Checkpoint inhibitors nel carcinoma polmonare
Francesco Grossi
UOS Tumori Polmonari
Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro
Genova
VI CORSO NAZIONALE AIOM E SIAPEC-IAP 2016 Roma, 15 Giugno 2016
Agenda
Clinical development of PD-1/PD-L1 inhibitors:
state of the art in 2016
Nivolumab
Pembrolizumab Atezolizumab Durvalumab
Challenges and open questions in 2016
Patients selection based on PD-L1 expression Response evaluation: RECIST vs iRC
Combination with other agents (chemotherapy,
immunotherapy, targeted therapies)
Agenda
Clinical development of PD-1/PD-L1 inhibitors:
state of the art in 2016
Nivolumab
Pembrolizumab Atezolizumab Durvalumab
Challenges and open questions in 2016
Patients selection based on PD-L1 expression Response evaluation: RECIST vs iRC
Combination with other agents (chemotherapy,
immunotherapy, targeted therapies)
Clinical development of PD-1 and PD-L1 inhibitors
PD-1 Nivolumab Fully human IgG4 mAb
BMS ph III
Pidilizumab Humanized IgG1 mAb Cure Tech ph II
Pembrolizumab Humanized IgG4 mAb Merck ph III
AMP-224 Recombinant PD-L2 Fc fusion protein
GSK ph I
PD-L1 BMS-936559 Fully human IgG4 mAb BMS ph I
MEDI4736 (Durvalumab)
Engineered human IgG1 mAb
MedImmune ph III
MPDL3280A (Atezolizumab)
Engineered human IgG1 mAb
Genentech ph III
MSB0010718C (Avelumab)
Engineered human IgG1 mAb
EMD Serono ph II
Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab
N 129 475 175 228 184
RR 14%
Squamous 17% 23.5% 27% 21%
Nonsquamous 18% 19% 21% 13%
Drug-related AEs
All grades 41% 71% 66% 50% 77%
Grade 3/4 4.7% 9.5% 11% 8% 12%
RR
PDL-1 + 16% 42% (>50%) 83% (IHC3) PDL-1 - 13% 10% (<1%)
Anti PD1/PDL1 efficacy
in pretreated patients
CheckMate 017 (NCT01642004) study design
One pre-planned interim analysis for OS
At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)
The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
Patients stratified by region and prior paclitaxel use
Nivolumab 3 mg/kg IV Q2W
until PD or unacceptable toxicity
n = 135
Docetaxel 75 mg/m2 IV Q3W
until PD or unacceptable toxicity
n = 137
Randomize 1:1
• Primary Endpoint:
– OS
• Additional Endpoints:
̶ Investigator-assessed ORR
̶ Investigator-assessed PFS
̶ Correlation between PD-L1 expression and efficacy
̶ Safety
̶ Quality of life (LCSS)
• Stage IIIb/IV SQ NSCLC
• 1 prior platinum doublet- based chemotherapy
• ECOG PS 0–1
• Pre-treatment (archival or fresh) tumor samples
required for PD-L1 analysis N = 272
Spigel DR , ASCO 2015
Check Mate 017: PFS and OS
Brahmer J, NEJM 2015; Reckamp K, WCLC 2015
CheckMate 017: response and duration of response
Brahmer J, NEJM 2015
CheckMate 017: OS and PFS by PD-L1 expression
Brahmer J, NEJM 2015 Spigel DR , ASCO 2015
CheckMate 017: treatment-related AEs reported in at least 5% of patients
and safety summary
Brahmer J, NEJM 2015; Spigel DR , ASCO 2015
CheckMate 057 (NCT01673867) study design
PD-L1 expression measured using the Dako/BMS automated IHC assay14,15
Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness
a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.
