largos supervivientes en cpnm · percent of cases & 5-year relative survival by stage at...

Largos Supervivientes en CPNMDra. Pilar Diz Taín

Servicio Oncología Médica

Complejo Asistencial Universitario de Léon (CAULE)

Formigal, 21 junio 2019

Definition of Long -Term Survival (LTS) in Advanced NSCLC

1. Okamoto et al. Lung cancer 2005; 2. Satoh et al. Anticancer res 2007; 3. Dujon et al. Rev Mal Respir2009; 4. Giroux Leprieur, et al. Respirology. 2012; 65 V. Van Damme et al. Lung cancer 2013

Literature series on long-term survivors with advanced NSCLC

Study (year) LTS N LTS patients (%) Predictive factors Remarks

Okamoto et al. (2005)1 > 2y 17 /222 (8%) PS, Adenoca, surgery, lower N-stage

19 patients surgery

Satoh et al. (2007)2 > 2y 14 /109 (13%) PS, EGFR-TKI

Dujon et al.(2009)3 > 2y 23 / 169 (13%) PS, comorbidity, response, EGFR-TKI

Giroux Leprieur et al. (2012)4 > 2y 39/245 (16%) PS, response, surgery, N of lines, treatment-free interval

Resectable patients

Van Damme V et al. (2013)5 > 2 y 31 vs 34 PS, gender, response, N of lines, treatment-free interval

Percent of Cases & 5-Year Relative Survival by Stage at Diagnosis

• SEER 18 2009-2015, All Races, Both Sexes by SEER Summary Stage 2000

National Cancer Institute (2019) Cancer Stat facts: lung and bronchus cancer. https ://seer.cance r.gov/statf acts/html/lungb .html. Accessed 15 april 2019

Substantial survival benefit for TKIs vs chemotherapy.

3.5 yr

Impact of subsequent therapy on OS with ALKi

mOS NR (95%CI, NR, NR)

mOS 49.5 m (95%CI, 41.0, NR)

mOS 20.8m (95%CI, 14.4, 31.8)mOS 12.1 m (95%CI, 2.2, NR)

Mok T et al, ESMO 2017; Duruisseaux. Oncotarget 2017

Mature data in 2L NSCLC highlight the role of I-O in improving patient prognoses

Combining I-O with other

therapeutic modalities is a promising approach to providing durable clinical benefit and treating

biomarker-selected patient populations in 1L

NSCLC

I-O in Thoracic Cancers

I-O monotherapy

Targeted therapy

Chemotherapy/TKI

Combination with I-O therapy

Where we want to be*

Where we are

Su

rviv

al

Time

*Hypothetical chart illustrating a scientific concept that is beyond data available so far. This chart is not intended to predict what may actually be observed in clinical studies.Adapted from Sharma P, Allison JP. Cell. 2015;161(2):205-214.

Study (N) Phase Population ICI OS I-O/CT*

CA 209-003 (N=129)1 I Heavily pretreated Nivolumab 16% (at 5 yr)

CM 017 (N= 222)2 III Sq NSCLC Nivolumab 16% (at 3 yr)/6%* vs Docetaxel

CM 057 (N= 240)2 III Non Sq NSCLC Nivolumab 18% (at 3 yr)/9%* vs Docetaxel

KN 001 (N= 550)3 I Treatment naïve (N=101) Pembrolizumab 27.2% (at 4 yr)

Previously treated (N=449) 16.4% (at 4 yr)

KN 010 (N=1034)4 II/III Previously treated Pembro PD-L1 TPS≥ 50% 35%/13%(at 3yr)* vs Docetaxel

Pembro PD-L1 TPS≥ 1% 23%/11% (at 3yr)* vs Docetaxel

POPLAR (N= 144)5 II Previously treated Atezolizumab 19% (at 3 yr)/10%* vs Docetaxel

OAK (N= 850)6 III Previously treated Atezolizumab 31% (at 2 yr)/21%* vs Docetaxel

ATLANTIC (N= 265)7 II Heavily treated Durvalumab 22% (at 2 yr)

KN 024 (N=305)8 III First Line Pembro PD-L1 TPS≥50% 51.5%/34.5% (at 2 yr)* vs P-doublets

