cáncer microcítico de pulmón: ¿el final de la sequía? · sclc and nsclc wahbah et al. ann...
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Cáncer microcítico de pulmón: ¿El final de la sequía?
Rosario García Campelo
Medical Oncology Unit
Thoracic Tumors and Research Program
University Hospital A Coruña, Spain
INIBIC, A Coruña, Spain
DroughtMysterious, fascinatingHope for the future
SCLC and NSCLC
Wahbah et al. Ann Diagnostic Pathol 2007.
13,68 18,31
86,32
81,69
0
10
20
30
40
50
60
70
80
90
100
Perc
en
tag
e o
f p
ati
en
ts (
%)
SCLC NSCLC
Male
Female
• >200,000 cases/year globally
• ~98% tobacco-related
• Two-thirds present with Stage IV SCLC
Extensive Stage SCLCTHE LAST 20 YEARS SUMMARY…
▪ SCLC is highly sensitive tochemotherapy and radiotherapy
▪ Despite the high chemosensitivity,median survival remains poor forpatients with ES ranges only from 7to 11 months
▪ Platinum-etoposide is the standardof care in first line treatment sincethe 1980s
• ORR: 50-60%
• Median Survival: 9-12 months
• Topotecan is the standard of carein second-line setting
Reasons for the failure
• Wrong drugs
• Wrong targets
• Wrong design of clinical trials
• Wrong doses
• Difficult disease
• Unknown molecular mechanisms of the disease
• …….
How do we think about targeted therapy for lung cancer?
Jordan et al., Cancer Discov. 2017
Rudin C. WCLC 2018
Lung adenocarcinoma Small cell lung cancer
Comprehensive genomic profiles of small cell lung cancer
George et al. Nature 2015
No clear actionable mutations
Dr Reguart ELCC 2017
Lorvotuzumab Mertansine
Alexandrov LB, Nature 2013
IMMUNOTHERAPY CHANGES THE GAMEMutational Load of SCLC
High non-synonymous mutation rate 5.5-7.4/Mb (ADK 8.9, SqCC 8.1)SCLC exhibits high mutation rates compared with other cancers
potentially contributes to the aggressive nature of SCLC
The very beginning…Ipilimumab, the first failure in 1L ED
Reck M, et al. J Clin Oncol 2016
• No signal of efficacy was observed with the addition of ipilimumab• Toxicity was significantly higher (mainly diarrhea and rash) in the ipilimumab
Nivolumab/Ipilimumab in previously treated SCLCCheckMate 032 trial Phase I/II trial
• CK 032 ph 1/2 trial1,2:
– Nivo (N 98): ORR 11%; Median DOR 17.9 m; MST: 4.1 m; 2-y OS 14%
– Nivo + IPI: (61): ORR 23%, Median DOR 14.2 m; MST 7.8 m; 2-y OS 26%
• CK 032 ph 1/2 trial randomized cohort2
– A randomized cohort was added to further evaluate Nivolumab + Ipilimumab in pretreated SCLC patients.
– Nivo (N: 147): ORR 12%;
– Nivo + IPI (N: 95): ORR 21%;
• Responses regardless platinum sensitivity, line of therapy or PD-L1 status
• Combo increases toxicity: 37% Gr 3- 4 vs. 12%; 5 treatment related deaths (4:1)
Antonia S. Lancet Oncology 2016Hellman M, WCLC 2017
CheckMate 032 Exploratory TMB Analysis Nivo ± Ipi in Previously Treated SCLC
100
75
50
25
0
0 3 6 9 12 15 18 21 24 27 30 33 36
OS,
%
1-y OS = 35.2%
1-y OS = 22.1%
1-y OS = 26.0%
100
75
50
25
0
0 3 6 9 12 15 18 21 24 27 30 33 36
1-y OS = 62.4%
1-y OS = 19.6%
1-y OS = 23.4%
Months
Low TMB Med TMB High TMB
Median OS
(95% CI), mo
3.4 (2.8, 7.3)
3.6 (1.8, 7.7)
22.0 (8.2, NR)
Nivolumab
Low TMB Med TMB High TMB
Median OS
(95% CI), mo
3.1
(2.4, 6.8)
3.9
(2.4, 9.9)
5.4
(2.8, 8.0)
Nivolumab + ipilimumab
42
27 44 25 47 26n 133 78
0
10
20
30
40
50
OR
R, %
Nivolumab Nivolumab + ipilimumab
Antonia S WCLC 17 Abs 11063Hellmann et al. Cancer Cell 2018
Third-Line Nivolumab monotherapy in recurrent SCLC: CM 032
Ready et al. J Thorac Oncol 2019
Dibonaventura et al. Ther Clin Risk Manag2019
HOW FREQUENTLY DO WE TREAT SCLC IN THE SECOND LINE SETTING AND BEYOND?
