1. No category

Immuno-Oncology 2015:
A New Landscape in Lung Cancer
David R. Spigel, M.D.
Lung Cancer Program Director
Sarah Cannon Research Institute/Tennessee Oncology, PLLC
Nashville, TN
Off-Label Use Disclosure(s)
I do not intend to discuss an off-label use of a product during
this activity.
2
Financial Disclosure(s)
I currently have or have had the following relevant financial
relations to disclose:
• Commercial Interest - Genentech, BMS
• Relationship with Commercial Interest – Advisory Board
3
Case: A 70-Year Old Man with Stage IV Squamous NSCLC
8
months
ago
• Diagnosed with metastases to lung,
lymph nodes and pleura
• Treated with carboplatin + paclitaxel
3
months
ago
• Disease progression noted
• Started treatment with
docetaxel
2 weeks
ago
• Disease progression noted
• PS=1
Poll
How would you proceed in managing this patient?
 Gemcitabine
 Erlotinib
 Nivolumab
 Pemetrexed
Gene Alterations in Lung Cancer
6
Perez-Moreno, CCR 2012
Mutations Across Cancers
7
Kandoth, Nature 2013
The Potential of Immunotherapy
Immune system in the Cancer Patient
• Normal immune systems fight invaders (bacteria, viruses) by recognizing
antigens, and destroying anything with those antigens
• Cancer cells also produce antigens, and should be killed by “killer T cells”
Sometimes the immune system is “tricked” into not recognizing the antigens
on the cancer cells
Some cancer cells don’t produce antigens
8
PD-1, PDL-1, B7.1 – Cancer Immunotherapy
9
Chen, CCR 2012
Cancer Immunotherapy
10
PD-L1 is Broadly Expressed in NSCLC
Adenocarcinoma
Squamous cell carcinoma
Prevalence of PD-L1 ≈ 45%
Prevalence of PD-L1 ≈ 50%
PD-L1
PD-L1
H&E
H&E
Koeppen H. and Kowanetz M., Genentech
Proprietary Genentech/Roche PD-L1 IHC
High sensitivity and specificity in FFPE samples
11
MPDL3280A: PDL1 Expression
Nature, 2014
12
Selected Trials with Checkpoint Inhibitors in NSCLC
IMMUNOTHERAPY IN LUNG CANCER:
ANTI-PD1 DRUG DEVELOPMENT –
NIVOLUMAB
CheckMate-003 Nivolumab in Patients with PreTreated, Advanced NSCLC: Duration of Response
•
Durable responses observed regardless of histology
Gettinger SN, et al. J Clin Oncol. 2015 Apr 20. [Epub ahead of print].
Slide 5
Presented By Scott Gettinger at 2014 ASCO Annual Meeting
CheckMate-003 Phase 1 Study with Nivolumab in Patients
with Pre-Treated Advanced NSCLC: Overall Survival
At least 1 prior platinum containing regimen, no more than 5 lines. 54% of patients received
3 prior lines of therapy.
•
•
•
Gettinger SN, et al. J Clin Oncol. 2015 Apr 20. [Epub ahead of print].
Responses at all
dose levels.
Median OS across
doses was 9.9 mos
3 mg/kg dose chose
for further clinical
development
CheckMate-063 Phase 2 with Nivolumab in PreTreated Patients with Squamous NSCLC
65% of patients had failed three lines of therapy
Endpoint
ORR, % (n) [95% CI]
Disease control rate, % (n)
Median DOR, months (range)
IRC Assessed (per RECIST v1.1)
15 (17) [9, 22]
40 (47)
NR (2+, 12+)
Ongoing responders, % (n)
76 (13)
Median time to response, months
(range)
3 (2, 9)
PFS rate at 1-year, % (95% CI)
20 (13, 29)
Median OS, months (95% CI)
8.2 (6.1, 11)
OS rate at 1-year, % (95% CI)
41 (32, 50)
• Nivolumab demonstrated activity in previously treated patients with advanced
squamous NSCLC.
Rizvi NA, et al. Lancet Oncol. 2015 Mar;16(3):257-65.
