risultati e prospettive nel nsclc - sacro...
TRANSCRIPT
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Giulia Pasello Oncologia Medica 2
Istituto Oncologico Veneto
Risultati e prospettive nel NSCLC
PD-1 and PD-L1 inhibitors
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Disclosures
• Advisory Boards/Honoraria/Consultant for: – Eli-Lilly, Boehringer Ing.
• Research Support / Grants from: – E.S.M.O (European Society for Medical Oncology)
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Targeting the immune system, not the tumor itself A paradigm shift
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CANCER IMMUNOSURVEILLANCE: WHAT HAPPENS IN NSCLC?
Evidence of immunosuppressive microenvironment and immunosurveillance evasion in lung cancer:
- increase of functionally Treg cells - increase of functionally immunosuppressive cytokines Woo EY et al, J Immunol 2002
The magnitude of immune response to lung tumors correlates with patient outcome
Al-Shibli et al, Clin Cancer Res 2008
Petersen et al, Cancer 2006
Prognostic immune markers in tumor microenvironment and peripheral blood; genes involved in cancer immunity and inflammation and correlated with recurrence Suzuki K et al, Clin Cancer Res 2011
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Champiat S, J Thorac Oncol 2014
Arnessing the immune system against cancer: strategies in NSCLC
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VACCINATION STRATEGIES
PHASE III CLINICAL
TRIAL
STAGE VACCINE PRIMARY ENDPOINT
RESULTS
MAGRIT I-IIIA MAGE DSF NEGATIVE
START IIIA-B L-BLP25 OS* NEGATIVE*
STOP III-IV LUCANIX OS NEGATIVE
* POSITIVE FOR PATIENTS RECEIVING CONCURRENT CHEMO-RADIOTHERAPY
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ANTI-CTLA4 IPILIMUMAB Ongoing phase III trial design (CA 184104 )
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PD-1 and PD-L1 blockade in NSCLC: response across trials with single agents
Soria JC, Clin Cancer Res 2015
Good BUT new safety profile Long lasting tumor response
Clinical benefit in pre-treated and in SQCC Predictive biomarkers?
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NIVOLUMAB Phase I expansion cohort trial (pre-treated) Phase II study (refractory) 2 phase IIIR trials (2L) ATEZOLIZUMAB Phase IIR trial (2L-3L)
PEMBROLIZUMAB Phase I trial (pretreated)
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Gettinger SN et al, JCO 2015
Nivolumab in pretreated patients: phase I expansion cohort
54%: 3 to 5 prior therapies 50% of responders: at the first assessment (8 weeks) Median DOR: 17 months 41%: responses ongoing (data lock)
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Nivolumab in refractory NSCLC: CheckMate 063 phase II study
Horn L, 16th WCLC
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Nivolumab in refractory NSCLC: CheckMate 063 phase II study
Horn L, 16th WCLC
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Clinical relevance of long-term response in NSCLC
Peters S, 16th WCLC
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Besse B, 2014 ESMO
Clinical relevance of long-term response in NSCLC
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Clinical relevance of long-term response in NSCLC
Asahina H et al, Clin Lung Cancer 2012
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Nivolumab: phase III trials in all comers NSCLC, 2L
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Overall Survival
Spigel D and Paz-Ares L, 2015 ASCO Annual Meeting; Reckamp K, 16th WCLC
CheckMate 017 SQCC
CheckMate 057 non-SQCC
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CheckMate 017 SQCC
CheckMate 057 non-SQCC
Spigel D and Paz-Ares L, 2015 ASCO Annual Meeting; Reckamp K, 16th WCLC
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CheckMate 017 in squamous NSCLC
Reckamp K, 16th WCLC
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MARCH 2015
MAY 2015
Nivolumab as second line treatment of advanced squamous NSCLC
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Nivolumab: different trials, different ‘performance’? 2015 scenarios for squamous and non-squamous NSCLC
PD-L1 status and selection criteria for treatment
CheckMate 017 and 057 : key points
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Modified from Garassino MC, 2015 ASCO Annual Meeting
Nivolumab: different trials, different ‘performance’?
