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Dra. LianesHospital de Mataró
Tratamiento actual del CMP
TRATAMIENTO ACTUAL DEL CMP
GGCP2019 La Coruña
Ponente: Lianes Barragan, Pilar
Hospital de Mataró.
Instituto de Investigación IGTIP.
Disclosure Information
Honoraria: Roche,
Consulting or advisory role: AstraZeneca, Boehringer-Ingelheim, Roche/Genentech, Eli
Lilly and Company,, Merck Sharp & Dohme,and Bristol-Myers Squibb.
Travel financial support: Roche, Boehringer-Ingelheim, , and Bristol-Myers Squibb.
Resarch Clinical Trial: Roche, Boehringer-Ingelheim, Merck Sharp & Dohme
CMP ACTUAL
Introducción
Biología
Terapias dirigidas
Inmunoterapia
Agentes citotóxicos
Conclusiones
Agenda
CMP ACTUAL: Introducción
SCLC is a High-Grade Neuroendocrine Tumor
12-15% of total new lung cancer diagnosis
Strong association to tobacco (only 2% are never-smokers)
SCLC can also develop from histologic transformation of NSCLC
(5% adenocarcinoma series)
70% of cases with advanced disease at diagnosis
High response rates with 1L CT (~75%)
Rapid emergence of resistance and poor long-term survival rates
(15-20% at 2y and <2% at 5y) and mOS of 10-12 months
H&E Stain of SCLC Specimen
CMP ACTUAL
Introducción
Biología
Terapias dirigidas
Inmunoterapia
Agentes citotóxicos
Conclusiones
Agenda
L i t t le p rogress in SCLC drug a rmamentar ium compared to NSCLC
Jordan et al. Cancer Discov. 2017; J S Ross et al. J Clin Pathol 2014;67:772-776
Lung Adenocarcinoma SCLC
D r i v e r s v s . Tu m o r s u p r e s s o r s
Complex genomic alterations in SCLC
WES of 110 SCLC tumor samples. But, important considerations: majority of surgical samples, primary lung organ and treatment-naïve George Nature 2015
• Nearly universal loss-of-function mutations in TP53 and RB
• Very few actionable targetable driver alterations
• Amplification of FGFR1, SOX2 and MYC family of oncogenes
• Inactivating mutations in NOTCH family genes found in 25% of SCLC
Molecular subtypes in SCLC
Rudin et al. Nat Rev Cancer 2019
Molecular subtypes in SCLC
Rudin et al. Nat Rev Cancer 2019
• Based on transcriptomic and epigenomic data
SCLC-A
ASCL1 high
NeuroD1 low
MYCL
SCLC-N
NeuroD1
high
MYC
SCLC-Y
YAP1
Intact
RB
SCLC-P
POU2F3
NE (INSM1) Not NE
Drug sensitivity differs among the different subgroups
IGFR1
AURKA
DLL3 BCL2LSD1
SCLC-Inflamed (SCLC-I) is a new SCLC subtype
Carl Gay, WCLC 2019
more
mesenchym
al
more
epith
elia
l
Gay et al.)
SCLC-I demonstrate high expression of HLAs, IFN-γ-responsive
genes, immune checkpoints, suggesting vulnerability to immune
checkpoint blockade (ICB).
Expression of antigen presentation genes Expression of IFN-γ T-cell GEP
Ayers et al., JCI, 2017;
Cristescu et al., Science 2018
Carl M. Gay, MD Anderson Cancer Center, USA
SCLC-I demonstrate high expression of HLAs, IFN-γ-responsive genes,
immune checkpoints, suggesting vulnerability to ICB
Adapted from Sabari, J. K. et al. (2017) Unravelling the biology of SCLC: implications for therapyNat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.71
QUE HAY DE NUEVO EN PRIMERA LÍNEA?
CARCINOMA MICROCÍTICO
CONVERT trial: Normo vs hyperfractionated RT in LS-SCLC
Faivre-Finn et al. Lancet Oncol 2017.
CONVERT trial: Normo vs hyperfractionated RT in LS-SCLC
Faivre-Finn et al. Lancet Oncol 2017.
