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