CheckMate 017: mOS 9.2 (N) vs 6 (D) mos HR 0.59 (95% CI, 0.44-0.79; p=0.00025) CheckMate 057: mOS 12.2 (N) vs 9.4 (D) mos HR 0.73 (95% CI, 0.59-0.89; p= 0.0015)
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Peters S, 16th WCLC
Nivolumab: different trials, different ‘performance’?
nonSQCC: mOS 8-10 months SQCC: mOS 6-8.7 months
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Garassino MC, 2015 ASCO Annual Meeting
Nivolumab: different trials, different ‘performance’?
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Nivolumab: different trials, different ‘performance’? Different performance of docetaxel in the two histologies? Delayed effect of nivolumab in non-squamous cell carcinoma? Mixed populations? Subsequent therapies?
2015 scenarios for squamous and non-squamous NSCLC
CheckMate 017 and 057 : key points
PD-L1 status and selection criteria for treatment
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Cddp+ gem Cddp +doc/vnb
Erlotinib*/Gefitinib*/Afatinib*
Non squamous/ No smoker
Squamous/ Smoker
Cddp+pem (+maint) Cddp+doc/vnb
PG/CP+beva (+maint) Monoct o doppietta con carbo
Crizotinib§
Docetaxel Pemetrexed EGFR TKI*
Pemetrexed Docetaxel
• EGFR mut + • § ALK-EML4+
Docetaxel
I° linea
II° linea
Second line treatment options in NSCLC patients
Docetaxel+Ramucirumab
Docetaxel+Nintedanib
Nivolumab
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Meaningful advantage? Raising the bar!
Ellis ME et al, J Clin Oncol 2014
SURVIVAL ADVANTAGE/CLINICAL BENEFIT SAFETY COSTS
PREDICTIVE BIOMARKERS PATIENT SELECTION
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New second line treatment options in non-oncogene addicted NSCLC
SQCC (mOS months)
Non-SQCC (mOS months)
Docetaxel+Ramucirumab vs Docetaxel
9.5 vs 8.2 (HR 0.88)
11.1 vs 9.7 (HR 0.83)
Docetaxel+Nintedanib vs Docetaxel
/ 12.6 vs 10.3§
(HR 0.83)
Nivolumab vs docetaxel 9.2 vs 6 (HR 0.62)
12.2 vs 9.4 (HR 0.73)
§secondary endpoint
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Nivolumab safety in PS 2 patients a “ real life study”
Hussein M, 16th WCLC
CA209-153
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Nivolumab: different trials, different ‘performance’? Different performance of docetaxel in the two histologies? Delayed effect of nivolumab in non-squamous cell carcinoma? Mixed populations? Subsequent therapies?
2015 scenarios for squamous and non-squamous NSCLC Clinical benefit, safety and costs should be integrated with predictive biomarkers for patients selection Importance of a ‘personalized’ sequence
PD-L1 status and selection criteria for treatment
CheckMate 017 and 057 : key points
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PD-L1 status and selection criteria for treatment CheckMate 017
Spigel D 2015 ASCO Annual Meeting; Reckamp K, 16th WCLC
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PD-L1 status and selection criteria for treatment CheckMate 057
Paz-Ares L, 2015 ASCO Annual Meeting;
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Spigel D and Paz-Ares L, 2015 ASCO Annual Meeting; Reckamp K, 16th WCLC
CheckMate 017 CheckMate 057
Treatment outcome according to PD-L1 expression
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Dumb and smart tumors
EGFR+ NSCLC: Example of dumb cancer
• Single dominant mutation • Small mutational load • Monotherapy is effective • Resistance rare, late, same
pathway
NSCLC in smokers: Example of smart cancer
• Multiple mutational drivers
• Large mutational load • Multi-targeted therapy
required • Resistance common, early
Sledge GW, ASCO Meeting 2010
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Lawrence MS et al, Nature 2014
Somatic mutation frequencies in cancer
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Mutational load, smoking signature, neoantigen burden and response to checkpoint inhibitors
Rizvi NA et al, Science 2015
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Nivolumab: different trials, different ‘performance’? Different performance of docetaxel in the two histologies? Delayed effect of nivolumab in non-squamous cell carcinoma? Mixed populations? Subsequent therapies?
