Post on 16-Apr-2017
transcript
Lung Cancer – Taming through a ‘Novel Pathway’ #immunoncology!
Ashok .K. VaidMedical Oncology & Hematology
Medanta Cancer Institute : Medanta – The Medicity,Gurgaon (New Delhi), India
Excerpts from ASCO 2015
• Lung Cancer Background• Immunity and Cancer• Biomarkers- ASC0 2015• Advanced NSCLC• Other Malignancies
SCLC and mesothelioma
Lung Cancer Incidence and Mortality
• New cases in 2013: 228,190– 40% with stage IV disease at presentation
(~ 90,000)
• ~ 160,000 deaths in 2013, comparable to prostate, pancreas, breast, and colon cancer combined
• 5-year relative survival rate: 13% overall (2% for patients with distant-stage) disease
NCI. Non-small-cell lung cancer treatment (PDQ®). ACS. Cancer facts & figures: 2013.
Estimated Cancer Deaths by Site, 2013
Other Cancers Lung Cancer
180,000160,000
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
Lung cancer
Prostate
Pancreas
Breast
Colon
1975 1980 1985 1990 1995 2000 20050
5
10
15
20
Year of Diagnosis
5-ye
ar O
S (%
)
Gain in 5-year OS over the past 3 decades in lung cancer
http://seer.cancer.gov, Accessed Nov. 2014
History of Therapy in Advanced NSCLC: FDA Approval Dates
First lineSecond lineThird lineMaintenanceNot approved
1970 1980 1990 2000
MedianOS (mos)
12+
~ 6~ 2-4
BSC Single-agent platinum DoubletsBevacizumab + PC
Carboplatin*1989
ErlotinibPemetrexed
2004
Docetaxel1999
PaclitaxelGemcitabine
1998
Vinorelbine1994
Docetaxel2002
Bevacizumab2006
Gefitinib2003
Standard therapies
*Label does not include NSCLC-specific indication Pemetrexed
2008/2009
Histology-directed therapy
~ 8-10
Cisplatin*1978
1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
Role of immune system in cancer prevention• Eliminate/ suppress viral
infections: protection from viral induced tumors.
• Prevent establishment of an inflammatory environment
• Identify and eliminate tumor cells based on the expression of tumor-specific antigens: cancer immuno surveillance
• Cytotoxic T cells play a key role in cancer immune response
Cytotoxic T cells play a key role in cancer immune response
• Regulated by a range of immune cells.
• T cells- potent mediators of anti-tumor immunity
• T cell immune response: – recognize a "non-self" target– Involves processing &
presentation– Cytotoxic T cells: effector cells– Activated, search of cells
bearing that unique MHC Class I + peptide
Cancer immunotherapy
CTLA-4: cytotoxic T lymphocyte associated protein 4PD-1: programed cell death protein 1Mellman Nature 2011
T cell response is regulated by co-stimulatory (“Go”)and co-inhibitory/checkpoint (“Stop”) factors
“Brakes”“Accelerator”
Immune checkpoint inhibitors
Attenuate T cell response
Promote T cell response
T cell regulation is important!Prevents immune mediated damage
Immune checkpoint inhibitorsPharmaceutical Compound Status
CTLA-4 inhibitor
BMS Ipilimumab Approved for melanoma
AZ/MedImmune Tremelimumab Phase III
PD-1 inhibitor
BMS Nivolumab Approved for melanoma, NSCLC (SCC)
MSD Pembrolizumab Approved for melanoma
Curetech Pidilizumab Phase II
Novartis PDR001 Phase I-II
PD-L1 inhibitor
Genentech/ Roche Atezolizumab Phase III
AZ/MedImmune Durvalumab Phase III
Merck Serono Avelumab Phase III