Nivolumab Multi-Dose: <br />Safety in Total Population
Presented By Mario Sznol at 2014 ASCO Annual Meeting
CheckMate-017: Nivolumab in Pre-Treated
Squamous NSCLC
Open label, randomized phase 3 study evaluating nivolumab versus docetaxel
in previously treated patients with advanced, squamous cell NSCLC1
Previously treated
patients with
advanced or
metastatic
squamous cell
NSCLC
(N = 272)
R
Nivolumab [3 mg/kg IV q 2 wks]
(N=135)
• Primary endpoint: OS
Docetaxel [75 mg/m2 IV q 3 wks]
(N=137)
• Nivolumab demonstrated significantly superior OS vs docetaxel, with 41%
reduction in risk of death (hazard ratio: 0.59 [95% CI:0.44, 0.79; p=0.00025]2
• Median OS with nivolumab was 9.2 months [95% CI = 5.1–7.3
months]compared with 6 months [95% CI = 5.1–7.3 months] with docetaxel2
Based in part on the results from CheckMate-063 and CheckMate017, the FDA approved nivolumab for treatment of patients with
metastatic squamous NSCLC with progression on or after
platinum-based chemotherapy3
1. ClinicalTrials.gov identifier NCT01642004.; 2. http://www.ascopost.com/issues/april-10,-2015/nivolumabin-metastatic-squamous-non–small-cell-lung-cancer-after-platinum-therapy.aspx;
3.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm
CheckMate-057: Nivolumab in Pre-Treated NonSquamous NSCLC
Open label, randomized phase 3 study evaluating nivolumab versus docetaxel
in previously treated patients with advanced, non-squamous NSCLC1
Previously treated
patients with
advanced or
metastatic nonsquamous NSCLC
(N = 582)
Nivolumab [3 mg/kg IV q 2 wks]
R
• Primary endpoint: OS
Docetaxel [75 mg/m2 IV q 3 wks]
Results expected soon!
1. ClinicalTrials.gov identifier NCT01673867.; http://news.bms.com/press-release/checkmate-057-pivotalphase-iii-opdivo-nivolumab-lung-cancer-trial-stopped-early
IMMUNOTHERAPY IN LUNG CANCER:
ANTI-PD1 DRUG DEVELOPMENT –
PEMBROLIZUMAB (MK3475)
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: Efficacy
(N=90)
(N=33)
(N=38)
(N=280)
(N=43)
Randomized
(N=11)
• PD-L1+tumors
• Treatment naive
R
1:2
Pembro
2 mg/kg
Q3 W
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
Pembro
10 mg/kg
Q3W
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: Efficacy
•
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
Best overall
response rate was
stable disease in
21.8% of patients
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: Efficacy
PS>50%
PS 1-49%
PS<1
•
Total ORR- n
(%)
[95% CI]
33 (45.2)
[33.5-57.3]
17 (16.5)
[9.9-25.1]
3 (10.7)
[2.3-28.2]
Previously
Treated
ORR- n (%)
[95% CI]
25 (43.9)
[30.7-57.6]
12 (15.6)
[8.3-25.6]
2 (9.1)
[1.1-29.2]
Treatment
naïve ORR –
n (%)
[95% CI]
8 (50.0)
[24.7-75.3]
•
5 (19.2)
[6.6-39.4]
1 (16.7)
[0.4-64.7]
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
Overall response
rate was 19.4%
– 18.0% in
previously
treated
patients
– 24.8% in
un-treated
patients
Similar response
rate among dose,
schedule and
histology
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: PFS
•
•
•
mPFS was 3.7 months for all patients
mPFS was 3.0 months for previously treated patients
mPFS was 6.0 months for treatment naïve patients
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: OS
•
•
•
mOS was 12.0 months for all patients
mOS was 9.3 months for previously treated patients
mOS was 16.2 months for treatment naïve patients
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
KEYNOTE-001 Phase 1 Study with Pembrolizumab in
NSCLC: Efficacy
Overall Survival
Progression Free Survival
PD-L1 expression in at least 50% of tumor cells correlated
with improved efficacy of pembrolizumab.
Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of print].
Merck Press Release – October 27, 2014
Merck Receives FDA Breakthrough Therapy Designation for
KEYTRUDA® (pembrolizumab) in Advanced Non-Small Cell Lung
Cancer
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD
outside the United States and Canada, announced today that the U.S. Food and Drug
Administration (FDA) has granted Breakthrough Therapy Designation to KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of patients with
Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma
Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease
has progressed on or following platinum-based chemotherapy. This is the second
Breakthrough Therapy Designation granted for KEYTRUDA.