Conclusions of CONVERT trial
• Survival in both arms was higher than previously reported [CONVERT 5y OS 34% and 31 % (ns) vs Turrisi 26% vs 16% (sign)]
• RT-related toxicities were lower than expected likely due to the use of modern RT techniques (3D and IMRT) and involved instead of elective nodal RT
• No difference in G3/4 acute oesophagitis (BD vs OD) • 45Gy in 30F BD should continue to be regarded as SoC because CONVERT is not
an equivalence trial
• EORTC: Once daily (OD) RT 60-66 Gy still the most common used regimen
• After CONVERT publication, concurrent BD RT increased (32% 42%)
Clinical trials assessing consolidation: ADRIATIC, STIMULI & ACHILES
ADRIATIC (AZ) STIMULI (ETOP)
ACHILES (Roche
MO40379)
Clinical trials assessing concurrent CRT+ IO: MK7339-013, NRG
NCT03811002(NIH-NRG)
MK7339-013(MSD)
SEGUNDA LÍNEA
Del3p (1982) TP53m (1989) TNM (2007)
ASCL1(1997)
GNW (2012/16)
Current Standard of Care in SCLC
Inicial treatment
Concurrent thoracicradiation for limitedstage disease
+/- PCI +/- thoracicRT
First line therapy: Standard of care is platinum + etoposide
Maintenance
Not approvedSOC
Recurrent disease
< 6 months:
Subsequent Therapy
TopotecanOther options?
>6 months:
Subsequent Therapy:
Original regimen
*May be considered in selected patints with low-bulk metastasic ES ho have complete or nearcomplete response after initial systemic therapy
* EORTC trial: patients who has responded to ChT, PCI improved OS
• Keyresults
Pro
po
rtio
n o
f o
ve
rall
su
rviv
al 1.0
0.8
0.6
0.4
0.2
0
0 10 20 30Months after randomization
40 50
OS
Carboplatin +
etoposide
Topotecan
Pro
po
rtio
n o
f p
rog
ressio
n-f
ree
su
rviv
al
1.0
0.8
0.6
0.4
0.2
0
0 10 122 4 6 8
Months after randomization
PFS
Carboplatin +
etoposide
Topotecan
Carboplatin-Etoposide Versus Topotecan as Second-Line Treatment for Sensitive Relapsed Small-Cell Lung Cancer: Phase 3 Trial
– Grade 3–4 neutropenia was observed in 23% vs. 36% (p=0.035) patients in the carboplatin + etoposide
vs. topotecan arms, respectively. Treatment-related death occurred in 2 patients in the topotecan arm
(both febrile neutropenia)
• Conclusion
– In patients with sensitive relapsed SCLC, carboplatin + etoposide demonstrated significant
improvements in PFS and ORR, but not OS, compared with topotecan and had a lower incidenceof
neutropenia
CMP ACTUAL
Introducción
Biología
Terapias dirigidas
Inmunoterapia
Agentes citotóxicos
Conclusiones
Agenda
CDK4/6 inhibition may protect Rb-intact cells from chemotherapy toxicitywithout diminishing the therapeutic effect in SCLC Rb mutant tumors
Rb-deficient SCLC
Chemotherapy
High chemo-toxicity Antitumor efficacy
M
G2 SCLCRb mut G1
S
M
G2 SCLC ChemotherapyRb mut G1
S
Reduced chemo-toxicity in Rb-intact cells
Antitumor efficacy not reduced
CDK4/6 inhibitionG1-arrest Rb-intact cells
M
G2
Rb wtG1
S
G1 Therapeutics Announces Positive Trilaciclib Phase 2a ToplineData Showing Robust Myelopreservation Benefits in Patients withSmall Cell Lung Cancer
Weiss JM et a. Annals of Oncology. 27 August2019
• 77 1L ES SCLC patients, EP+/- trilaciblib. Primary endpoint:
myelopreservation
• Improved myelopreservation endpoints including G3/4 Heme AEs
• Fewer supportive care interventions and dose reductions
• ORR trilaciclib 66.7%, placebo 62.2% (p=0.6759)
• PFS trilaciclib 6.2 months, placebo 5.0 months (hazard ratio 0.6, p=0.06)
SLFN11 expression in SCLC shifts with chemoresistance and predicts PARPi sensitivity
Cell lines Primary tumors
1. Rudin WCLC 2017. 2. Gardner et al., Cancer Cell 2017. 3. Lok et al., Clin Cancer Res, 2017
High SLFN11 predicts improved outcome withTemozolomide/veliparib
Placebo/TMZ Veliparib/TMZ
SLFN11-positive tumors (p=0.01)
Pro
gres
sio
n F
ree
Surv
ival
Months
SLFN11+ (Veliparib/TMZ, n=14)
SLFN11+ (Placebo/TMZ, n=11)
SLFN11 positive = H-score ≥1
PFS
OS
Pietanza, Byers et al., J Clin Oncol
2018
ORR 41.7%
Combination Olaparib and Temozolomide in
Relapsed Small Cell Lung Cancer
Farago A. et al., Cancer Discovery.