Biomarkers- ASCO 2015
Primary endpoint• OS
Study objective• To investigate the efficacy and safety of atezolizumab (MPDL3280A) in NSCLC and
correlation of response with PD-L1 expression on tumour-infiltrating immune cells (IC) and/or tumour cells (TC)
• PD-L1 expression was evaluated by IHC using the SP142 antibody assay• Patients were scored as TC0, 1, 2 or 3 and IC0, 1, 2 or 3
Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010
Secondary endpoints• PFS, ORR, duration of response, safety
8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al
Stratification• PD-L1 IC expression (0 vs. 1 vs. 2 vs. 3)• Histology (squamous vs. non-squamous)• Prior chemotherapy regimens (1 vs. 2)
R
PD
Loss of clinical benefitKey patient inclusion criteria
• Metastatic or locally advanced NSCLC
• At least 1 prior platinum-based chemotherapy
(n=287) Docetaxel 75 mg/m2 q3w (n=143)
Atezolizumab 1200 mg IV q3w (n=144)
• Key results– Across the ITT interim population, survival was similar between atezolizumab and
docetaxel (HR 0.77; 95%CI 0.55, 1.06; p=0.11)– However, OS with atezolizumab increased with increasing PD-L1 expression (TC/IC ≥1);
those with <1% expression did not derive benefit relative to docetaxel
8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al
Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010
p=0.070
p=0.026
p=0.024
p=0.70
p=0.11
Interim OSSubgroup (% of enrolled patients)
TC3 or IC3 (16%)
TC2/3 or IC2/3 (37%)
TC1/2/3 or IC1/2/3 (68%)
TC0 or IC0 (32%)
ITT (N=287)
0.46
0.56
0.63
1.12
0.77
0.2 1 2Hazard ratioa
In favour of atezolizumab In favour of docetaxel
a Unstratified HR for subgroups and stratified HR for ITT. Data cut-off Jan 30, 2015
• Key results (cont.)– Patients with higher PD-L1 expression also had better outcomes with atezolizumab than with docetaxel (ORR 38% vs.
13% in patients with the highest levels)
– Atezolizumab was well tolerated with fewer treatment-related Grade 3/4 AEs (12% atezolizumab; 39% docetaxel) despite a longer treatment duration (3.7 vs. 2.1 months)
• Conclusions– Improved survival with atezolizumab was associated with increasing PD-L1 expression– PD-L1 is a predictive diagnostic biomarker that can be used to identify those patients with NSCLC who will
benefit most from atezolizumab therapy
Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010
8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al
TC3 or IC3 TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0 ITT0
10
20
30
40
5038
2218
81513 15 18
1015
Atezolizumab (n=144)
Docetaxel (n=143)
OR
R (c
onfir
med
,R
EC
IST
v1.1
), %
Gainor et al. J Clin Oncol 2015; 33 (suppl): abstr 8012
8012: Clinical correlation and frequency of PD-L1 expression in EGFR-mutant and ALK-rearranged NSCLC – Gainor JF et al
• Study objective– To evaluate PD-L1 expression patterns and clinical outcomes in EGFR-mutant and ALK-
rearranged NSCLC patients receiving TKIs• Study design
– Retrospective analysis of IHC data of biopsy and resection specimens from patients with metastatic, EGFR-mutant (n=68) and ALK-rearranged (n=28), NSCLC. Expression of PD-L1 in >5% tumour cells was defined as positive. CD8+ tumour-infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0−3)
