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