2019
DNA Damage and Repair: PARP inhibitors
Owonikoko TK. et al. J Clin Oncol.
2019
Veliparib Combined with Cisplatin or Carboplatin and Etoposide in Front-
Line Extensive SCLC
DNA Damage and Repair: PARP inhibitors
• In the context of TP53/RB1 deletion, MYC:• Accelerates oncogenesis and promotes metastasis
• Drives shift to NEUROD1-high, neuroendocrine-low subtype of SCLC
• Correlates with sensitivity to aurora kinase inhibition
Mollaoglu et al., Cancer Cell 2017
Barr AR, Gergely F. J Cell Sci 2007;120:2987–96; Marumoto T, et al. J Biol Chem 2003;278:51786–95; Sos ML et al. PNAS 2012; Owonikoko et al. WCLC 2016.
The role of AAK in mitosis
Metaphase in wild
type/control cells
Metaphase in cells treated with AAK inhibitor
Chromosomes Mitotic spindle Centrosome
Cell entering
mitosis
Bipolar spindles
(alignment defects)
Lagging
chromosomes
Telophase
bridges
Stages of mitosis where AAK inhibitor exerts its effects
MYC and sensitivity to aurora kinase inhibition
SCLC: an heterogeneous disease treated as a single one
Potentially effective therapies considered as “no useful” drugs due to negative results in clinical trials, but with theissue of inappropiate patient selection
Study Drug arms Results Key message
Pietanza et al. JCO 2018
Temozolamide +/-veliparib (PARPi)
Negative SLFN11 IHC expression may predict significantimprovement in PFS and OS for the combination
Owonikoko et al. JTO 2019
Paclitaxel +/- alisertib(AURKAi)
Negative MYC IHC expression & mutations in the cell cycle detectedby ctDNA may predict longer PFS for the combination
Chung et al. AACR2019
Pembrolizumab ORR 19% PDL1 CPS positivity do predict an improved ORR (36% vs 6%) and OS (14.6m vs 7.7m)
Delta-Like Protein 3 (DLL3): A Novel Target in Neuroendocrine Tumors
• The Notch signaling pathway acts as a developmental pathway essential in the control of differentiation of neuroendocrine cells of the lung
• An atypical inhibitory Notch ligand normally expressed during development
• Induced by the key neuroendocrine transcription factor, ASCL1
• Cell surface expression in > 80% of small cell lung cancer (SCLC) and large cell neuroendocrine cancers
• On both cancer stem cells and other tumor cells, but not normal adult tissues
• Not prognostic, and does not predict response to chemotherapy
p53-/-
Precancerous Lung
Stem Cell
MatureNeuroendocrine
Tumor Cell
p53-/- RB1-/-
ASCL1
NotchDLL3
Cancer Stem Cell
Tumor Progenitor
CellTum
or-
Init
iati
ng
Ce
lls
Saunders et al., Sci Transl Med 2015
SCLC
SCLC
Randomized Phase III Maintenance Trial (MERU)
Non
Progressors
Platinum-based Doublet
x 4
Placebo
Rova-T
Core needle biopsy preferred Stratified based on: DDL 3 high/low
PCIN = 750
Randomized Phase III Second-line Trial(TAHOE)
Relapsed Patients
Topotecan1.5mg/m2 x 5 days
q 21 days
Rova-T
2:1
Rova-T Phase III Trials
DLL-3 high
CMP ACTUAL
Introducción
Biología
Terapias dirigidas
Inmunoterapia
Agentes citotóxicos
Conclusiones
Agenda
Frontline Treatment
Immunotherapy in SCLC
Ipilimumab + Chemotherapy failed to improve survival in 1L ES-SCLC
Phase 3 Trials of I-O as 1L Induction + Maintenance
1. Clinicaltrials.gov. NCT03066778. Accessed September 17, 2018. 2. Clinicaltrials.gov. NCT03043872. Accessed September 17, 2018. 3. Horn L et al. Poster presentation at ESMO 2016. 1431TiP. 4. Clinicaltrials.gov. NCT02763579. Accessed September 17, 2018.