• Key results
– No significant difference was observed in PFS or OS between PD-L1 (+) and (-) patients. OS on ALK TKIs was shorter among PD-L1 (+) patients (p=0.045)
• Conclusion– EGFR-mutant and ALK-rearranged lung cancers can express PD-L1 and show
CD8+ immune infiltrates, but most do not have both. This may explain the low response rates observed with PD-1 inhibitors in never/light smokers
EGFR-mutant ALK-rearrangedn/N (%) Pre-TKI Post-TKI p Pre-TKI Post-TKI pPD-L1 (+) 9/62 (15) 16/64 (25) 0.181 11/21 (52) 3/14 (21) 0.089CD8+ TILs (2-3+) 12/62 (19) 13/65 (20) 1.000 6/18 (33) 0/14 (0) 0.024PD-L1 (+) and CD8+ TILs (2-3+) 3/61 (5) 8/64 (13) 0.207 3/18 (17) 0/14 (0) 0.238
7560: The association of T cells with survival in mesothelioma – Chee SJ et al
Chee et al. J Clin Oncol 2015; 33 (suppl): abstr 7560
• Study objective– To assess whether tumour infiltrating lymphocyte (TIL) density identifies patients with
mesothelioma and ongoing immune attack who may benefit from immune activation • Study design
– Tissue microarrays were performed on a consecutive series of 213 samples from patients with mesothelioma; slides were stained for CD3, CD4, CD8 and CD45RO
– The mean score was used to account for tumour heterogeneity• Key results
– There was no association between density of tumour infiltrating CD3 (p=0.224), CD4 (p=0.205) and CD8 (p=0.243) cells and survival outcomes
– Two variables were significantly associated with better survival:• High (>0.61) CD4:CD8 ratio (p=0.007)• Low CD45RO level (p=0.002)
• Conclusion– A high CD4:CD8 ratio and low density of CD45RO memory T cells are
associated with better survival in patients with mesothelioma
Advanced NSCLCLater lines
LBA109: Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO)- PD 1 inhibitor- versus docetaxel in advanced non-SQ NSCLC – Paz-Ares L et al
Primary endpoint• OS
Secondary endpoints• ORR, PFS, safety, efficacy by PD-L1
expression, QoL
R
PD or toxicity
PD or toxicity
Stratification• Prior maintenance therapy• Line of therapy (2nd vs. 3rd)
Key patient inclusion criteria• Stage IIIB/IV non-squamous
NSCLC• Pre-treatment (archival or
recent) tumor samples available for PD-L1 testing
• ECOG PS 0–1• Failed 1 prior platinum
doublet(n=582)
Docetaxel 75 mg/m2 IV q3w
(n=290)
Nivolumab 3 mg/kg IV q2w
(n=292)
Study objective• To evaluate the efficacy and safety of nivolumab vs. docetaxel in patients with advanced
non-squamous NSCLC after failure of platinum-based doublet chemotherapy
Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109
LBA109: Phase III, randomized trial of nivolumab (NIVO) versus docetaxel in advanced (non-SQ) NSCLC – Paz-Ares L et al
• Key results– Nivolumab was associated with a 27% reduction in risk of death
Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109
OS
0 3 6 9 12 15 18 21 24 27
292 232 194 169 146 123 62 32 9 0290 244 194 150 111 88 34 10 5 0
Time (months)
Nivolumab
Docetaxel
1-year OS rate=51%
1-year OS rate=39%
Symbols represent censored observations
NivolumabDocetaxel
Number of Patients at Risk
OS
(%)
Nivolumab (n=292)
Docetaxel(n=290)
mOS, months 12.2 9.4
HR 0.73 (96%CI 0.59, 0.89); p=0.0015
100
90
80
70
60
50
40
30
20
10