Long -Term Survival with ICIs

1. Gettinger S,et al. J Clin Oncol 2018; 2. Vokes EE, et al. Ann Oncol 2018; 3. Felip E, et al. ASCO 2018; abstract 9030; 4. Herbst R et al. ESMO 2018; 5. Park et al. WCLC 2017; 6. Satouchi et al. WCLC 2017; 7. Garassimo et al. Lancet Oncol 2018; 8. reck M, et al. J Clin Oncol 2019

Multivariate Analysis of Overall Survival• In the pooled pembrolizumab group,longer OS was associated with:Asian vs non-Asian race,baseline tumor size ≤80 vs >80 mm, baseline ECOG PS of 0 vs ≥1, nonsquamous vs squamous histology, normal vs elevated baseline LDH, PD-L1 TPS ≥50% vs TPS 1%–49%, and wild-type vs mutant EGFR

Herbst, et al. ASCO 2017

TPS ≥ 50% 290 (42) 58 (73)

KN 010: Characteristics of the patients treated with pembrolizumab for 24 months

Herbst, et al. ESMO 2018; abstract LBA63

Long term Survival (2-year) in patients treated with atezolizumab vs docetaxel: Results from the randomised phase III OAK study

Non-LTSa

(Non‒long-term survivors)

Patients that died within 24 months of

randomization

LTS(Long-term survivors)Patients who lived ≥ 24

months since randomization

R

1:1

Locally advanced

or

metastatic NSCLC

• 1–2 prior lines of

chemotherapy

including at least

1 platinum-based

therapy

• Any PD-L1 status

Atezolizumab 1200 mg IV

q3w

Docetaxel75 mg/m2 IV

q3w

PD or loss of clinical benefit

PD

Survival follow-

up

No crossover to

atezolizumab

allowed

• Primary endpoint (first 850 enrolled patients): OS in the ITT population (ITT850)• Data cutoff: 23 January, 2017; Minimum follow-up: 26 months

Satouchi et al. WCLC 2017

Overall survival (OS) in ITT850

OAK study: Baseline characteristics LTS and non-LTSAtezolizumab (N = 398) Docetaxel (N = 376)

Baseline characteristicLTS

(n = 119)

Non-LTS

(n = 279)

LTS

(n = 77)

Non-LTS

(n = 299)

Median age (range), years 63 (35-81) 64 (33-82) 62 (41-84) 64 (34-85)

Aged ≥ 65 years, n (%) 52 (44%) 127 (46%) 31 (40%) 149 (50%)

Sex, female, % 49% 34% 42% 38%

Histologya, non-squamous, % 85% 70% 84% 69%

ECOG PS, 0, % 50% 32% 62% 32%

Tobacco use history, never smoker, % 24% 17% 18% 15%

Prior lines of therapy, 1, % 75% 75% 71% 77%

EGFR mutation status, positive, % 9% 9% 13% 8%

PD-L1 expression, %TC3 or IC3TC1/2/3 or IC1/2/3TC0 and IC0

24%60%40%

14%56%43%

13%58%42%

16%50%49%

T-effector gene expressionMedianInterquartile rangeBelow the limit of detection, n(%)

-1.61-2.64, -0.58

6 (5%)

-2.40- 3.39, -0.87

13 (17%)

-2.01-3.76, -1.2129 (10%)

-2.41-4.13. -1.2737 (12%)

Satouchi et al. WCLC 2017 von Pawel J, et al. Eur J Cancer 2019

OAK: LTS by BoR

von Pawel J, et al. Eur J Cancer 2019

Be

st

Re

sp

on

se

With ≥ 26 months of follow-up.