IMpower133: Global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated atezolizumab + carboplatin + etoposide in 1L ES-SCLC
Inmunoterapia microcítico EE: Impower133
This article was published on September25, 2018, at NEJM.org. DOI: 10.1056/NEJMoa1809064
IMpower133: atezolizumab + carboplatin + etoposide in 1L ES-SCLC
CARCINOMA MICROCÍTICO
Horn et al., N Engl J Med, 2018
Inmunoterapia microcítico EE: Impower133
PFS
OS
Febrile neutropenia
Leukopenia
Neutropenia
Anemia
Neutrophil count decreased
Thrombocytopenia
PlaceboAtezolizumab
40% 30% 20% 10% 0 10% 20% 30% 40%
40% 30% 20% 10% 0 10% 20% 30% 40%
Hepatitis
Rash
Grade 3–4 AEs
Grade 1–2 AEs
Grade 3–4 AEs
Grade 1–2 AEs
Infusion-related reaction
Pneumonitis
Colitis
Pancreatitis
Grade 3–4 AEsGrade 1–2 AEs
Grade 3–4 AEs
Grade 1–2 AEs
Grade 5 AE
PlaceboAtezolizumab
IMpower133: atezolizumab + carboplatin + etoposide in 1L ES-SCLC
CARCINOMA MICROCÍTICO
ADVERSE EFFECTS
Reck ESMO 19
IMpower133: Primary PFS, OS, and safetycin a Ph I/III study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC
IMPOWER133: UPDATED OVERALL SURVIVAL (OS) ANALYSIS OF FIRST-LINE (1L) ATEZOLIZUMAB (ATEZO) + CARBOPLATIN + ETOPOSIDE
IN EXTENSIVE-STAGE SCLC (ES-SCLC)
Reck M, et al ESMO 2019
Does brain RT increase CNS toxicity in IMpower133?
21 patients
23patients
EP + Atezo
EP
Prophylactic cranial irradiation (PCI)
was permitted
44 patients in IMpower133
received PCI
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.
Mok, et al. ESMO Asia 2018 (LBA1)
AEs in patients who underwent PCI or palliative TR
CNS-related AEs —
no. (%)Atezolizumab + CP/ET Placebo + CP/ET
All patients
(N = 198)a
Patients with PCI
(N = 23)a
Patients with AEs after PCIb
(N = 23)a
All patients(N = 196)a
Patients with PCI
(N = 21)a
Patients with AEs after PCIb
(N = 21)a
Headache 24 (12.1) 8 (34.8) 5 (21.7) 23 (11.7) 4 (19.0) 4 (19.0)
Aesthenia 25 (12.6) 5 (21.7) 1 (4.3) 20 (10.2) 2 (9.5) 0
Dizziness 19 (9.6) 2 (8.7) 0 11 (5.6) 0 0
Insomnia 15 (7.6) 2 (8.7) 1 (4.3) 13 (6.6) 1 (4.8) 1 (4.8)
Fall 8 (4.0) 2 (8.7) 1 (4.3) 4 (2.0) 1 (4.8) 1 (4.8)
Balance disorder 2 (1.0) 1 (4.3) 1 (4.3) 0 0 0
Lethargy 2 (1.0) 1 (4.3) 1 (4.3) 1 (0.5) 0 0
Syncope 5 (2.5) 1 (4.3) 0 1 (0.5) 0 0
Agitation 1 (0.5) 0 0 1 (0.5) 1 (4.8) 1 (4.8)
Confusional state 3 (1.5) 0 0 3 (1.5) 1 (4.8) 1 (4.8)
• In patients with PCI, 1 patient in the atezolizumab group withdrew from treatment due to a CNS-related AE (aesthenia)
• The number of patients who received palliative TR was very low and no unexpected AEs were observed
Overall survival with durvalumab plus platinum-etoposide in first-line extensive-stage SCLC: Results from the CASPIAN study