0
LBA109: Phase III, randomized trial of nivolumab (NIVO) versus docetaxel in advanced non-squamous cell (non-SQ) NSCLC – Paz-Ares L et al• Key results
• PD-L1 expressors benefitted more from nivolumab than PD-L1 non-expressors
– Nivolumab improved survival vs. docetaxel in previously treated patients with advanced non-squamous NSCLC with efficacy being correlated with PD-L1 expression
Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109
PD-L1 expression levelNivolumab
(n)Docetaxel
(n)Unstratisfied HR
(95% CI)Interaction
p-value*
OS
≥1% 123 123 0.59 (0.43, 0.82)0.0646
<1% 108 101 0.90 (0.66, 1.24)
≥5% 95 86 0.43 (0.30, 0.63)0.0004
<5% 136 138 1.01 (0.77, 1.34)
≥10% 86 79 0.40 (0.26, 0.59)0.0002
<10% 145 145 1.00 (0.76, 1.31)
Not quantifiable at baseline 61 66 0.91 (0.61, 1.35)
PFS
≥1% 123 123 0.70 (0.53, 0.94)0.0227
<1% 108 101 1.19 (0.88, 1.61)
≥5% 95 86 0.54 (0.39, 0.76)<0.0001
<5% 136 138 1.31 (1.01, 1.71)
≥10% 86 79 0.52 (0.37, 0.75)0.0002
<10% 145 145 1.24 (0.96, 1.61)
Not quantifiable at baseline 61 66 1.06 (0.73, 1.56)
PD-L1 expressors
PD-L1 non-expressors
PD-L1 not quantifiable
0.25 0.5 1.0 2.0
Nivolumab Docetaxel
Next step
• Combination of immune targeted drugs
Study objective• To investigate the antitumour activity and tolerability of the combination of MEDI4736 (M)
and tremelimumab (T) in patients with advanced NSCLC who have failed to respond or relapsed after any line of therapy
Study design• Phase 1b, open-label, dose-escalation study in patients with advanced NSCLC• Treated with M (3, 10, 15, or 20 mg/kg q4w or 10 mg/kg q2w) and T (1, 3, or 10 mg/kg q4w
for 6 doses then q12w for 12 doses) administered for 12 months Key results
G, grade; D/C, discontinuation
3014: Phase Ib study of MEDI4736, a PD-L1 antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in advanced NSCLC – Antonia SJ et al
Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 3014
N (%)
M3q4wT1
n=3
M10q4wT1
n=3
M15q4wT1
n=18
M20q4wT1
n=18
M10q2wT1
n=17
M10q4wT3
n=3
M15q4wT3
n=14
M20q4wT3
n=6
M10q2wT3
n=11
M15q4wT10n=9
All cohortsn=102
Any AE 3 (100) 3 (100) 17 (94) 14 (78) 15 (88) 3 (100) 14 (100) 6 (100) 11 (100) 9 (100) 95 (93)Any G3/G4 AE 0 (0) 2 (67) 11 (61) 8 (44) 6 (35) 3 (100) 10 (71) 6 (100) 7 (64) 8 (89) 61 (60)Any deaths 0 (0) 1 (33) 3 (17) 2 (11) 2 (12) 0 (0) 3 (21) 2 (33) 1 (9) 1 (11) 15 (15)*SAE 1 (33) 2 (67) 11 (61) 7 (39) 4 (24) 2 (67) 10 (71) 6 (100) 5 (45) 8 (89) 56 (55)AE to D/C 1 (33) 1 (33) 4 (22) 1 (6) 2 (12) 2 (67) 5 (36) 4 (67) 3 (27) 4 (44) 27 (26)Related AE 1 (33) 3 (100) 11 (61) 9 (50) 12 (71) 3 (100) 12 (86) 5 (83) 10 (91) 8 (89) 74 (73)Related G3/G4 0 (0) 2 (67) 7 (39) 4 (22) 3 (18) 2 (67) 6 (43) 5 (83) 5 (45) 7 (78) 41 (40)Related deaths 0 (0) 1 (33)† 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (17)‡ 0 (0) 0 (0) 2 (2)Relates SAE 0 (0) 1 (33) 4 (22) 4 (22) 1 (6) 2 (67) 6 (43) 5 (83) 4 (36) 7 (78) 34 (33)Related AE to D/C 0 (0) 1 (33) 2 (11) 1 (6) 0 (0) 2 (67) 4 (29) 3 (50) 3 (27) 4 (44) 20 (20)
*Death excluding disease progression=8%; †Related death due to polymyositis (complications arising from drug-related myasthenia gravis); ‡Related death due to neuromuscular disorder. Red box=selected phase 3 dose.