Higginbottom et al, WCLC 2017
KN 028: Ph IB Multicohort in PDL1 +
• PDL1 screening (patients)
– Tested 163
– Positive 46 (28.6%)
– Treated 24
• Progressive Disease 54.2%
• RR 33%, Median DOR 19.4 m
• Median PFS 1.9 m
• Median OS 9.7 m
• 1y SV 37.7%
Ott et al. J Clin Oncol 2017
1 yPFS: 23.8%
1 yOS: 37.7%
Chung et al. ASCO 2018
POOLED ANALYSIS KN 028 AND KN 158
Chung et al. AACR 2019
A randomized non-comparative phase II study of atezolizumabor CT as 2L in SCLC: IFCT 1603 trial
Pujol et al. ESMO 2018
Phase III CheckMate 331Nivo vs QT in 2L ED-SCLC
Reck M, et al. ESMO 2018
Relapsed or primary
progressive disease
Subsequent chemotherapy*
NCCN SEOM
Relapse >6 mo
• 1L rechallenge (2A)
• Clinical trial
Sensitive (>3 mo)
• IV/PO TOPO
• CAV*
• 1L rechallenge (V,C)
Relapse < 6 mo Resistant (< 3mo, PR)
• IV/PO TOPO (II,B)
• CAV*
• Clinical trial (II,C)
• BSC (II,C)
Refractory (< 3 mo, PD)
• Clinical trial (II,C)
• BSC (II,C)
NCCN[1] ESMO[2]
• Topo IV/PO (1)
• Paclitaxel
• Docetaxel
• Irinotecan
• Bendamustine (2B)
• Gemcitabine
• Vinorelbine
• Etoposide PO
• Temozolomide
• CAV*
• Nivo+/-pi
Subsequent Treatment
See slide notes for references and abbreviations.
1. NCCN Guidelines 2019; 2. 2. M. ESMO guidelines 2013, Fruh, Annals Oncol 2013. 3. Domine, Clin Trans Oncol 2013
BEYOND FIRST LINE…CLINICAL GUIDELINES
SEOM[2]
• Clinical trial • IV/PO TOPO• VAC• 1L rechallenge Sensitive
(>3 mo)• BSC • Docetaxel• Irinotecan• Temozolamide• Gemcitabine• Ifofosfamide
Immunotherapy in previously treated SCLC
▪ Disappointing results in second line settingo Immunotherapy active
o Not superior to 2nd line chemotherapy (survival)
▪ Greater challenges in later lines of therapyo Fewer patients eligible
o Increased heterogeneity
o Different underlying biology
▪ Is earlier use more appropriate?
Courtesy Dr Liu
The earlier approach….in localized setting
Hann C, et al. ASCO Ed Book 2019
The earlier approach….in metastatic setting
Phase II study of pembrolizumab as maintenance
• ED SCLC with CR, PR or SD after 4-6 cycles of
standard first line CT
• Primary endpoint PFS
• N: 45. No PDL1 selection
• Efficacy:
– Median PFS 1.4m
• Median PFS in PDL1 + (3 p /30 assessed):
4.8-9.8 m
– Median OS 9.6m; 1-y OS 30%
• Pembrolizumab did not improve median PFS in this
study
Gadgeel SM, et al. ASCO 2017Gadgeel SM et al. J Thorac Oncol 2018
CM 451: Maintenance Nivolumab/Ipilimumab
CM 451: Maintenance Nivolumab/Ipilimumab vs placebo OS
Owonikoko – ELCC 2019.
275 237 181 139 105 65 41 23 16 7 2 0Placebo
279 230 177 130 100 65 43 30 14 8 3 0Nivolumab + ipilimumab
Nivolumab + ipilimumab
Placebo
1-y OS = 41%
1-y OS = 40%
0 3 6 9 12 15 18 21 24 27 30 33
OS
(%)
Months
100
80
60
40
20
0
No. at risk
NIVO + IPI
(n = 279)
Placebo
(n = 275)
Events, n (%) 189 (68) 211 (77)
Median OS, mo (95% CI)
9.2
(8.2–10.2)
9.6
(8.2–11.0)
HRa
(95% CI)P value
0.92 (0.8–1.1)
0.37
CM 451: Maintenance Nivolumab vs Placebo OS
Owonikoko – ELCC 2019.