Paz Ares WCLC 19
CASPIAN STUDY: Overall survival with durvalumab plus platinum-etoposide in first-line extensive-stage
SCLC: Results from the CASPIAN study
Paz Ares
WCLC 19
• 94.9% and 77.6% of patients had PD-L1 expression <1% on TCs and ICs,
respectively
• Due to low PD-L1 expression, a 1% cut-off was used in post-hoc analyses
80,1
14,8
3,6 0,4 1,1
58,1
19,510,8 7,2 4,3
0
20
40
60
80
100
0 >0–<1% ≥1–<25% ≥25–<50% ≥50%
TCIC
PREVALENCE OF PD-L1 EXPRESSION ON TCs OR ICs*P
atie
nts
(%)
†
Paz Ares ESMO 19
OVERALL SURVIVAL BASED ON PD-L1 EXPRESSION
• Durvalumab + EP was associated with improved OS vs EP, regardless
of PD-L1 expression with a 1% cut-off
• No significant interaction was observed with OS based on PD-L1 expression
as a continuous variable
(TC, p=0.54; IC, p=0.23); similar results were observed with PFS and ORR
HR (95% CI)
ITT (n=537) 0.73 (0.591–0.910)
PD-L1 evaluable (n=277) 0.65 (0.482–0.864)
IC <1 (n=215) 0.64 (0.462–0.897)
IC ≥1 (n=62) 0.69 (0.370–1.283)
TC <1 (n=263) 0.66 (0.491–0.896)
TC ≥1 (n=14) 0.46 (0.119–1.793)
2.00.500.250.10 1.0
Favours durvalumab + EP Favours EP
CASPIAN vs IMpower 133 CASPIAN
Durvalumab+EP EP
(n=268) (n=269)
IMpower 133
Atezolizumab +EC EC + placebo
(n= 201 ) (n=202)
Median age 62 63 64 64
Male,% 70.9 68.4 64 65
White/Asian,% 85.4/13.4 82.2/15.6 81/16 79/18
PS 0/1,% 36.9/63.1 33.5/66.5 36/64 33/67
Smoker,% 91.8 94.4 95.5 98.5
Brain meta,% 10.4 10.0 8 9
Liver meta,% 40.3 38.7 38 36
Study design Open label Open label Placebo control Placebo control
Carbo/cispla 78.5/24.5 78.2/25.2 100/- 100/-
No.chemo (med) 4 6 4 4
PCI,% - 8 11 10
CASPIAN vs IMpower 133
CASPIAN
Durvalumab+EP EP
(n=268) (n=269)
IMpower 133
Atezolizumab +EC EC + placebo
(n= 201 ) (n=202)
OS,m 13.0 10.3
HR=0.73
12.3 10.3
HR=0.7
OS at 12m,% 53.7 39.8 51.7 38.2
PFS, m 5.1 5.4
HR=0.78
5.2 4.3
HR=0.77
ORR, % 67.9 57.6 60.2 64.4
DOR, m 5.1 5.1 4.2 3.9
G 3/4 AEs 61.5 62.4 67.2 63.8
irAE 19.6 2.6 39.9 24.5
Biomarker NA NA Only bTMB available
Poststudy Tx 42 44 50/14/1/5 57/18/7
Differences in irAEs reporting may be explained by the open design of
the CASPIAN trial
1. Maintenance effect or Delayed effect of IO?
Horn L et al NEJM 2018Paz-Ares L et al WCLC 2019
CASPIAN IMpower133
OS
PFS
OS
PFS
Nivolumab, Nivolumab + Ipilimumab (CM-451), and Pembrolizumab
failed in the maintenance setting
2. Predictive Biomarker to Select Patients Benefit from IO?
Horn L et al NEJM 2018Paz-Ares L et al WCLC 2019
CASPIAN IMpower133
OS
PFS
OS
PFS
bTMB did not differentiate benefit of atezolizumab in IMpower133
Horn L et al NEJM 2018
Biomarker study is not available in CASPIAN study !
