)

– Inconvenience

– Toxicity (>gr 3), prolonged low grade toxicity

• Economic resources

THE EVIDENCE…

SCARCE

Duration: Pivotal Advanced IO Lung Trials

First Line Advanced NSCLC Second LineKN-024 2 yrs (35 cycles) KN-010 2 yrsKN-189 2 yrs CM-057 IndefiniteKN-407 2 yrs CM-017 IndefiniteKN-042 2 yrs OAK IndefiniteCM 227 2 yrsIM150 IndefiniteIM132 Indefinite

Reck, NEJM 2016 Herbst, Lancet 2015Gandhi, NEJM 2018 Borghaei, NEJM 2015Paz-Ares, ASCO 2018 Brahmer, NEJM 2015Lopes, ASCO 2018 Rittmeyer, Lancet 2017Hellman, NEJM 2018Socinski, NEJM 2018

Spigel WCLC 2018

aConventional systemic therapies, excluding immuno-oncology therapies; bTreatment until PD, unacceptable toxicity or withdrawal of consent; treatment beyond investigator-assessed PD permitted; cAll patients on treatment at 1 year were randomized regardless of response status; dPrimary endpoint was incidence of high-grade select treatment-related AEs1,2

Exploratory endpointsd: safety/efficacy with continuous vs 1-year treatment, efficacy, other (eg, biomarkers, PK)

Key eligibility criteria

• Advanced/ metastatic NSCLC

• ≥1 prior systemic therapya

• ECOG PS 0−2

• Treated CNS metastases allowed

Stop nivolumab

Continuous nivolumab

Nivolumab3 mg/kg IV Q2W

Treatment for 1 yearb

Rc

Nivolumab retreatment allowed at PD

Spigel, ESMO 2017

Checkmate 153Continuous vs 1-Year Fixed-Duration

36

aPatients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 monthsbWith optional retreatment allowed at PDtx = treatment

Median, months(95% CI)

PFS rate, %

6-month 1-year

Continuous tx NR (NR) 80 65

1-year txb 10.3 (6.4, 15.2) 69 40

HR: 0.42 (95% CI: 0.25, 0.71)

No. at risk

1-year tx

Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

No. at risk

1-year tx

Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

Time post-randomization (months)

PF

S (

%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24

Spigel, ESMO 2017

Checkmate 153PFS from Randomization

37

Median, months(95% CI)

Continuous tx NR (NR)

1-year txb,c 10.6 (4.8, NA)

HR: 0.45 (95% CI: 0.24, 0.85)

Median, months(95% CI)

Continuous tx NR (5.6, NA)

1-year txb 9.6 (4.5, 12.6)

HR: 0.44 (95% CI: 0.17, 1.09)

CR/PR SD

1-year tx 49 29 26 20 14 11 3 1 0

Continuous tx 53 45 41 39 28 17 7 2 0

No. at risk

0

20

40

60

80

100

PF

S (

%)

0 3 6 9 12 15 18 21 24

Time post-randomization (months)

38 21 17 13 7 5 2 0 0

23 15 12 10 7 5 3 1 0

0

20

40

60

80

100

PF

S (

%)

0 3 6 9 12 15 18 21 24

Time post-randomization (months)

Spigel, ESMO 2017

Checkmate 153PFS by Response

38

Median, months(95% CI)

OS rate, %

6-month

1-year

Continuous tx NR (NR) 97 88

1-year txb 23.2 (23.2, NA) 88 81

HR: 0.63 (95% CI: 0.33, 1.20)

74 72 67 62 41 29 7 2 0

79 74 70 61 38 23 4 0 0

No. at risk

1-year tx

Continuous tx

87

76

Time post-randomization (months)

0

20

40

60

80

100

OS

(%

)

0 3 6 9 12 15 18 21 24 27

Spigel, ESMO 2017

Checkmate 153OS from Randomization

5-Year Estimates of OS <br />Phase 1 nivolumab

Presented By Solange Peters at 2018 ASCO Annual Meeting

CM 003: heavily pretreated NSCLC population

Nivolumab up to 96 weeks

Gettinger S, et al. J Clin Oncol 2018

▪ 12/16 p who achieved a reponse on Nivolumab therapy

▪ 12 5-year survivors (75%) received no subsequent

therapy and were without evidence of progressive

disease at last follow-up.