2015 scenarios for squamous and non-squamous NSCLC Clinical benefit, safety and costs should be integrated with predictive biomarkers for patients selection
PD-L1 status and selection criteria for treatment Different mutational load in the two histologies? Different proportion of smokers? Gene signature as predictive to PD-1/PD-L1 inhibition?
CheckMate 017 and 057 : key points
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NIVOLUMAB Phase I expansion cohort trial (pre-treated) Phase II study (refractory) 2 phase IIIR trials (2L) ATEZOLIZUMAB Phase IIR trial (2L-3L)
PEMBROLIZUMAB Phase I trial (pretreated)
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Spira A et all, 2015 ASCO Annual Meeting
The POPLAR phase IIR study in NSCLC all comers, 2L-3L
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POPLAR: All Patient Efficacy<br />ITT interim OS (N = 287)
Spira A et all, 2015 ASCO Annual Meeting
The POPLAR phase IIR study in NSCLC
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POPLAR: PD-L1 Expression Subgroups<br />Interim OS
Modified from Spira A et all, 2015 ASCO Annual Meeting
TC ≥ 50% or IC ≥ 10%
TC or IC ≥ 5%
TC or IC ≥ 1%
TC and IC < 1%
The POPLAR phase IIR study in NSCLC
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Atezolizumab: predictive correlates of response
Herbst RS et al, Science 2014
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NIVOLUMAB Phase I expansion cohort trial (pre-treated) Phase II study (refractory) 2 phase IIIR trials (2L) ATEZOLIZUMAB Phase IIR trial (2L-3L)
PEMBROLIZUMAB Phase I trial (pretreated)
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PFS OS
The KEYNOTE 001 phase I study in pretreated NSCLC
Estimated prevalence of PD-L1: approximately 20-25%
___ ___ ___
Garon EB et al, NEJM 2015
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PD-L1 as a predictive immune biomarker: assays, sample collection and analysis in NSCLC studies
PD-L1 Assay
Sample Source and Collection
Definition of
Positivity†
Pembrolizumab Merck
• Proprietary IHC assay1
• Surface expression of PD-L1 on tumour specimen*
• Ph I: Fresh tissue • Ph II/III: Archival or fresh
tissue1
IHC Staining: • Strong vs weak
expression1
• PD-L1 expression required for NSCLC for enrollment1
Tumour PD-L1 expression
• PD-L1+ cut-point: 24% (4/7)
• PD-L1+ ≥0 : 61% (23/38)
Nivolumab Bristol-Myers Squibb
• Dako automated IHC assay (28-8 Ab)2
• Surface expression of PD-L1 on tumour cells*
• Archival3 or fresh tissue
IHC Staining: • Strong vs weak
expression2,3,4
• Patients not restricted in PD-L1 status in 2nd- & 3rd-line3
• Ph III 1st-line trial in PD-L1+2
Tumour PD-L1 expression:
• 5% PD-L1+ cut-off: 49% (33/68)3
MPDL3280A Roche/Genentech
• Ventana automated IHC assay
• Surface expression of PD-L1 on TILs4
• Archival or fresh tissue
IHC Staining intensity (0, 1, 2, 3):
• IHC 3 (≥10% PD-L1+): Ph III trial4
• IHC 2,3 (≥5% PD-L1+)4
• IHC 1,2,3 (≥1% PD-L1+)4
• IHC 1, 0, or unknown • PD-L1 expression required
for NSCLC for enrollment • x
TIL PD-L1 expression: • 11% (6/53) IHC 3 (≥10% PD-
L1+) • 75% (40/53) PD-L1 low (IHC
1, 0)
MEDI4736 AstraZeneca
• 1st generation or Ventana automated IHC (BenchMark ULTRA) assay (Ventana PD-L1 (SP263) clone) 5,6
• Surface expression of PD-L1 on TILs
• PhI: Fresh tissue
IHC Staining intensity :
• Not presented to date5,6
TIL PD-L1 expression: • Not presented to date5,6
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PD-L1 is dynamic and heterogeneous…..
Herbst R, 2015 ASCO meeting
…and variable according to the antibody
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Peters S, 16th WCLC
Patients who might benefit
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Peters S, 16th WCLC
Patients who probably don’t benefit
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Future perspectives
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