TBP Atezolizumab(n= 398)

LTS (n=119)

Non-LTS (n= 279)

PD per RECIST 1.1, n (%)

85(71%) 231 (83%)

TBP, n/N (%) 53/85 (62%)

105/231 (45%)mDOR LTS 26.3 m (95% CI 17.6, NE)/no LTS 6.2 m (95%CI 4.2, 9.4)

CA209-003, Phase I with nivolumab in Heavily pretreated patients. Characteristics Overall and in 5-Year Survivors

CharacteristicAll Treated

Patients(N = 129)

5-Year Survivors(n = 16)

Median age, years (range) 65 (38, 85) 62 (44, 80)

≥65 years, n (%) 66 (51) 6 (38)

Male, n (%) 79 (61) 9 (56)

ECOG PS, n (%)a

0 1

27 (21)100 (78)

4 (25)12 (75)

No. of prior systemic regimens, n (%)

1−2≥ 3

59 (46)70 (54)

6 (38)10 (62)

Smoking status, n (%)Former smokerCurrent smokerUnknown

16 (12)b

92 (71)21 (16)

3 (19)b

11 (69)2 (12)

Tumor histology, n (%)c

SquamousNon-squamous

54 (42)74 (57)

8 (50)8 (50)

CharacteristicAll Treated

Patients(N = 129)

5-Year Survivors(n = 16)

EGFR status, n (%)Not evaluableEvaluable

MutantWild-type

61 (47)68 (53)13 (19)d,e

55 (81)d

9 (56)7 (44)2 (29)d,e

5 (71)d

PD-L1 status, n (%)Not evaluableEvaluable

<1%≥1%≥50%

61 (47)68 (53)30 (44)d

38 (56)d

13 (19)d

6 (38)10 (62)3 (30)d

7 (70)d

5 (50)d

Select TRAEsf on nivolumab, n (%)Any gradeGrade 3−4

56 (43)7 (5)

11 (69)1 (6)

aTwo patients in the overall population had ECOG PS 2 bSmoking status in 1 patient was confirmed by the investigatorcOne patient in the overall population had unknown tumor histology dPercent of evaluable patientseEGFR mutation in 1 patient was confirmed by the investigatorfDefined as TRAEs with potential immunologic causeBrahmer et al. AACR 2017 Yamada T, et al. Cancer Med 2019

CA209-003, Phase I with nivolumab in Heavily pretreated patients. 5-Year Estimates of OS

Gettinger S,et al. J Clin Oncol 2018

CA209-003, Phase I with nivolumab in Heavily pretreated patients. 5-Year Estimates of OS by Histology


CA209-003, Phase I with nivolumab in Heavily pretreated patients : 5-Year Estimates of OS by PD-L1 Status


CA209-003: Outcomes of 5-Year Survivors (n = 16)

Completed maximum cycles of treatment per protocol


• Among the 60 patients who received ≥ 2year of Pembrolizumab treatment,

– More than 85% had an objetive response

– 5yr OS %, exceeded 75% , and 77% were alive at data cutoff.

5y OS 23.2% 5y OS 15.5%

5y OS %, 95% CI29.6% (7.7- 56.1)15.7 (7.3-26.9)

5y OS %, 95% CI25.0% (18.0- 32.5)12.6 (7.9-18.5)

3.5 (0.7-10.0)

5-Year OS from KEYNOTE-001

Garon EB, et al. J Clin Oncol 2019

Brahmer J, et al. AACR 2019

mDoR in all patients with a CR/PR (n = 122): 19.1 months (95% CI, 14.7−29.9).

4-year OS %, PD-L1 < 1%: 11%; PD-L1 ≥ 1%: 19%

Nivolumab(N = 664)

Median OS(95% CI), mo

10.3

(9.2, 11.9)

OS in all nivolumab-treated patients

CheckMate 003/063/ 017/ 057

Nivolumab(n = 427)

Docetaxel(n = 427)


11.1

(9.2, 13.1)

8.1

(7.2, 9.2)

OS with nivolumab vs docetaxel

CheckMate 017/ 057

aIn all randomized patients from CheckMate 017 and 057 with evaluable PD-L1 expression.