KN 010: Pembrolizumab in previously treated advanced

NSCLC

Herbst R, et al. ESMO 2018

▪ 79 patients completed 35 cycles or 2

years of pembrolizumab

▪ 75 of 79 (95%) patients had a complete

response or partial response

▪ Response was ongoing in 48 patients

(64%)

Ipilimumab in melanoma: association

of response with survivalKN006. Pembrolizumab in melanoma:

association of response with survival

Relapse by PET response in melanoma patients receiving

checkpoint inhibition

Tan AC, et al. Ann Oncol 2018

PET and rebiopsy predictive value

Christainsen et al ASCO 2018

Long term toxicity…

¿PODEMOS CORRELACIONAR EL DESARROLLO DE

EFECTOS ADVEROS IR CON EL BENEFICIO A LA IO?

Weber et al. J Clin Oncol 2016

Los pacientes con CNMP que desarrollaron efectos adversos IR

alcanzaron mayor SG (13.2 vs 5.8 meses, p = 0.018). Owen et al, ASCO 2017

¿PODEMOS CORRELACIONAR EL DESARROLLO DE

EFECTOS ADVEROS IR CON EL BENEFICIO A LA IO?

Weber et al. J Clin Oncol 2016

Los pacientes con CNMP que desarrollaron efectos adversos IR

alcanzaron mayor SG (13.2 vs 5.8 meses, p = 0.018). Owen et al, ASCO 2017

¿PODEMOS CORRELACIONAR EL DESARROLLO DE

EFECTOS ADVEROS IR CON EL BENEFICIO A LA IO?

Weber et al. J Clin Oncol 2016Von Pawel J, et al. ESMO 2017

Slide 13

¿Cómo “de seguro” es retratar a los pacientes con IO

tras EA inmunorelacionados?

▪ 62 years old male

▪ Active smoker 45 pack/year

▪ Stage IV SCC in April 2014

▪ OAK trial: Atezolimumab 2nd

line since September 2014 to

April 2018, 62 cycles

▪ Gr 3 pneumonitis

▪ Stop therapy

▪ Ongoing complete response

▪ 55 years old female

▪ Active smoker 35 pack/year

▪ Stage IV Non-SCC January

2013

▪ OAK trial: Atezolimumab 2nd

line since February 2015: 66

cycles

▪ No significant toxicity

▪ Treatment ongoing

▪ 62 years old male

▪ Active smoker 45 pack/year

▪ Stage IV SCC in April 2014

▪ OAK trial: Atezolimumab 2nd

line since September 2014 to

April 2018, 62 cycles

▪ Gr 3 pneumonitis

▪ Stop therapy

▪ Ongoing complete response

▪ 55 years old female

▪ Active smoker 35 pack/year

▪ Stage IV Non-SCC January

2013

▪ OAK trial: Atezolimumab 2nd

line since February 2015: 66

cycles

▪ No significant toxicity

▪ Treatment ongoing

▪ 62 years old male

▪ Active smoker 45 pack/year

▪ Stage IV SCC in April 2014

▪ OAK trial: Atezolimumab 2nd

line since September 2014 to

April 2018, 62 cycles

▪ Gr 3 pneumonitis

▪ Stop therapy

▪ Ongoing complete response

▪ 55 years old female

▪ Active smoker 35 pack/year

▪ Stage IV Non-SCC January

2013

▪ OAK trial: Atezolimumab 2nd

line since February 2015: 66

cycles

▪ No significant toxicity

▪ Treatment ongoing

Presented By Sarah Goldberg at 2018 ASCO Annual Meeting

Take Home Message

Optimal duration of therapy in advanced cancer is still an issue to debate…overall talking about IO

Duration should be based on regimen data from pivotal trials• Two years can be an option for IO…• But care must be individualized for efficacy, QoL, toxicity, and patient choice

Future research is needed to study:• Shorter durations• Alternative schedules• Redosing / Repriming• Biomarkers to predict benefit

TENDIENDO PUENTES….THE WAY TO MOVE FORWARD