luis paz-ares hospital universitario doce de …...le tourneau c. et al. lancet oncol 2015;16:1324...

Luis Paz-AresHospital Universitario Doce de Octubre,

Madrid, Spain

• Agentes dirigidos a Dianas moleculares específicas

• Inmunoterapia• Medicina personalizada• Desarrollo de nuevos fármacos y

EECC

• Agentes dirigidos a Dianas moleculares específicas

• Inmunoterapia• Medicina personalizada• Desarrollo de nuevos fármacos y

EECC

NSCLC - Genotype

NTRK fusions

2015

EUCROSS StudyALK+, ROS +, NTRK + NSCLC

Entrectenib Phase I study

MET mut+ NSCLCCrizotinib Phase II Trial (Korea)

Drilon et al., ASCO 2016

N= 21; RR= 44%

Gainor et al. Cancer Discov 2016

Acquired Resistance to 2nd Generation TKIs

Gainor et al. Cancer Discov 2016

Acquired Resistance to 2nd Generation TKIs

J-ALEX study:PFS and response by IRF

Nokihara, et al. ASCO 2016. Abs 9008

…

CRIZOTINIB NEXT-GEN ALK TKI

NEXT-GENERATION ALK TKI

10-11 months 9-12 months

≈ 20 months

PFS1 PFS2

PFS

…

??+

Re-genotyping may be key for optimal sequencing strategies

• Sequencing strategies should be flexible; in some cases revisiting previous agents may be the best approach

Shaw AT, et al. N Engl J Med 2016;374:54−61.

Crizotinib Chemotherapy Lorlatinib Crizotinib

Ceritinib AUY922 Crizotinib

Biopsy Biopsy Biopsy Biopsy

Months: 6 12 18 24 30 36 42 48

Effect of therapy

Before lorlatinib Response to lorlatinib Resistance to lorlatinib Response to crizotinib

C1156YL1198FC1156Y

NSCLC - Genotype

NTRK fusions

2015

Lito et al. Science 2016Patricelli et al. Cancer Discov 2016

KRAS G12C Covalent Inhibitors

Lito et al. Science 2016Patricelli et al. Cancer Discov 2016

KRAS G12C Covalent Inhibitors

• Agentes dirigidos a Dianas moleculares específicas

• Inmunoterapia• Medicina personalizada• Desarrollo de nuevos fármacos y

EECC

Keynote 024: RR and OS

1. Reck, et al. N Engl J Med 2016; 2. Reck, et al. ESMO 2016

Response Rate

Rationale for Combining Immunotherapy With Other Therapeutic Modalities

Multiple mechanisms of potential synergy between the different treatment modalitiesCD8 T cellAdhesion molecules

(CAM-1) and death receptors (FAS)

Peptide pools

Vascular normalisationT-cell initiation

Cytokine release

CD8 T cellsT-cell functionMDSC

Tregs

Activation of apoptosisBlockage of cell cycle

TAAUpregulates MHCIAdhesion molecules/death receptorsAPM

CD8 T-cells(homeostatic peripheral expansion)

MDSC

Tregs

M2 macrophages

TAA cross-presentation

CD8 T-cells

Effector immune infiltrateRelease of tumor antigens (cascade)

Translocation of calreticulin

Radiation

Chemotherapy Targeted therapies

DC

Upregulation of MHCI

Uploading of APM

APM = antigen processing machinery; TAA = tumor-associated antigen.1. Adapted from Hodge JW. Semin Oncol. 2012;39:323–339; 2. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41–viii46; 3. Ménard C, et al. Cancer ImmunolImmunother. 2008;57:1579–1587; 4. Hannani D, et al. Cancer J. 2011;17:351–358; 5. Ribas A at al. Curr Opin Immunol. 2013:25:291–296.