30
Anti-PD-1 Monotherapy in Heavily Pretreated Patients
with Advanced NSCLC: Summary of Safety
Agent
N
Safety Data
Nivolumab1
117
74% of patients experienced at least 1
TRAE; most common: fatigue (33%),
decreased appetite (19%), asthenia (12%),
and nausea (15%); 17% gr3-4 TRAEs:
fatigue (4%), pneumonitis (3%), diarrhea
(3%), and 2 treatment-associated deaths
caused by pneumonia and ischemic stroke
Pembrolizumab2
495
71% of patients experienced at least 1 TRAE;
most common: fatigue (19%), pruritus (11%),
decreased appetite (10.5%), rash (10%); 9.5% gr
3-5 TRAEs: dyspnea (4%); pneumonitis (1.8%)including one who died
1. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265. 2. Garon E, et al. N Engl J Med 2015 Apr 19. [Epub ahead of
print].
IMMUNOTHERAPY IN LUNG CANCER:
ANTI-PDL1 DRUG DEVELOPMENT –
MPDL3280A
MPDL3280A: ORR
33
MPDL3280A
34
Clinical Activity of MPDL3280A in NSCLC (Squamous)
Baseline
Post C2 (Week 6)
Post C6 (Week 18)
Post C16 (Week 48)
73-year-old male, s/p deep neck mass excision, ramucirumab + gemcitabine + carboplatin
PD-L1 positive
35
3
36
MPDL3280A – Clinical Trial Program
[TITLE]
37
Rizvi, ASCO 2014
Genentech Press Release – Feb 1, 2015
FDA Grants Breakthrough Therapy Designation for Genentech’s
Investigational Cancer Immunotherapy MPDL3280A (anti-PDL1) in
Non-Small Cell Lung Cancer
Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced
today that it has received a second Breakthrough Therapy Designation from the U.S.
Food and Drug Administration (FDA) for its investigational cancer immunotherapy
MPDL3280A (anti-PDL1). The designation was granted for the treatment of people with
PD-L1 (Programmed Death-Ligand 1) positive non-small cell lung cancer (NSCLC) whose
disease has progressed during or after platinum-based chemotherapy (and an
appropriate targeted therapy for those with an EGFR mutation-positive or ALK-positive
tumor).
38
IMMUNOTHERAPY IN LUNG CANCER:
ANTI-PDL1 DRUG DEVELOPMENT –
MEDI-4736
Majority Remain on Treatment<br />
Presented By Neil Segal at 2014 ASCO Annual Meeting
Objective Response Rate<br />
Presented By Neil Segal at 2014 ASCO Annual Meeting
Phase 1 Dose Expansion Study with MEDI4736: Efficacy
Segal NH, et al. ASCO 2014. Abstract 3002.
Atlantic 3rd/4th-line NSCLC Phase II – SAT
MEDI4736 in cohorts by EGFR mutation/ALK status
Implement
patient selection
for PD-L1+
patients only
Recent
(≤ 3 mo)
Biopsy
NSCLC Patients with
(Stage IIIB-IV) who
have Received at
Least Two Prior
Systemic Regimens
including one
Platinum-based
Therapy
N= Up to 700
COHORT 1b
(EGFR mut /ALK rearrangment +)
PDL1+only
N=94*
Subsequent
treatments
Objective
Disease
Progression
MEDI4736
10mg/Kg IV, Q2W
up to 12 mos
Follow up
for OS
COHORT 2b
(EGFR mut /ALK rearrangment -)
PDL1+only
N=94*
*With an assumed 15% non measurable disease rate according
to central review, 94 patients are expected to result in 80
patients with measurable disease.
Analysis of overall cohort population will also be conducted
Primary Endpoint: ORR
Blinded Independent Central Review
RECIST 1.1*
Q 12 weeks during tx; then Q 6 mos.
43
STUDY 1 - (PACIFIC)
Phase III RCT: D4191C00001
1st line Stage 3 Locally Advanced, Unresectable NSCLC
n=702
Concomitant
Platinumbased
Chemo-XRT
(≥ 2 cycles)
PD
CR + PR + SD
R
A
N
D
O
M
I
S
E
+1 day
2:1
 Stratification
 Age
 PS 0-1
 Gender
MEDI4736
10mg/Kg IV, Q2W
up to 12 mos.