Randomize 1:1
• Stage IIIB/IV non-SQ NSCLC
• Pre-treatment (archival or recent) tumor samples required for PD-L1
• ECOG PS 0–1
• Failed 1 prior platinum doublet
• Prior maintenance therapy alloweda
• Prior TKI therapy allowed for known ALK translocation or EGFR mutation
N = 582
Nivolumab 3 mg/kg IV Q2W
until PD or unacceptable toxicity
n = 292
Docetaxel 75 mg/m2 IV Q3W
until PD or unacceptable toxicity
n = 290
• Primary Endpoint – OS
• Additional Endpoints – ORRb
– PFSb – Safety
– Efficacy by tumor PD-L1 expression
– Quality of life (LCSS)
Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line)
Paz-Ares L , ASCO 2015
Check Mate 057: PFS and OS
Borghaei H , NEJM 2015; Horn L , ECCO/ESMO 2015
CheckMate 057: response and duration of response
Borghaei H , NEJM 2015
CheckMate 057: OS by PD-L1 expression and treatment effect on OS according
to subgroups
Borghaei H , NEJM 2015; Horn L , ECCO/ESMO 2015
Landmark OS in PD-L1 Non-expressors (<1%)
The majority of patients with no PD-L1 expression are alive at month 3
OS HR and separation of curves favoring nivolumab are observed in the landmark analysis Randomized Subjects with
PD-L1 Expression <1%
Randomized Subjects with
PD-L1 Expression <1% Alive at Month 3
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0 3 6 9 12 15 18 21 24 27
Overall Survival (Months)
Probability of Survival
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0 3 6 9 12 15 18 21 24 27
Overall Survival (Months)
Probability of Survival Nivolumab
Docetaxel
CheckMate 057: treatment-related AEs reported in at least 5% of
patients and safety summary
Borghaei H , NEJM 2015; Paz-Ares L , ASCO 2015
Keynote-010: trial profile
Herbst RS, Lancet 2015
Keynote-010: OS and PFS for pts with a PD-L1 of 50% or greater and for all pts
Herbst RS, Lancet 2015 & ESMO Asia 2015
Keynote-010: ORR (RECIST v.1.1, central review)
Herbst RS, ESMO Asia 2015
Keynote-010: treatment exposure and adverse event summary
Herbst RS, ESMO Asia 2015
POPLAR: a randomized phase II study with atezolizumab
Fehrenbacher L, Lancet 2016
POPLAR: PD-L1 expression subgroup
TC1/2/3 or IC 1/2/3 & TC0 & IC0 interim OS
Fehrenbacher L, Lancet 2016
OS HRs over time and updated median OS
Smith D , ASCO 2016
OS HRs for Individual TC and IC PD-L1 subgroups
Smith D , ASCO 2016
Early-phase trials with durvalumab
Agent Population Efficacy Tolerability Durvalumab
(anti–PD-L1)
Squamous (n = 88)
Nonsquamous (n = 112)
ORR: 16%
27% in PD- L1+
5% in PD-L1-
Squamous: 21%
Nonsquamous:
13%
Tx-related AEs:
Any 50% of pts
Grade 3/4 8%
Leading to discontinuation:
5%
No Tx-related colitis or
hyperglycemia, no grade 3/4 pneumonitis
Durvalumab +
tremelimumab (anti–CTLA-4)
Advanced NSCLC (n = 102)
ORR: 27%
33% PD-L1+
27% PD-L1-
Most frequent Tx-related AEs:
diarrhea (27%), fatigue (23%), pruritus (15%), increased
amylase (15%), rash (13%), and colitis (12%)
Grade 3/4 immune-related AEs: colitis (9%), pneumonitis (4%), and hypothyroidism
(1%) Rizvi NA, ASCO 2015; Antonia SJ, Lancet Oncol 2016
Agenda
Clinical development of PD-1/PD-L1 inhibitors:
state of the art in 2016
Nivolumab
Pembrolizumab Atezolizumab Durvalumab
Challenges and open questions in 2016
Patients selection based on PD-L1 expression Response evaluation: RECIST vs iRC
Combination with other agents (chemotherapy,
immunotherapy, targeted therapies)
Candidate predictive PD-L1antibodies
PD-L1 Drug and Vendor
Nivolumab BMS
Pembrolizumab Merck
Atezolizumab Roche
Durvalumab AstraZeneca
Clone and Source
28-8 Abcam
22c3 Dako
SP142 Spring Bio
SP263 Spring Bio IVD Class III
partner
Dako Dako Ventana Ventana
Scoring Method % cells with membrane staining at any intensity
% cells with membrane staining at any intensity
TC =Tumor cell IC= Immune cell Combine both percentage and subjective
intensity
% cells with membrane staining at any intensity
Thresholds 1%, 5%, or 10% >1%
1-49%
>50%
TC3 =TC>50%
IC3 = IC>10%
TC2/IC2 = TC or IC >5%
TC1/IC1 = TC or IC >1%
>25%
Method Pathologist/
Subjective
Pathologist/
Subjective
Pathologist/
Subjective
Pathologist/
Subjective
Rimm DL, WCLC 2015
PDL1 expression positive
or negative?
PDL1 expression positive
or negative?
Response to Nivolumab
Grossi F, Nivolumab EAP 2015/16
Progression with Nivolumab?
