41
Inmunoterapia en cáncer de pulmón Mariano Provencio Servicio de Oncología Médica Hospital Universitario Puerta de Hierro
Inmunoterapia en cáncer de pulmón
Mariano Provencio
Servicio de Oncología Médica
Hospital Universitario Puerta de Hierro
Current Therapeutic Landscape
for NSCLC
• Current treatment strategies in NSCLC
– Various chemotherapy regimens based on histologic diagnosis
– Targeted therapy options available for specific molecular
mutations
• Anti-EGFR–targeted therapy for patients with EGFR mutations
• ALK inhibitors for patients with ALK translocations
• ROS, Her2,…
• Even with various personalized approaches, the 5-yr survival
rate for patients with NSCLC (all stages) is only 17%
• The role of immunotherapy in lung cancer have
historically been associated with disappointing results
1. American Cancer Society. Cancer facts and figures 2013.
Anti-CTLA-4 Blockade
In preclinical mouse models, CTLA4 blockade in combination with various
chemotherapeutic agents was synergistic in inducing tumor regression and
elicited prolonged anti-tumor effects and induction of a memory immune response
Reck M et al. Ann Oncol 2013;24:75-83
ED-SCLC naive
Were randomized 1:1:1
Concurrent regimen:
4 doses of ipilimumab/paclitaxel/carbo followed by 2 doses of carbo/paclitaxel
Phased-ipilimumab regimen:
2 doses placebo/carbo/taxol followed 4 doses of ipilimumab/taxol/carbo
Control regimen:
Up to six doses of placebo/taxol/carbo
Ipilimumab: 10mg/Kg; taxol: 175mg/m2; carbo (AUC:6), every 3 weeks
Primary end point: immune-relatedPFS. Secondary: mWHO-PFS;OS, OPP, iBORR
Reck M et al. Ann Oncol 2013;24:75-83
Efficay
Phased-regimen
improved irPFS compared control
HR, 0.64; p:0.03
Median 5.3 vs 6.4 m
OS: phased: 12.9 m vs 9.9 m (HR:0.75) mWHO-PFS: 5.2 m vs 5.2 m control
Reck M et al. Ann Oncol 2013;24:75-83
Reck M et al. Ann Oncol 2013;24:75-83
Tumor response rates appeared to favor phased ipi,
the differences being greater when assessed by iRC
A phase III clinical trial is currently ongoing to evaluated the efficacy of ipilimumab
in addition to chemotherapy with platinum/etoposide in patients with ES-SCLC
with the primary endpoint of OS (NCT014507661)
Reck M et al. Ann Oncol 2013;24:75-83
Discontinuation were similar across arms: control 9%; concurrent 7% and phased: 5%
Overall incidence
grade 3 / 4 AES
9% control
21% concurrent
17% phased
204 patients chemotherapy-naive NSCLC
were randomly 1:1:1
Primary end point: irPFS
Other end points: PFS, ORR, irORR, OS and safety
Kaplan-Meier plots for progression-free survival
per immune-related response criteria (irPFS).
Lynch T J et al. JCO 2012;30:2046-2054
©2012 by American Society of Clinical Oncology
Phased ipilimumab regimen
improved irPFS significantly
compared with control
HR: 0.72; p: 0.05
Median irPFS: 4.6 m control
5.7 m phased
5.5 m concurrent
Median WHO-PFS: 4.2 m control
5.1 m phased
4.1 concurrent
Kaplan-Meier plots for overall
survival (OS).
Lynch T J et al. JCO 2012;30:2046-2054
Median OS phased ipili was: 12.2 m vs 8.3 m control (> 3.9m) HR: 0.87, p:0.23
in squamous/phased regimen: HR: 0.48 (0.22-1.03) vs nonsquamous HR: 1.17
In phased regimen
irPFS greater in patients with squamous histology: HR: 0.55 (95% CI, 0.27-1.12)
also in WHO-PFS ( HR: 0.40 (95% CI, 0-18-0.87)
PD-1 and PD-L1 Antibodies
Agent
Anti PD-L1
MPDL3280A (Genetech)
MEDI-4736 (Astra)
BMS 936559 (BMS)
MSB0010718C (Merck)
Anti PD 1
Nivolumab (BMS)
MK-3475 Pembrolizumab (Merck)
Pidilizumab (CureTch)
AMP 224 (Glaxo)
AMP 514 (Astra)
PD-L2–mediated
inhibition of TH2 T cells Stromal PD-L1
modulation of T cells
Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1
(PD-L1) in the treatment of advanced human cancer.
Blockade of PD-1 Binding to PD-L1 (B7-H1) and PD-L2 (B7-DC) Revives T Cells
• PD-L1 expression on tumor cells is induced by γ-interferon
• In other words, activated T cells that could kill tumors are specifically disabled by those tumors
PD-1
PD-L1
PD-L2
T-cell receptor
MHC-1
CD28
Shp-2
B7.1
IFN-γ–mediated
upregulation of
tumor PD-L1 PD-L1/PD-1–mediated
inhibition of tumor cell killing
Priming and
activation of
T cells
Immune cell
modulation of T cells
Tumor cell
IFN-γR
IFN-γ
Tumor-associated
fibroblast M2
macrophage
Treg
cell
Th2
T cell
Other NFκB P13K
CD8+ cytoxic
T lymphocyte
T-cell polarization
TGF-β
IL-4/13
Can you generate
tumor-killing T cells?
Dendritic
cell
Antigen priming
Can the T cells
get to the tumor?
T-cell trafficking
Can the T cells
see the tumor?
Peptide-MHC
expression
Can the T cells
be turned off?