PD
FU
Placebo
IV, Q2W
up to 12 mos.
Primary End point: PFS + OS
• RECIST 1.1
• q 8 weeks during treatment;
then q 12 weeks until PD
• Blinded central review
44
SWOG - LUNG MASTER PROTOCOL
Phase II/III - S1400
Specific markers for screening:
P13K – PI3KCA mutation
CDK4/6 – CCND1, Cdk6 amplification,
CDKN2 deletion and mutation
FGFR – FGFR amplification, mutation,
fusion
HGF – c-Met expression
Advanced stage refractory
SCCA patients
Screening registration
Common Broad Platform
CLIA Biomarker Profiling*
Sub-study Assessment**
Match
(known positive
biomarker)
Non-match
(unknown negative
biomarker)
Non-match
CT
Sub-study A
Anti-PD-L1
MEDI4736
AZ/MedImmune
Biomarker-driven
Sub-study B
Target P13K
GDC-0032
CT
Genentech
Endpoint
(interim PFS)
OS
Sub-study C
Target CDK4/6
Palbociclib
Sub-study D
Target FGFR
CT
AZD4547 + CT
Pfizer
AZ
Endpoint
(interim PFS)
OS
Endpoint
(interim PFS)
OS
CT
Sub-study E
Target HGF
Rilotumumab + E
E
Amgen
Endpoint
(interim PFS)
OS
45
Selected Trials with Checkpoint Inhibitors in NSCLC
Slide 22
Presented By Scott Gettinger at 2014 ASCO Annual Meeting
Phase 2 Study with Ipilimumab + Chemotherapy in
Untreated Patients with Advanced NSCLC: Efficacy
•
•
•
Phased ipilimumab in combination with paclitaxel and carboplatin significantly
improved irPFS and mWHO-PFS
Most common nonhematologic AEs (≥15%, any grade) typically associated with
paclitaxel and carboplatin, including fatigue, alopecia, nausea, vomiting, and
peripheral sensory neuropathy, were generally similar across arms.
Common AEs, such as rash, pruritus, and diarrhea, showed a trend for increased
incidence in the ipilimumab-containing arms than in paclitaxel and carboplatin arms,
and these AEs were also identified as irAEs per protocol-defined criteria.
Lynch T, et al. J Clin Oncol. 2012; 30:2046-2054.
Ipilimumab + Chemotherapy in Untreated Patients
with Advanced NSCLC: Histology Subgroup Analysis
•
Phased ipilimumab appeares to show improved efficacy for squamous histology
Lynch T, et al. J Clin Oncol. 2012; 30:2046-2054.
Nivolumab (anti-PD1) plus ipilimumab<br /> in advanced melanoma
Presented By Laura Chow at 2014 ASCO Annual Meeting
CheckMate 012 Phase 1 Study with Nivolumab +
Ipilimumab: Efficacy
•
•
Overall RR = 22%
Nivolumab + ipilimumab demonstrates antitumor activity in chemotherapy naïve patients
Antonia SJ et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8023).
CheckMate 012 with Nivolumab + Ipilimumab :
Select Adverse Events
• Safety profile of nivolumab combination reflected additive toxicities of
each agent
Gettinger S et al. J Clin Oncol. 32:5s, 2014; abstract 8024 ; Antonia SJ et al. J Clin Oncol 32:5s, 2014 (suppl;
abstr 8023).
Phase 1b Study with MEDI4736 + Tremelimumab:
Efficacy
Antonia S, et al. ESMO 2014. abstr 15924.
Select Clinical Trials with Immune Checkpoint
Inhibitors Combined with Immunotherapy in NSCLC
Regimen Evaluated
a
Phase
Setting
Trial Number
Pembrolizumab +
ipilimumab
1/2
Advanced or metastatic
NSCLC
NCT02039674
MEDI4736 +
tremelimumab
1/2
Advanced NSCLC
NCT02000947
MEDI4736 +
MEDI0680
1
Solid tumors
NCT02118337
Nivolumab +
ipilimumab
1
Chemotherapy-naïve,
advanced NSCLC
NCT01454102
Nivolumab +
interleukin-21
1
Solid tumors
NCT01629758
Insert, if applicable; always end with a period 16 pt.