IMpower 133:
THE FIRST POSITIVE SYSTEMIC STUDY IN 1L IN MANY, MANY YEARS…
IMpower133: Global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated atezolizumab + carboplatin + etoposide in 1L ES-SCLC
• a Due to the low number of patients with brain metastases, the presence of brain metastases was excluded as a stratification factor in stratified data analyses. b Patients who met prespecified criteria were allowed to be treated beyond disease progression per RECIST v1.1 criteria until loss of clinical benefit in a blinded fashion. Adapted from The New England Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, Epub ahead of print. Copyright © 2018. Massachusetts Medical Society.
MaintenanceInduction (4 x 21-day cycles)
Patients with (N = 403):
• Measurable
(RECIST v1.1) ES-SCLC
• ECOG PS 0 or 1
• No prior systemic
treatment for ES-SCLC Su
rviv
al fo
llo
w-u
p
Co-primary end points:
• Overall survival
• Investigator-assessed PFS
Key secondary end points:
• Objective response rate
• Duration of response
• Safety
PCITreat until
PDb
Placebo
Atezolizumab
R
1:1
Atezolizumab group
Atezolizumab (1200 mg IV, Day 1)
+ carboplatin (AUC 5 mg/mL/min IV, Day 1)
+ etoposide (100 mg/m2 IV, Days 1–3)
Placebo group
Placebo
+ carboplatin (AUC 5 mg/mL/min IV, Day 1)
+ etoposide (100 mg/m2 IV, Days 1–3)
Stratification:
• Sex (male vs. female)
• ECOG PS (0 vs. 1)
• Brain metastases (yes vs. no)a
o only if the metastases were
treated and asymptomatic
o 9% patients met these criteria
Overall survival
• Clinical data cut-off date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval. HR, hazard ratio; CP/ET, carboplatin + etoposide.• Adapted from The New England Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, Epub ahead of print.
Copyright © 2018. Massachusetts Medical Society.
No. at risk
Atezolizumab 201 191 187 182 180 174 159 142 130 121 108 92 74 58 46 33 21 11 5 3 2 1
Placebo 202 194 189 186 183 171 160 146 131 114 96 81 59 36 27 21 13 8 3 3 2 2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months
100
90
80
70
60
50
40
30
20
10
0
Ove
rall
su
rviv
al
(%)
12-month OS
51.7%
38.2%
Atezolizumab
+ CP/ET
Placebo
+ CP/ET
Censored+
Atezolizumab
+ CP/ET
(N = 201)
Placebo
+ CP/ET
(N = 202)
OS events — no. (%) 104 (51.7) 134 (66.3)
Median OS — months (95% CI)
12.3 (10.8, 15.9)
10.3(9.3, 11.3)
HR (95% CI)0.70 (0.54, 0.91)
p = 0.0069
Median follow-up, months 13.9
Horn L, et al. NEJM 2018Mok T, et al ESMO IO 2018
Investigator-assessed progression-free survival
No. at risk
Atezolizumab 201 190 178 158 147 98 58 48 41 32 29 26 21 15 12 11 3 3 2 2 1 1
Placebo 202 193 184 167 147 80 44 30 25 23 16 15 9 9 6 5 3 3
Months
6-month PFS
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
100
90
80
70
60
50
40
30
20
10
0
12-month PFS30.9%
22.4%5.4%
12.6%
Pro
gre
ss
ion
-fre
e s
urv
iva
l (%
)
Atezolizumab
+ CP/ET
Placebo
+ CP/ET
Censored+
Atezolizumab
+ CP/ET
(N = 201)
Placebo
+ CP/ET
(N = 202)
PFS events — no. (%) 171 (85.1) 189 (93.6)
Median PFS — months (95% CI)
5.2(4.4, 5.6)
4.3(4.2, 4.5)
HR (95% CI)0.77 (0.62, 0.96)
p = 0.017
Median follow-up, months 13.9
Clinical data cut-off date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval. HR, hazard ratio; CP/ET, carboplatin + etoposide.Adapted from The New England Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, Epub ahead of print. Copyright © 2018. Massachusetts Medical Society.