Grossi F, Nivolumab EAP 2015/16
Influence on post-therapeutic evaluation
Immunomodulators and immune checkpoint inhibitors lead to tumor regression but can also potentially increase inflammatory cell infiltration The immune reaction driven by
immunotherapy may causes
inflammatory cells to flock around the target lesions, thus increasing the size of both target and non-
target lesions, even the appearance of new lesions
The radiological evaluation of
patients treated by immunotherapy should therefore take this into
account
Chen DS, Immunity 2013
Immunotherapy creates patterns of response different from those of CT
Four patterns of tumor response to immunotherapy have been
described:
regression of the initial lesions
without appearance of new lesions;
unchanged tumor burden but followed by a slow, continuous regression of the overall tumor burden in some patients;
regression of initial lesions
associated with the appearance of new lesions;
regression of lesions after an initial increase of the overall tumor burden (flare)
Wolchok JD, Clin Cancer Res. 2009
Pseudoprogression (Flare)
In studies of immunotherapies, durable CR, PR or SD have occurred after initial PD by WHO or RECIST criteria
Longer time may be necessary for immune response
West HJ, JAMA Oncol 2015; Brahmer JR, N Engl J Med 2012
How to differentiate pseudo-PD from actual PD
Progression is more common than pseudoprogression
Pseudo-PD often occurs earlier, but can occur later as well Discontinuation of immunotherapy after “early” PD by
WHO or RECIST may not be appropriate unless confirmed If PD is misidentified and patient continues treatment
Actual disease progression occurs
Patients may not be physically able to go on additional therapies
Actual progression likely in patients who are symptomatic New immune-related response criteria (irRC) have been proposed to take into account the specificities of
immunotherapy.
Comparison between the RECIST 1.1, the WHO and the irRC criteria
Adapted from Wolchok JD, Clin Cancer Res 2009
irRC focus on central concepts for capturing immunotherapy response patterns
Image-based confirmation of progression via
subsequent scan(s) to detect delayed responses
confirmatory scan 4 weeks after first detection of progression
in diseases with less aggressive 4-week interval can be adjusted, for example, to 8 or 12 weeks
Measuring new lesions to include them into the total tumor volume
Accounting for durable stable disease as a benefit Treating beyond conventional progression if the clinical situation allows
Wolchok JD, N Engl J Med 2013; Ferretti GR , Diagnostic and Interventional Imaging 2016; Hoos A, Clin Cancer Res 2015
Advances of irRC utility between 2009 and 2015
Transferability of irRC concepts between WHO (bidimensional) and RECIST (unidimensional)
Application of irRC to diseases beyond melanoma Inclusion of irRC concepts into regulatory guidance documents of the FDA and EMA
Expansion of irRC concepts beyond the initial implementation
new studies with PD-1/PDL1 checkpoint blocking antibodies are demonstrating the expansion of irRC concepts via longer follow-up periods beyond progression and describing patterns such as
"spikes,“ "waves," and "blips"
Demonstration of an irRC-detected class effect across several immunotherapies
Hoos A, Clin Cancer Res 2015
Limitations to the irRC criteria
The bidimensional measurements are in line with WHO criteria, but are now rarely used in clinical studies and are replaced by the
unidirectional measurement of the larger axis of target lesions (RECIST 1.0 and 1.1)
Such bidimensional measurements introduce a greater variability than unidirectional
measurements and make it difficult to compare
the responses with studies using the RECIST
criteria
irRC criteria revised into new immune- related RECIST 1.1 (irRECIST 1.1)
irRC: immune-related response criteria; irRECIST 1.1: immune-related RECIST 1.1; CR: complete response; PR: partial response; PD:
progressive disease.
Modified from Nishino M, Clin Cancer Res 2013
Anti–PD-1 therapy past progression in NSCLC: Conclusions
Findings indicate a subset of pts receiving TPP obtain subsequent PR (8%)
Unclear whether response due to TPP or delayed immunotherapy effect
Additional research needed to determine pt/disease features that predict benefit from TPP
FDA advises that risks of continued treatment (ie, immune-related
adverse reactions) should be balanced with possibility of further tumor shrinkage
Future RCTs needed to prospectively establish benefit of TPP
Findings may influence treatment at individual pt level, but unlikely to change FDA regulatory endpoint results or benefit/risk determination
Kazandjian DG, ASCO 2016
Therapies that might affect the cancer-immunity cycle
Chen DS, Immunity 2013
Potential characteristics of immunogenic and nonimmunogenic tumors
Evaluation of tumor tissues may reveal an immunogenic tumor microenvironment consisting of many immunologic markers, including CD8 T cells, CD4 T cells, PD-L1, granzyme B, and CD45 RO, which may be effectively treated with immune checkpoint therapy to elicit clinical benefit.