Reference(s) 14 pt.
CheckMate 012 Phase 1 Study with Nivolumab +
Erlotinib: Efficacy
•
•
•
ORR = 19%
Results suggest nivolumab + erlotinib may provide clinical benefit in TKI refractory,
EGFR mutated advanced NSCLC
Safety findings: Additive toxicities of both agents (grade 3/4 AEs was 24%)
Rizvi N et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8022).
Select Clinical Trials with Immune Checkpoint
Inhibitors Combined with Targeted Therapy in NSCLC
Regimen Evaluated
Phase
Setting
Trial Number
Pembrolizumab +
1/2
erlotinib or gefitinib
Advanced/metastatic
NSCLC
NCT02039674
Nivolumab +
erlotinib
1
EGFR+, non-squamous
NSCLC
NCT01454102
MEDI4736 +
gefitinib
1
EGFR TKI naïve and
expansion in EGFR+
advanced NSCLC
NCT02088112
MPDL3280A +
cobimetinib
1
Solid tumors, expanded
in NSCLC
NCT01988896
CheckMate 012 Phase 1 Study with Nivolumab +
Chemotherapy: Efficacy
Antonia SJ et al. ASCO 2014; abstr 8113.
Grade 3-4 treatment-related AEs reported in 45% of patients.
• Pneumonitis (7%), fatigue (5%), and acute renal failure
(5%)
Select Clinical Trials with Immune Checkpoint Inhibitors
in Combination with Chemotherapy in NSCLC
Regimen Evaluated
Phase
Setting
Trial Number
Ipilimumab + pac/carbo
3
Advanced/recurrent squamous NSCLC
NCT01285609
Nivolumab + gem/cis,
pem/cis, or pac/carbo
1
Chemotherapy-naïve, advanced/recurrent NCT01454102
NSCLC
Nivolumab + bevacizumab
1
Given as maintenance therapy in
advanced NSCLC
NCT01454102
Pembrolizumab + cis/pem
or or pem/carbo or
pac/carbo + bev
1/2
Advanced or metastatic NSCLC
NCT02039674
MPDL3280A + pem/carbo
or cis
3
PD-L1+, chemotherapy-naïve, nonsquamous metastatic NSCLC
NCT02409342
MPDL3280A + gem/cis or
carbo
3
PD-L1+, chemotherapy-naïve, squamous
metastatic NSCLC
NCT02409355
MPDL3280A + carbo/pac or
carbo/nab-pac
3
Chemotherapy-naïve, squamous
metastatic NSCLC
NCT02367794
MPDL3280A + carbo/nabpac
3
Chemotherapy-naïve, non-squamous
metastatic NSCLC
NCT02367781
Questions and Challenges
• What is the optimal agent or combination?
• Schedule and duration (and sequence)?
• Can we select the best patients?
• How can we assess benefit?
• Is safety fully established?
59
Slide 9
Presented By Mario Sznol at 2014 ASCO Annual Meeting
PD-L1 Expression as a Biomarker: Response (2)
Agent(s)
N
Testing Method
PD-L1 +/Total
RR
Nivolumab1
N = 49
Manual staining – 5H1
5% cutoff
Tumor staining
13/31
42%
Nivolumab2
N = 38
Dako automated
5% cutoff
Tumor staining
7/17
41%
MPDL3280A3
N = 184
Automated
Roche Dx IHC
>5% cutoff
Tumor staining on
tumor cells and tumorinfiltrating immune cells
Ipilimumab +
Nivolumab4
N = 56
Dako automated
5% cutoff
Tumor staining
8/14
57%
Pembrolizumab5
N = 182
Dako automated
50% cutoff
Tumor staining
33/73
45%
12/53
23%
Immunotherapy in Lung Cancer Summary
• Multiple Agents in Development:
Anti-PD1, PDL1, Anti-CTLA4, Vaccine
Several Registrational Trials in Progress
Nivolumab FDA-Approved – Squamous (2nd+-Line v. Docetaxel)
Adencaracinoma Phase III Positive
2 Agents Fast Tracked – Break-Through Status
• Safety and Early efficacy signals encouraging
• Many questions and challenges remain:
Combinations
Patient selection
Schedule
Sequencing
62
Duration
Assessing Benefit