Hellmann, et al. ASCO 2016

ORR

(%)

72 52 17 14 44 32 35 26 28 20 18 18 13 12

Overall <1% ≥1% ≥5% ≥10% ≥25% ≥50%

PD-L1 expressionTotal n=129

43

18

5754

64

78

92

23

14

2831

4044

50

0

20

40

60

80

100Nivo 3 q2w + ipi 1 q6/12w (pooled) Nivo 3 q2w

First-line immunotherapy combinations: nivolumab plus ipilimumab (CheckMate 012)

19

aObjective response rate in the response evaluable population (n=26) is 31%.

Ramucirumab + Pembro Phase I Trial

77% of evaluable patients experienced a decrease in target lesions

Herbst et al. al. ESMO 2016

IDO Inhibition

¿Como seleccionar pacientes candidatos a anti-PD-1/L1?

Teng et al. Cancer Res 2015

PEARLS Adjuvant ETOP-EORTC Trial (KeyNote 091) Randomized Phase III Trial

♦ Stage IB, II-IIIA NSCLC♦ Radically resected (R0)♦ Standard of care as

adjuvant CT

Pembrolizumab 3mg q21 for 18 injections

Placebo q21 for 18 injections

Stratification factors•Stage (IB versus II versus IIIA)•Histology (non-squamous versus squamous)•PDL-1 IHC expression (0 versus 1-49% versus > 50%)•No chemotherapy versus adjuvant platinum-based chemotherapy

PIs: L Paz-Ares & M O´Brien

Radiographic response (N=18)RECIST 1.1

N (%)

Partial Response 4 (22)

Stable Disease 13 (72)

Progressive Disease

1 (6)

Pathologic downstagingfrom pre-treatment clinical stage (N=18)

N (%)

Yes 7 (39)

No 11 (61)

Tumor pathologic response after neoadjuvant anti-PD-1 (N=17)

39% (95% CI 20-61% ) of per protocol patients, 7 of 18, had <10% residual viable tumor at resection

1 patient had a pathologic complete response

0 10 20 30 40 50 60 70 80 90 100

123456789

1011121314151617

Percent Pathologic Response

Major pathologic response

Minor or no response

Neo-Adjuvant Nivolumab – WOO trial

<10% residual viable tumor cells defines major pathologic response per Pataeret al. JTO 2012 Resected

Tumors

Forde et al., ESMO 2016

• Agentes dirigidos a Dianas moleculares específicas

• Inmunoterapia• Medicina personalizada• Desarrollo de nuevos fármacos y

EECC

InformationCommons

Kris M. et al. JAMA 2014; 311:1998

De S., Ganesan S. Ann. Oncol. 2016; ahead of print

Crowley E et al. Nat Rev Clin Oncol. 2013;10(8):472-84.

Blank CU et al. Science 2016; 352:658

Skoulidis et al. Cancer Discov 2015

Tumor Inmune Landscape of KRAS driven NSCLC

Koyama et al. Cancer Res 2016

KRAS-STK-11 NSCLC

Skoulidis et al. WCLC 2016

KRAS driven NSCLC -Co-mutations, Inmune landscape

and Benefit from anti-PD-1 inhibitors

Research programsConsortia, Cancer Moonshot but still fragmented

Clinical studiesLCMC, SHIVA, MATRIX

Molecular targeted agentsPartial inhibition of the pathwayToxicity of the combination

Intratumor heterogeneityCost

Tannock IF & Hickman JA NEJM 2016; 375: 1289

• Agentes dirigidos a Dianas moleculares específicas

• Inmunoterapia• Medicina personalizada• Desarrollo de nuevos fármacos y

EECC

Right Target Right Drug(specificity, selectivity, potency,

PK, bioavailability, ...)

Don’t advancemarginal drugs or

drugs to marginal targets

Don’t advance unless clear efficacy seen in clear

population in Ph.II

Right Patients

Marc Tessier-Lavigne, Yale Lecture 2011

[…] in contrast to the extensive number of hits one finds for the terms “cancer” and “biomarker” in a search on the PubMed database, the true number of clinically applied predictive biomarkers is staggeringly small.