3014: Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC – Antonia SJ et al
KEY RESULTS
Lowest frequency of AEs was in the T1 cohorts and generally increased for doses above T1 (previous slide)
Treatment-related AEs across all cohortsGrade 3/4 occurred in 40% of patients (most frequently colitis, diarrhoea, elevated lipase and elevated liver function tests)31% of patients used corticosteroids and 20% discontinued therapy
Treatment-related AEs among patients treated at M20 q4w T1Grade 3/4 occurred in 22% of patients (most frequently diarrhoea, pruritus, rash and elevated AST/ALTs)17% of patients used corticosteroids and 6% discontinued therapy Clinical activity in patients with PD-L1 positive tumours in the T1 cohorts:ORR of 33% (95%CI 13, 59)DCR at ≥16 weeks of 44% (95%CI 14, 79)
Clinical activity in patients with PD-L1 negative tumours in the T1 cohorts:ORR of 38% (95%CI 14, 68)DCR at ≥16 weeks of 62% (95%CI 32, 86)
Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 3014
Conclusions The combination of M + T has a manageable safety profile with evidence of clinical activity,
including in PD-L1-negative disease The M20 q4w T1 dose combination will be investigated in phase 3 studies
AST, aspartate aminotransferase; ALT, alanine aminotransferase
Study objective• To evaluate the efficacy and safety of MEDI4736, a human IgG1 monoclonal anti-PD-L1
antibody, combined with gefitinib (G) in patients with NSCLCStudy design• Phase 1, dose escalation (n=10) and dose expansion (n=15) study • Expansion study undertaken in TKI-naïve patients with EGFR sensitising mutant NSCLC
• Arm 1: MEDI4736 10 mg/kg q2w plus G 250 mg qd• Arm 2: G 250mg qd for 4 weeks followed by MEDI4736 10 mg/kg q2w + G 250 mg qd
Key results• All patients in the dose-escalation phase demonstrated tumour reductions
Conclusions• MEDI4736 in combination with gefitinib shows acceptable tolerability and tumour reductions
with early signs of activity in TKI-naïve EGFR mutant population
3047: Safety and tolerability results from a phase I study of MEDI4736, (PD-L1 antibody), combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC) : – Creelan BC et al
Creelan et al. J Clin Oncol 2015; 33 (suppl): abstr 3047
Cohort A* (n=3)Cohort B† (n=6)
Cha
nge
in ta
rget
lesi
on
diam
eter
from
bas
elin
e, %
70605040302010
0–10–20–30–40–50
0 8 16 24 32 40 48Time (weeks)
xx
*Cohort A: G 250 mg qd + MEDI4736 3 mg/kg q2w;†Cohort B: G 250 mg qd + MEDI4736 10 mg/kg q2w
8011: Phase 1 study of pembrolizumab- PD 1 inhibitor- (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D – Patnaik A et al
• Study objective– To evaluate in a phase I study pembrolizumab + ipilimumab in patients with recurrent NSCLC of any histology (interim
results provided) • Key results
– As of 31 March 2015, 18 patients have been enrolled:• 3 in the pembrolizumab 10 mg/kg + ipilimumab 1 mg/kg, 3 in the pembrolizumab
10 mg/kg + ipilimumab 3 mg/kg, and 12 in the pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg
– No DLTs have been reported– 15 patients experienced treatment-related AEs; 2 led to discontinuation (1 each with pembrolizumab 10 mg/kg +
ipilimumab 3 mg/kg and pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg)
Patnaik et al. J Clin Oncol 2015; 33 (suppl): abstr 8011
• Key results (cont.)– Pembrolizumab + ipilimumab showed antitumour activity with all responses ongoing at
data cut-off
• Conclusions– Preliminary data demonstrate robust and durable antitumour activity with an
acceptable toxicity profile for pembrolizumab + ipilimumab in unselected patients with recurrent NSCLC
– The use of a lower ipilimumab dose did not appear to negatively impact efficacy
8011: Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D – Patnaik A et al
Patnaik et al. J Clin Oncol 2015; 33 (suppl): abstr 8011
Pembro 10 mg/kg + IPI 1 or 3 mg/kg,
(n=6)
Pembro 2 mg/kg + IPI 1 mg/kg,
(n=12) Total
(n=18)ORR, n (%) [95%CI] 3 (50) [12, 88] 4 (33) [10, 65] 7 (39) [17, 64]
DCR, n (%) [95%CI] 6 (100) [54, 100] 9 (75) [43, 94] 15 (83) [59, 96]
Best overall response, n (%) CR PR SD ≥6 weeks PD
1 (17)2 (33)3 (50)
0
04 (33)5 (42)3 (25)
1 (6)6 (33)8 (44)3 (17)
Other malignanciesSCLC and Mesothelioma
Primary endpoints• ORR per RECIST v1.1, safety