Horn L, et al. NEJM 2018Mok T, et al ESMO IO 2018
Confirmed objective response and duration of response
• a Censored. b At clinical cut-off date: April 24, 2018. CR, complete response; EFS, event-free survival; PD, progressive disease; PR, partial response; SD, stable disease. • Data derived from The New England Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, Epub ahead of print.
2,5
60,2
20,9
10,9
1,0
64,4
21,3
6,9
CR CR/PR SD PD
70
60
50
40
30
20
10
0
Re
sp
on
se
(%
)
Atezolizumab + CP/ET
Placebo + CP/ET
Duration of response
Atezolizumab
+ CP/ET
(N = 121)
Placebo
+ CP/ET
(N = 130)
Median duration — months
(range)
4.2
(1.4a to 19.5)
3.9
(2.0 to 16.1a)
HR (95% CI) 0.70 (0.53, 0.92)
6-month event-free rate — % 32.2 17.1
12-month event-free rate — % 14.9 6.2
Patients with ongoing
response — no. (%)b18 (14.9) 7 (5.4)
Horn L, et al. NEJM 2018Mok T, et al ESMO IO 2018
Horn L, et al. NEJM 2018Mok T, et al ESMO IO 2018
T Mok, et al. IMpower133 https://bit.ly/2JZp0E6
• Median duration of treatment (range):
– Atezolizumab: 4.7 months (0–21)
– Median duration of chemotherapy (range) in atezolizumab + CP/ET vs. placebo + CP/ET
– Carboplatin: 2.3 (0–4) vs. 2.2 months (0–4)
– Etoposide: 2.3 (0–4) vs. 2.2 months (0–4)
• Median no. of treatment doses (range):
– Atezolizumab: 7 (1–30)
• Median no. of doses of chemotherapy (range) in atezolizumab + CP/ET vs. placebo + CP/ET:
– Carboplatin: 4 (1–6) vs. 4 (1–5)
– Etoposide: 12 (1–18) vs. 12 (2–15)
Safety summary
A Safety population; safety analyses were conducted according to the treatment received. b Incidence of treatment-related AEs and AEs leading to withdrawal from any treatment are for any
treatment component. Multiple occurrences of the same AE in one patient were counted once at the highest grade for the preferred term. AE, adverse event.
Table from The New England Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, Epub ahead of print. Copyright ©
2018. Massachusetts Medical Society. Reprinted with permission. Additional data derived from The New England Journal of Medicine, Horn L, et al, Epub ahead of print.
Patients — no. (%)
Atezolizumab
+ CP/ET
(N = 198)a
Placebo +
CP/ET
(N = 196)a
Patients with ≥ 1 AE 198 (100) 189 (96.4)
Grade 3–4 AEs 133 (67.2) 125 (63.8)
Grade 5 AEs 4 (2.0) 11 (5.6)
Treatment-related AEsb 188 (94.9) 181 (92.3)
Treatment-related Grade 3–4 AEs 112 (56.6) 110 (56.1)
Treatment-related Grade 5 AEs 3 (1.5) 3 (1.5)
Serious AEs 74 (37.4) 68 (34.7)
Treatment-related serious AEsb 45 (22.7) 37 (18.9)
AEs leading to withdrawal from any treatmentb 22 (11.1) 6 (3.1)
AEs leading to withdrawal from carboplatin 5 (2.5) 1 (0.5)
AEs leading to withdrawal from etoposide 8 (4.0) 2 (1.0)
T Mok, et al. IMpower133 https://bit.ly/2JZp0E6
Most frequently observed AEs
a Safety population; safety analyses were conducted according to the treatment received. Table from The New England
Journal of Medicine, Horn L, et al, First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung
Cancer, Epub ahead of print. Copyright © 2018. Massachusetts Medical Society.