KEYNOTE-604: Study Design
Only patients with treated brain metastases were eligible.
Study NCT03066778. Clinicaltrials.gov website. Accessed July 2, 2019.
Eligibility Criteria:
• Newly diagnosed ES-SCLC
• ECOG PS 0 to 1
• No previous systemic
therapy for SCLC
• Tumor biopsy sample
Stratification
• Type of platinum (cisplatin
vs carboplatin)
• ECOG PS (0 vs 1)
• LDH (≤ULN vs ≥ULN)
(N=430)Co-primary end points
• Overall survival
• PFS-blinded independent central
review
Key secondary end points
• Objective response rate
• Duration of response
• Safety
• Patient-reported outcomes
Patients may be offered PCI at the discretion of the
investigator if they have an objective response after
4 study treatment cycles
Etoposide 100 mg/m2 on Days 1-3 combined with
either cisplatin 75 mg/m2 or carboplatin AUC 5 on
Day 1 of treatment cycle
Treat until PD,
unacceptable
toxicity,
treatment-
limiting
concomitant
illness,
noncompliancePlacebo IV x
31 cycles
Pembrolizumab
200 mg IV q3w x
31 cycles
Pembrolizumab 200 mg (q3w x 4)
+ Etoposide/Platinum IV
Placebo
+ Etoposide/Platinum IV
q3w x 4 cycles
Phase 3 study of first-line etoposide/platinum with or without pembrolizumab in ES-SCLC
R
1:1
Treatment after platinum 1L
Immunotherapy in SCLC
Efficacy of PD-1 Targeted Immunotherapy Agents in Relapsed SCLC
Median PFS(Months)
1-year PFS rate (%)
Median OS(months)
1-year OS rate (%)
Remarks
2L(+)
AtezolizumabIFCT-1603
1.4 <6.3 11.4 42.5 Platinum sensitive only
Pembrolizumab/Keynote 028 1.9 23.8 9.7 37.7 PD-L1 (+) only
Pembrolizumab/Keynote 158 2.0 23.7 8.7 40.2 Unselected
Nivolumab/Checkmate 032 1.4 11 4.1 27 Unselected
3L(+)
Durvalumab/Goldman et al. 1.5 14 4.8 28 Unselected
Nivolumab/Checkmate 032 1.4 19 5.6 28.3 Unselected
Pembrolizumab/KN028/158 2.0 16.9 7.7 34.3 PD-L1+/-
GEP (inflamed score) signature for prediction of benefitfrom pembrolizumab in advanced SCLC
T-cell-inflamed gene expression profile predicts for response and PFS among patients across 19 tumor types, including SCLC
Ott JCO 2019
CheckMate 451: study design10
• Currently enrolling patients
• Primary outcome measures:
– OS, PFS
• Secondary outcome measures:
– OS and PFS descriptive analyses: nivolumab vs nivolumab +
ipilimumab
CheckMate 331: study design11
• Primary outcome measures:
– OS
• Secondary outcome measures:
– PFS, ORR
Key eligibility criteria
• ED-SCLC
• Ongoing SD/PR/CR after 4 cycles of 1L PLT-CT
• No symptomatic CNS metastases
• Toxicities from prior therapy resolved to grade ≤1
• ECOG PS ≤1
Nivolumab
Placebo
Nivolumab+
Ipilimumab
Key eligibility criteria
• SCLC
• Recurrence/PD after 1L PLT-CT or CRT (≥4 cycles)
• ECOG PS ≤1
• No symptomatic CNS metastases
• No prior therapy with anti–CTLA-4, anti–CD137, anti–PD-1/PD-L1/PD-L2
Topotecan or Amrubicina
Ran
do
miz
e 1
:1:1
Ran
do
miz
e 1
:1
1L = first-line; CT = chemotherapy; CRT = chemoradiation therapy; CTLA-4 = cytotoxic T lymphocyte antigen-4; PD-1 = programmed-death 1; PD-L2 = PD ligand 2PLT = platinum-based; aWhere locally approved