Study objective• To assess the efficacy and safety of pembrolizumab, an anti-PD-1 monoclonal antibody, in
patients with PD-L1+ SCLC
*Defined as membranous PD-L1 expression in ≥1% of cells in tumour nestsor positive bands in stroma;†Every 8 weeks for the first 6 months; every 12 weeks thereafter
7502: Pembrolizumab (MK-3475- PD 1 inhibior) in patients with extensive-stage SCLC: Preliminary safety and efficacy results from KEYNOTE-028 – Ott PA et al
Ott et al. J Clin Oncol 2015; 33 (suppl): abstr 7502
Secondary endpoints• PFS, OS, duration of response
Pembrolizumab 10 mg/kg q2w
CR, PR or SD
Key patient inclusion criteria• SCLC• PD-L1 positivity*• Failure of standard
therapy• ≥1 measurable lesion• ECOG PS 0 or 1• Absence of autoimmune
disease or interstitial lung disease
(n=20)
Treat for 24 months or
until PD/toxicity
Confirmed PD/
toxicity
Discontinue pembrolizumab
Response assessment†
• Key results– Pembrolizumab showed promising antitumour activity
– No unexpected toxicity• Most common AEs occurring in ≥2% were arthralgia and asthenia (15% of patients) followed by nausea and rash (10%)• One treatment-related death was reported (colitis) and one treatment-related discontinuation (grade 2 autoimmune
thyroiditis)• Conclusions
– Pembrolizumab was generally well tolerated and demonstrated preliminary promising antitumour activity in patients with PD-L1+ SCLC
7502: Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028 – Ott PA et al
* Ott et al. J Clin Oncol 2015; 33 (suppl): abstr 7502
Best overall response n % 95%CI
ORR* 7 35 15−59
Complete response 0 0 0−17
Partial response 7 35 15−59
Stable disease 1 5 0−25
Progressive disease 9 45 23−69
No assessment# 3 15 3–38
Primary endpoint• ORR per RECIST v1.1
Study objective• To assess the efficacy and safety of nivolumab, an IgG4 PD-1 immune checkpoint inhibitor,
with or without ipilimumab, a CTLA-4 checkpoint inhibitor, in previously treated SCLC patients
7503: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032 : Antonia SJ et al
Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 7503
Secondary endpoints• Safety, PFS, OS, biomarker analysis
Key patient inclusion criteria• SCLC• Progressive disease• ≥1 prior therapy including
first-line platinum-based therapy
• Unselected by PD-L1 expression
(n=128)
Nivolumab 1 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=3)
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV q3w for 4 cycles (n=47)
Nivolumab 3 mg/kg IV q2w (n=40)
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=38)
Nivolumab 3 mg/kg IV q2w
Data from this cohort were not presented
• Key results– Clinical responses occurred in patients regardless of PD-L1 expression
• Conclusions– Nivolumab alone or in combination with ipilimumab showed activity and durable responses in patients with SCLC and
progressive disease– Nivolumab alone or in combination with ipilimumab had a manageable safety profile– These regimens will be explored in future trials of patients with SCLC
7503: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032: Antonia SJ et al
Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 7503
Bes
t red
uctio
n fro
m b
asel
ine
inta
rget
lesi
on (%
)
150125100
7550250
–25–50–75
–100
Nivolumab + Ipilimumab
<1% PD-L1≥1% PD-L1Not evaluable*Confirmed responders
150125100755025
0–25–50–75
–100
Nivolumab
Evaluable samples (40 of 96) PD-L1 expression level, n (%)<1% ≥1%
Nivolumab (n=22) 15 (68) 7 (32)Nivolumab + ipilimumab (n=18) 12 (67) 6 (33)
Side effects of immunotherapy
Hypophysitis
Thyroiditis
Adrenal insufficiencyEnterocolitis
Dermatitis, itch, vitiligo, alopecia
Motor & sensory neuropathy
Hepatitis
Pneumonitis
Pancreatitis
Arthritis
Ocular: scleritis/uveitis
Renal toxicity: GNLower incidence of imAEs with PD-1/PD-L1 inhibitors compared with Ipilimumab (but not devoid of them) Most frequent toxicities reported are mild fatigue, rash, pruritis, diarrhoea and colitis
Conclusion
1. Immunotherapies represent a new pillar of treatment for NSCLC.2. PD-L1 is a potential predictive biomarker.3. Development of biomarker key to further development as a single
agent and in combination with other therapies.4. Unique side effects consistent with the immune mechanism of action.
MOVING AHEAD!