Tumor tissues that lack expression of many immunologic markers may indicate a
nonimmunogenic tumor microenvironment, which may require combination therapies consisting of an agent to create an
immunogenic tumor microenvironment plus an immune checkpoint agent to further
enhance the immune response for clinical benefit
Sharma P, Science
Potential mechanisms of action to mediate synergistic effects of combined therapies
Melero I, Nat Rev Cancer 2015
Rapid evolution of combination
immunotherapy in cancer treatment
Adapted from Melero I, Nat Rev Cancer 2015
Challenges
Pardoll DM, Nature Rev Cancer 2012
Which combination and sequence?
Scientific rationale is lacking With or without chemotherapy Which combination of
checkpoint inhibitor
Sequencing duration of treatment Patient selection → biomarker
Differences per tumor location
Differences within a tumor location
Building immunotherapy
combinations on the pillar of PD1 or PDL1 blockade
Melero I, Nat Rev Cancer 2015
Examples of phase III anti-PD1/PD-L1
combination trials in 1 st -line advanced NSCLC
CheckMate 012: study design
Nivolumab monotherapy
Nivolumab +
Erlotinib
Nivolumab +
Ipilimumab Nivolumab
+ PT-DC
Nivolumab +
Bevacizumab
Stage IIIB/IV NSCLC; no prior chemotherapy for advanced disease; ECOG PS 0 or 1
Rizvi N, WCLC 2015
CheckMate 012: summary of efficacy
NC = not calculated (when >25% of patients are censored); NR = not reached
Combination data based on a February 2016 database lock; monotherapy data based on a March 2015 database lock except for OS data, which are based on an August 2015 database lock
Hellmann MD, ASCO 2016
CheckMate 012: safety summary
•There were no treatment-related deaths
•Treatment-related grade 3–4 AEs led to discontinuation at a third of the rate seen with older combination arms using higher or more frequent doses of ipilimumab6
Hellmann MD, ASCO 2016
Safety and antitumour activity of durvalumab plus tremelimumab in NSCLC: a multicentre,
phase 1b study: design and efficacy
Antonia S, Lancet Oncol 2016
Safety and antitumour activity of durvalumab plus tremelimumab in NSCLC: a multicentre,
phase 1b study: safety
Antonia S, Lancet Oncol 2016
Phase Ib GP28328 (NCT01633970): study design and endpoints: NSCLC Cohort
Primary endpoint: safety (including dose-limiting toxicities)
Secondary endpoints: pharmacokinetics; best overall response; objective response rate (ORR); duration of response (DOR); progression-free survival (PFS)
Date of cut-off: 10 Feb 2015; median safety follow-up: 128.5 days (4.2 months)
Atezolizumab 15 mg/kg i.v. q3w + CBDCA AUC=6 i.v. q3w + paclitaxel 200 mg/m2 i.v. q3w (4-6 cycles)
Atezolizumab 15mg/kg i.v. q3w + CBDCA AUC=6 i.v. q3w (4–6 cycles) + pemetrexed 500 mg/m2 i.v. q3w
(maintenance pemetrexed)
Solid tumors ECOG PS 0–1 (n = 58 NSCLC cohort at data cut-off; n = 25 per arm
planned)
Atezolizumab 15mg/kg i.v. q3w + CBDCA AUC=6 i.v. q3w + nab-paclitaxel 100 mg/m2 i.v. q1w (4–6 cycles)
Arm C: NSCLC
Arm D: NSCLC
Arm E: NSCLC
Camidge DR, WCLC 2015
Phase Ib GP28328 (NCT01633970):
summary of response by RECIST criteria
Camidge DR, WCLC 2015
Phase Ib GP28328 (NCT01633970): depth of response and changes in tumor burden by
treatment arm
Camidge DR, WCLC 2015
Phase Ib GP28328 (NCT01633970):
summary of safety data
Camidge DR, WCLC 2015
Take home messages
Clinical trials of immune checkpoint blockade have reported striking and durable clinical outcomes in a variety of tumors, including NSCLC
Immune checkpoint agents have considerable potential not only as single agents, but also as part of combination therapy with other
immunotherapies, or current standard therapies (including chemotherapy, radiotherapy and targeted therapy) A number of Phase III clinical trials in NSCLC are currently ongoing to
evaluate these agents and their
results are eagerly anticipated, in the hope that they will transform present therapeutic regimes in this lethal
disease Sharma P, Cell 2015