OS with nivolumab vs docetaxel by tumor PD-L1 expressionCheckMate 017/ 057a

163 73105 52 38 27 1518 12 9 5 0

PD-L1 expression < 1% 100

0

40

60

80

20

Months

153 5095 31 20 13 910 6 3 1 0

OS

(%

)

0 126 18 24 30 4236 48 54 60 66

34%

13%

7% 4%9%12%

45%

24%

Nivolumab

Docetaxel

No. at risk

Nivolumab

Docetaxel

Months

Nivolumab

Docetaxel

OS

(%

)

100

0

40

60

80

20

0 126 18 24 30 4236 48 54 60 66

34%

15%10%

21%

4%

20%

54%

32%

185 99123 76 58 42 3638 33 20 4 0

179 61112 36 27 23 1017 8 5 0 0

No. at risk

Nivolumab

Docetaxel

PD-L1 expression ≥ 1%


Nivolumab(n = 163)

Docetaxel(n = 153)


9.7

(7.6 13.3)

7.8

(6.7, 10.5)

Nivolumab(n = 185)

Docetaxel(n = 179)


13.4

(10.0, 17.7)

8.5

(7.0, 9.3)

Impact of response category on LT OS in CheckMate 017/ 057


OS was calculated from the time of response (CR/PR) for each responder.

OS from time of response with nivolumab vs docetaxel in CheckMate 017/ 057


• Good tolerability and did not reveal any new safety signals • The most common TRAE was fatigue (in 21.7% of patients)• Two treatment-related deaths occurred; 1 patient died of pneumonia and 1 of sepsis

Safety summary for all nivolumab-treated patientsa

Patients with event,bAll nivolumab-treated patients (N = 664)

Any grade Grade 3–4

Any TRAE, % 69.7 13.0

Serious TRAEs, % 9.6 5.4

TRAEs leading to discontinuation, % 8.7 5.4aAnalysis includes CheckMate 003, 063, 017 and 057 studies. bIncludes events reported between first dose and 30 days after last dose of study drug


Exposure-adjusted rates of treatment-related select AEs inall nivolumab-treated patients

Categorya

Incidence rate per 100 person-years of exposureb

< 1 year

(N = 664c)

1 – < 2 years

(n = 122c)

2 – < 3 years

(n = 59c)

3 – < 4 years

(n = 34c)

≥ 4 years

(n = 26c)

Total

(N = 664)

Skin 51.3 22.8 22.0 10.2 0 38.6

Gastrointestinal 26.4 16.3 6.6 13.6 0 20.7

Hepatic 16.4 13.0 11.0 0 0 13.6

Endocrine 18.8 4.3 0 0 0 12.4

Pulmonary 11.0 9.8 8.8 0 0 9.4

Hypersensitivity/ infusion reaction

8.2 4.3 0 0 0 5.9

Renal 6.8 2.2 0 0 0 4.6aIncludes events reported between first dose and 30 days after last dose of study drug; bIncidence rate per 100 person-years of exposure = event count X 100/person-years of exposure; cNumber of patients on treatment at the start of the time interval.


Biomarkers and Long-Term Survival

1. Horn L et al. J Clin Oncol. 2017;35:3924-3933. 2. Fehrenbacher L et al. J Thorac Oncol. 2018;13(8):1156-1170. 3. Herbst RS et al. Lancet. 2016;387(10027):1540-1550

Clinical Benefit of I-O Across PD-L1 Expression Levels in 2L NSCLC

Why PD-L1 expression might not predict benefit from anti PD-1/PD-L1

PD-L1 expressionnot necessary

Hypothesis

PD-L1 expressionnot sufficient

PD-L1 absent by IHC butclinical benefit seen from

anti PD-1/PD-L1

PD-L1 present by IHC butno clinical benefit from

anti PD-1/PD-L1

Evidence

• Spatial and/or temporal variability in PD-L1 expression(sampling error)

• Variation between IHC assays (false negative results)

• A bypass mechanism for immunosuppression (e.g. PD-L2)

• Elevation in PD-L1 expression for reasons other than in response to a primed immune attack

• Engagement of other immune checkpoints in addition to thePD-1/PD-L1 axis (IDO1, LAG3, TIM3, OX40)

• The measured the extent of PD-L1 positivity (a continuousvariable) might be insufficient for a response to anti PD-1/ PD-L1.