N = 810 N = 480
Nivolumab
Phase 3 Studies With Nivolumab ± Ipilimumab in SCLC
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
Impact of Tumor Mutation Burden in patient selection
44 23 17 12 6 2 2 1 0 0 0 0 0 25 15 9 4 3 2 2 2 2 1 1 0 0
47 29 20 14 8 5 5 5 2 2 2 2 2 26 20 17 14 10 9 8 8 6 2 0 0 0
42 19 13 9 4 3 1 0 0 0 0 0 0 27 15 9 7 5 2 2 1 1 1 1 1 1
Months
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%
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)
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 Nivolumab + ipilimumab
Median (95% CI) OS, overall TMB-evaluable population: 3.9 (2.8, 6.1) months for nivolumab and 7.0 (3.2, 8.8) months for nivolumab + ipilimumab
NR = not reached
No. at risk
Medium
High
Low
CheckMate 032 Exploratory TMB Analysis Nivo ± Ipi in Previously Treated SCLC
• Consecutive SCLC pts treated with PD1/PD-L1 inhibitors alone, or in combination with CTLA-4
inhibitors at 6 US academic institutions
• Recruitment period 7/2014 – 12/2018; n = 183
Overall Survival
Biagio Ricciuti et al. WCLC 2019
Impact of irAEs in SCLC patient outcomes in
SCLC has a relative “immune-cold” fenotype
Multiplexed immunofluoresceassay of 90 SCLC tumor samples
Stroma of SCLC containsabundance of T-reg
Immune-cold phenotypeconsisting of:
low PDL1 expressionlow TILshigh B7-H3 expression
Carvajal-Hausdorf JITC 2019
Reasons to explain the not-reached expectations fromimmune checkpoint blockade in SCLC
Strategies to increase the number of T cells generated within the lymphoid compartment.
1. Chemotherapy2. Anti-CTLA.43. Vaccines4. Radiation5. DC activation: CD40, TLR agonists6. T cell stimulatory molecule agonists: GITR, OX40, 4-1BB7. ACT with CAR or TCR transgenic T cells8. ACT with TILs9. IL2 10.Important to target both the lymphoid compartment and
the tumor microenvironment
CMP ACTUAL
Introducción
Biología
Terapias dirigidas
Inmunoterapia
Agentes citotóxicos
Conclusiones
Agenda
Background
• Liposomal irinotecan (nal-IRI) is a long-acting, liposomal encapsulation of irinotecan
•
•
The half-life (t½) of total irinotecan following administration of nal-IRI is 25.8 hours
95% of irinotecan remains contained within the liposome during circulation
• The ratio between total and encapsulated forms did not change from 0 to 169.5 hours post-dose
• ~5-fold higher levels of drug are found in tumors compared with plasma at 72 hours, suggesting
local metabolic activation of irinotecan
~80,000
Irinotecan
Salt
Molecules
PEG-DSPE
~110 nm
Internal
Aqueous
Space
Lipid
Membrane
Paz-Ares L, et al. J Thorac Oncol 2019;14(suppl):Abstr OA03.03
Initial Efficacy and Safety Results of Irinotecan Liposome
Injection (nal-IRI) in Patients with Small Cell Lung
• Lurbinectedin (Zepsyre®, PM1183) is a novel anticancer drug that inhibits activated transcription, induces DNA double-strand breaks generating apoptosis, and modulates tumor microenvironment.
