Post on 28-Jul-2020
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
Gettinger S,et al. J Clin Oncol 2018
CA209-003, Phase I with nivolumab in Heavily pretreated patients : 5-Year Estimates of OS by PD-L1 Status
Gettinger S,et al. J Clin Oncol 2018
CA209-003: Outcomes of 5-Year Survivors (n = 16)
Completed maximum cycles of treatment per protocol
Gettinger S,et al. J Clin Oncol 2018
• 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)
Median OS(95% CI), mo
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%
Brahmer J, et al. AACR 2019
Nivolumab(n = 163)
Docetaxel(n = 153)
Median OS(95% CI), mo
9.7
(7.6 13.3)
7.8
(6.7, 10.5)
Nivolumab(n = 185)
Docetaxel(n = 179)
Median OS(95% CI), mo
13.4
(10.0, 17.7)
8.5
(7.0, 9.3)
Impact of response category on LT OS in CheckMate 017/ 057
Brahmer J, et al. AACR 2019
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
Brahmer J, et al. AACR 2019
• 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
Brahmer J, et al. AACR 2019
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.
Brahmer J, et al. AACR 2019
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
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
Relationship between toxicity and benefit of ICIs
Majen M, et al. ESMO 2018
Relationship between toxicity and benefit of ICIs
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.