Treatment-related AEs — no. (%)> 5% Grade 3–4 AEs in either treatment group
Atezolizumab + CP/ET
(N = 198)a
Placebo + CP/ET
(N = 196)a
Grade 1–2 Grade 3–4 Grade 5 Grade 1–2 Grade 3–4 Grade 5
Neutropenia 26 (13.1) 45 (22.7) 1 (0.5) 20 (10.2) 48 (24.5) 0
Anaemia 49 (24.7) 28 (14.1) 0 41 (20.9) 24 (12.2) 0
Neutrophil count decreased 7 (3.5) 28 (14.1) 0 12 (6.1) 33 (16.8) 0
Thrombocytopenia 12 (6.1) 20 (10.1) 0 14 (7.1) 15 (7.7) 0
Leukopenia 15 (7.6) 10 (5.1) 0 10 (5.1) 8 (4.1) 0
Febrile neutropenia 0 6 (3.0) 0 0 12 (6.1) 0
Immune-related AEs — no. (%)> 1% Grade 3–4 AEs in either treatment group
Atezolizumab + CP/ET
(N = 198)a
Placebo + CP/ET
(N = 196)a
Grade 1–2 Grade 3–4 Grade 5 Grade 1–2 Grade 3–4 Grade 5
Rash 33 (16.7) 4 (2.0) 0 20 (10.2) 0 0
Hepatitis 11 (5.6) 3 (1.5) 0 9 (4.6) 0 0
Infusion-related reaction 7 (3.5) 4 (2.0) 0 9 (4.6) 1 (0.5) 0
Pneumonitis 3 (1.5) 1 (0.5) 0 3 (1.5) 2 (1.0) 0
Colitis 1 (0.5) 2 (1.0) 0 0 0 0
Pancreatitis 0 1 (0.5) 0 0 2 (1.0) 0
T Mok, et al. IMpower133 https://bit.ly/2JZp0E6
AEs in patients who underwent PCI or palliative TR
a Safety population; safety analyses were conducted according to the treatment received (1 patient randomized to the control
arm received a dose of atezolizumab). b AEs with onset date on or after date of PCI administration.
CNS-related AEs — no. (%) Atezolizumab + CP/ET Placebo + CP/ET
All patients
(N = 198)a
Patients with PCI
(N = 23)a
All patients
(N = 196)a
Patients with PCI
(N = 21)a
Headache 24 (12.1) 8 (34.8) 23 (11.7) 4 (19.0)
Aesthenia 25 (12.6) 5 (21.7) 20 (10.2) 2 (9.5)
Dizziness 19 (9.6) 2 (8.7) 11 (5.6) 0
Insomnia 15 (7.6) 2 (8.7) 13 (6.6) 1 (4.8)
Fall 8 (4.0) 2 (8.7) 4 (2.0) 1 (4.8)
Balance disorder 2 (1.0) 1 (4.3) 0 0
Lethargy 2 (1.0) 1 (4.3) 1 (0.5) 0
Syncope 5 (2.5) 1 (4.3) 1 (0.5) 0
Agitation 1 (0.5) 0 1 (0.5) 1 (4.8)
Confusional state 3 (1.5) 0 3 (1.5) 1 (4.8)
Howrepresentative isthe population
included?
• No PS 2• 9% Brain Mets• LDH?
Horn L, et al. NEJM 2018
NCCN V1.2009Fruh M, et al. Ann Oncol 2013
Combination chemo
Consider PCI or MRI brain surveillance
Extensive[1]
(T3,4; Stage IV; no localized
symptomatic sites or brain metastases)
Metastatic[2]
(Stage IV)
Thoracic RT if responsive to therapy and good PS
(category 1 for LS)
Regimen NCCN ESMO Comments
EPATEZO ✓ 1 Preferred
EP ✓ 2A ✓ I,B
EC ✓ 2A ✓ I,B
IP ✓ 2A ✓ II,C If E not indicatedPreferred regimen in Japan
IC ✓ 2A
GC ✓ II,C Poor PS + E not indicated
IV/PO TP ✓ II,C If E not indicated
WHAT THE GUIDELINES SAY…
NCCN
ESMO
Both
Good PS with any response to first-line treatment should be evaluated for PCI [II, B]
Routine use of thoracic RT is not
recommended by ESMO (IIC)
Some notes to conclude…
▪ Majority of patients are diagnosed with advanced stage with poorprognosis with conventional EP
▪ Combination of CT/atezolizumabin the 1L setting did improve OS; pending results from KN604 and CASPIAN in 1L
▪ Disappointing results with ICIs in the 2L and in the maintenancesetting
▪ Immunotherapy in combination seems the most promising option; multiple immunotherapy combination trials ongoing
▪ Identifying subsets of patients more likely to benefit from ICIs, animportant research goal
Some hope for the future…
Hendriks L, et al. Expert Review Anticancer Therapy 2019