Potential explanations

Camidge DR, et al. Nat Rev Clin Oncol 2019

PD-L1 varies at different anatomic sites

Hong L, et al. ASCO 2019 Rizvi H, et al. ASCO 2019

Hong L, et al. ASCO 2019 Garassino M. ASCO 2019

PFS by different biopsy sites associated with PD-L1 expression

PD-L1 changes over time with or without treatment

Hong L, et al. ASCO 2019

Archival vs newly tumor samples

Herbst RS. Ann Oncol 2019

• Many factor can lead to increase TMB:

– Smoking

– Aging

– UV light exposure

– Impaired DNA mismatch repair(MSI, MMR, BRCA ½) POLE, POLD1 mutations

Hypothesis: High TMB may increase the immunogenicity of tumours

1. Schumacher TN, Schreiber RD. Science. 2015;348(6230):69-74. 2. Kim JM, Chen DS. Ann Oncol. 2016;27(8):1492-1504. 3. Liontos M et al. Ann Transl Med. 2016;4(14):264. 4. Sharma P, Allison JP. Science. 2015;348(6230):56-61. 5. Giannakis M et al. Cell Rep. 2016;15(4):857-865. 6. Chalmers ZR et al. Genome Med. 2017;9(1):34. doi:10.1186/s13073-017-0424-2.

TMB in Patients With NSCLC Treated With Nivolumab ± Ipilimumab

*High TMB was defined as ≥243 total missense mutations (highest tertile) as measured by whole-exome sequencing (WES). †Median TMB was 158 total missense mutations as measured by WES.1. Carbone DP et al. N Engl J Med. 2017:376(25);2415-2426. 2. Hellmann MD et al. Cancer Cell 2018. doi:10.1016/j.ccell.2018.03.018.3. ellmann MD et al. N Engl J Med. 2018; 378(22):2093-2104.

Checkmate 2273

Patients With NSCLC Treated With Durvalumab ± Tremelimumab vs CT (Mystic Trial)

Rizvi N. ESMO IO 2018

bTMB in Patients With NSCLC Treated With Durvalumab + Tremelimumab

Rizvi N. ASCO 2019

Neoantigen quality predicts immune response to ICIs

Maleki. J ImmunoTher Cancer 2018Response to ICI

Turajlic S, et al. Lancet oncol 2017

Nonsynonymous mutation

Chen and Mellman. Nature 2017

Relationship between toxicity and benefit of ICIs


Ricciuti B, et al. J Cancer Res and Clin Oncol 2019

• Multicenter retrospective study with nivolumab between oct. 2013 and Sep. 2017.

• N= 195

PFSMultivariate HR (95% CI)

PFSP value

OSMultivariate HR (95% CI)

OSP value

Any 0.48 (0.34 – 0.67) P< 0.0001 0.38 (0.26- 0.56) P< 0.0001

Lung irAEs 0.56 (0.33 – 0.96) P= 0.038 0.46 (0.24 – 0.89) P= 0.0022

Gastrointetinal irAEs 0.52 (0.3 – 0.9) P= 0.021 0.5 (0.26 – 0.98) P= 0.045

Endocrine irAEs 0.59 (0.4 – 0.89) P= 0.011 0.45 (0.28 – 0.72) P= 0.001

Skin irAEs 0.57 (0.35 – 0.95) P= 0.031 0.8 (0.46 – 1.39) P= 0.43

Hepatobiliary irAEs 0.72 (0.41 – 1.24) P= 0.23 0.94 (0.53 – 1.66) P= 0.83

Ricciuti B, et al. J Cancer Res and Clin Oncol 2019

• Multicenter retrospective study with nivolumab between oct. 2013 and Sep. 2017.

• N= 195


Majen M, et al. ESMO 2018


Conclusiones• El panorama del tratamiento del CPNM ha cambiado completamente debido a la reciente

aprobación de diferentes ICI.

• Los datos de supervivencia a largo plazo son consistentes en los diferentes estudios con diferentesICIs

• La expresión PD-L1 como biomarcador tiene muchas limitaciones, pero la alta expresión se haasociado sistemáticamente con una mayor tasa de respuesta y mayor OS.

• El tratamiento con ICI es efectivo en un subgrupo de pacientes largos supervivientes y laidentificación de biomarcadores predictivos robustos es necesaria para su mejor identificación.

largos supervivientes en cpnm · percent of cases & 5-year relative survival by stage at...

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