Simon R, Roychowdhury S. Implementing personalized cancer genomics in clinical trials. Nat Rev Drug Discov. 2013 May;12(5):358-69.

Chin L. et al. Nat. Med. 2011; 17:297

Biankin AV et al. Nature 2015; 526:361

• BATTLE• I-SPY2• LUNG-MAP• MATRIX

• Imatinib Basket

• BRAF+• NCI MATCH

Le Tourneau C. et al. Lancet Oncol 2015;16:1324

741 screened

496 profiled

293 enrolled

191 treated

Le Tourneau C. et al. Lancet Oncol 2015;16:1324

In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30).

Some ongoing phase III studies of anti-PDL1/PD1 therapy in combination with chemotherapy and

immune doubletsStudy name Study description

Chemo

Anti-CTLA4

Atezolizumab

IMpower130 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower131 Atezolizumab + platinum doublet chemotherapy (squamous)

IMpower132 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower150 Atezolizumab + platinum doublet chemotherapy ± bevacizumab (non-squamous)

Pembrolizumab

KEYNOTE-407 Pembrolizumab + platinum doublet chemotherapy (squamous)

KEYNOTE-189 Pembrolizumab + platinum doublet chemotherapy (non-squamous)

Nivolumab

CheckMate 227Nivolumab monotherapy or + ipilimumab or + platinum doublet chemotherapy(squamous and non-squamous)

Durvalumab

MYSTIC Durvalumab monotherapy or + tremelimumab (squamous and non-squamous)

NEPTUNE Durvalumab + tremelimumab (squamous and non-squamous)

Rosenblatt M. NEJM 2017; 376:52-60

• Analysis of PFS by BICR was consistent with the investigator-based analysis: HR 0.28 (95% CI 0.20, 0.38), p<0.001; median PFS 11.0 vs 4.2 months.

Population: intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data; CI, confidence interval

AURA3 primary endpoint:PFS by investigator assessment

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18

Prob

abili

ty o

fpr

ogre

ssio

n-fr

ee s

urvi

val

No. at riskOsimertinib

Platinum-pemetrexed

Months279140

24093

16244

8817

507

131

00

Median PFS, months (95% CI)

HR (95% CI)

10.1 (8.3, 12.3)

0.30 (0.23, 0.41)

p<0.0014.4 (4.2, 5.6)

OsimertinibPlatinum-pemetrexed

Phase I/II studies of osimertinib…AURA and AURA2data

cut off date

Meeting/Journal Year Author N

ORR for

T790M

mPFSfor

T790MWaterfall plot

AURA Ph 1Various

20-240mg9.27.201

3WCLC 2013 Ranson 34 50% N/A

AURA Ph 1Various

20-240mg4.27.201

4ASCO 2014 Janne 107 64%

AURA Ph 1Various

20-240mg8.1.2014 NEJM 2015 Janne 253

(138 T790M)61% 9.6m

AURA Ph 1Various

20-240mg12.2.201

4ELCC 2015 Janne 283 59% 13.5m

AURA extension 80mg 5.1.2015 WCLC 2015 Yang 201 61%Not

reached

AURA 2 80mg11.1.201

5Lancet Oncol 2016 Goss 210 70% 9.9m

AURA ext + AURA 2 80mg11.1.201

5ELCC 2016 Yang 397 66% 11.0m *********

Presented by T. Mitsudomi at the World Conference on Lung Cancer 2016Plenary Session: PL03 Presidential Symposium Discussion about abstract PL03.03

• Keep pace with genome discovery• Use genomics tools in pre-clinical studies• Consortia based molecular screening• Smaller studies in pre-selected population• Genotype based basket studies (agnostic of site of

origin)• Regulatory involvement- NGS as a “companion

diagnostic”• Use of genomic tools to refine patient selection using

extreme responders• Registry mechanisms- drug genome database

John Maynard Keynes