Inhibition of active transcription
I- Binding of Lurbinectedin to the DNA
(Cytosine Guanine-rich motifs)
II- Phosphorylation of Pol II
III- Stalling of elongating Pol II
IV- Recruitment of the ubiquitin-
proteasome machinery
V- RNA Pol II degradation
VI- Recruitment of XPF and
Generation of DNA breaks
VII- Induction of apoptosis
Tumor Microenvironment Effect
Inhibition of Tumor Associated Macrophages (TAM)
Lurbinectedin (Zepsyre®, PM1183)
Belgiovine et al, 2017 BrJ Cancer 117:628-38Cespedes et al 2016 Dis ModelMech. 9:1461-71
Sensitive disease: ORR= 45.0%Resistant disease: ORR= 22.2%
ORR: 35.2%; mOS: 9.3 months
Aug 2019: PharmaMar will submit NDA for lurbinectedin under acceleratedapproval in SCLC in the USA
Paz-Ares ASCO 2019
Lurbinectedin. Phase II single-agent lurbinectedin in 2nd line SCLC
Response
Evaluable patients
L+DOX
(q3wk)
L +TAX
(q3wk)L single-agent (q3wk)
Cohort A
L 3-5 mg FD D1 + DOX
50 mg/m2 D1
(n=21)
Cohort B
L 2 mg/m2 D1 + DOX
40 mg/m2 D1
(n=27)
L 2.2 mg/m2 D1
+ TAX 80 mg/m2 D1 &
D8
(n=7)
L 3.2 mg/m2 D1
(n=36)
CR 2 (10%) 1 (4%) 1 (14%) -
PR 12(57%) 9 (33%) 4 (57%) 13 (36%)
ORR 14 (67%) 10 (37%) 5 (71%) 14 (36%)
SD 3 (14%) 9 (33%) - 14 (39%)
PD 4 (19%) 8 (30%) 2 (29%) 9(25%)
DCR 17 (81%) 19 (70%) 5 (71%) 27 (75%)
DOR (mo) 4.5 5.2 2.3 6.2+
PFS (mo) CTFI >30d* 4.7 5.3 3.9 3.1+
PFS (mo) Platinum-
sensitive5.8 6.2 3.9 4.6+
D, day; DCR, disease control rate; DOR, duration of response; FD, flat dose; mo, months; q3wk, every 3 weeks; CTFI, chemotherapy free interval.
ATLANTIS: Phase 3 global randomized study in relapsed SCLC
Primary endpoint OS
Farago et al., Future Medicine 2018
Primary prophylaxis with GCSF is mandatory in both arms
Paz-Ares et al. J Clin Oncol (2019): 8506-8506. Foster et al. JTO (2018): S581. Pietenza et at. J Clin Oncol (2018): 2386-2394.
CMP ACTUAL
Conclusiones
Agenda
CONCLUSIONES GLOBALES: UN PASO ADELANTECARCINOMA MICROCÍTICO
Lung adenocarcinoma
Small cell lung cancer
SEGUNDA LÍNEA: CÓMO IGNORAMOS BIOMARCADORES EN SCLC
CARCINOMA MICROCÍTICO
CÓMO PODRIA SER UN INFORME DE SCLC
+ PD1/L
Modified from Rudin WCLC2018
Biomarker-guided strategy for clinical trial design
Platinum-etoposide+ anti-PDL1
Front-line setting Refractory setting
SLFN11
MYC & cell cyclemutations
DLL3
POU2F3
PARPi + TMZ
AURKAi or CHK1i + chemotherapy
AMG757 & otherDLL3i (not RovaT!)
IGFR1 inh
PDL1/TMB/GEP/ NK cells/MDSc...
Combination of anti-PD(L)1 drugs with DDR agents orwith low dose ipilimumab for highTMB?
• El CMP se irá incorporando a la medicina de precisión en nuestra práctica clínica :
necesitamos pedir material¡¡
• Se esta intentando la clasificación en subtipos moleculares : ASCL1, NEUROD1, POU2F3, YAP1
SCLC-Inflamed
• Están emergiendo oportunidades terapeúticas basadas en dianas moleculares :
MYC, EZH2, SLFN11, DLL3, PARP1, NFIB
• QuimioInmunoterapia es primera línea de CMP- enfermedad extendida en un nuevo standard
pero necesitamos marcadores predictivos (PDL1 CPS, TMB, GEP signatures, study of immunosupressive molecules….)
• La sinergia de inmunoterapia y nuevos citotóxicos a investigar en la enfermedad resistente
Avances en el manejo del CMP: Conclus iones
Moitas graziñas ¡¡¡i