Inhibitory cytokines
Can the T cells
be turned off?
PD-L1 expression
on tumor cells
Phase I Nivolumab Multidose Regimen
• Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC with
PD after 1-5 systemic therapies
– Brahmer JR. Phase I study of single-agent anti-programmed death-1 (MDX-
1106)…JCO 2010; 28:3167-75
• NSCLC Expansion Cohort: Pts randomized to 3 dose levels of
nivolumab (1, 3, or 10 mg/kg)
Day 1* 15* 29* 43* 57
Follow-up q8w x 6
(48 wks)
Treat to confirmed
CR, worsening PD,
unacceptable
toxicity, or 12 cycles
(96 wks)
Off study
*Dose administered IV q2w.
Scans done at baseline and following each 8-wk treatment cycle.
Rapid PD or
clinical
deterioration
Unacceptable
toxicity
CR/PR/SD or PD
but clinically
stable
8-wk treatment cycle
Brahmer JR, et al. WCLC 2013/ JCO 2013, abs 8030.
Efficacy of Nivolumab Monotherapy in Patients With NSCLC
(N=129)
• Durable responses: responses are ongoing in 45% of patients (10/22)
• Rapid responses: 50% of responding pts had response at first assessment (8 wks)
• 7/16 responders who discontinued for reasons other than disease progression
responded for ≥16 wks; 6/7 remain in response
• Responses in PD-L1 negative
• Similar OS by PDL1 or molecular status (EGFR or KRAS)
Dose, mg/kg ORR, % (n/N)
Median DOR, Wks (Range)
SD Rate 24 Wks, % (n/N)
Median PFS, Mos (95% CI)
Median OS, Mos (95% CI)
All doses 17.1%
(22/129)
74.0 (6.1+, 133.9+)
10.1 (13/129)
2.3 (1.9-3.7)
9.6 (7.8-12.4)
1 mg/Kg 3.0 % (1/33)
63.9 (63.9, 63.9)
15.2 (5/33)
1.9 (1.8-3.6)
9.2 (5.6-11.1)
3 mg/Kg 24.3 % (9/37)
74.0 (16.1+, 133.9+)
8.1 (3/37)
1.9 (1.7-7.3)
14.9 (9.5-NE)
10 mg/Kg 20.3 % (12/59)
83.1 (6.1+, 117.1+)
8.5 (5/59)
3.6 (1.9-3.8)
9.2 (5.2-12.4)
Brahmer JR, et al. WCLC 2013/ JCO 2013, abs 8030.
Heavily preteated (55% had received three or more prior lines of therapy)
Nivolumab: Duration of Response and OS
0 6 12 18 24 30 36 42 48 54
0
0.2
0.4
0.6
0.8
1.0
Mos Since Initiation of Treatment
129 82 48 31 20 4 3 2 1 0 Pts at Risk, n
All Treated Subjects With NSCLC
Died/Treated Median OS (95% CI)
94/129 9.9 (7.8-12.4)
Pro
po
rtio
n S
urv
iva
l
1-yr OS: 42% (48 pts at risk)
2-yr OS: 24% (20 pts at risk)
Brahmer JR, et al. WCLC 2013. Abstract MO18.03/JCO 2013
0 16 32 48 64 80 96 112 128 144 160
Wk
No
ns
qu
am
ou
s
Sq
uam
ou
s
NSCLC Responders by Histology
Duration of response up to discontinuation of therapy Ongoing response Time to response Response duration following discontinuation of therapy
1-yr OS: 44% and 41% squamous and non-squamous histology
Select AEs (≥ 1%) Occurring in Pts With NSCLC
Treated With Nivolumab (N = 129)
• Drug-related pneumonitis (any grade) occurred in 8 NSCLC pts (6%) vs 12
pts (4%) in the overall study population
– 3 pts (2%) with NSCLC had grade 3/4 pneumonitis
*AE severity was graded based on the Common Terminology Criteria for Adverse Events, v3.0.
Treatment-Related Select AE, % (n) Any Grade* Grade 3/4*
Any treatment-related select AE 41 (53) 5 (6)
Skin 16 (20) 0
Gastrointestinal 12 (15) 1 (1)
Pulmonary 7 (9) 2 (3)
Endocrinopathies 6 (8) 0
Hepatic 5 (6) 1 (1)
Infusion reaction 4 (5) 1 (1)
Renal 3 (4) 0
Brahmer JR, et al. ASCO 2013. Abstract 8030. Brahmer JR, et al. WCLC 2013. Abstract MO18.03.
1st-line nivolumab monotherapy (3mg/kg q 2 wks): Safety, efficacy, and correlation with PD-L1 status (n=20)
• Key results
– Overall ORR 30% (2 CR ,1 SCC, 1 non-SCC)
• Response at first assessment (11 weeks) in 83% (5/6 pts)
• PD-L1 expression status correlate with response (50% in PD-L1+; 0 PD-L1-) – PFS rate at 24 weeks was 60%, 1-year OS 75% – Grade 3–4 treatment-related AEs 20%
ASCO 2014 Gettinger 14, poster, abstr 8024
Responders by histology Responders by PDL-1
ORR 30% 22% SCC, 36% Non-SCC
Unprecedented RR seen in patients with heavily pretreated
NSCLC
Ongoing Nivolumab Clinical Trials in Patients With NSCLC
Line of therapy Phase PD-L1 Selection Comparator
Single agent Nivolumab
1st line[1] III Yes Chemotherapy maintenance
2nd line, squamous[2] III No Docetaxel
2nd line, adeno[3] III Yes Docetaxel
≥ 2nd line, squamous[4] II No NA
Combination Nivolumab
≥ 2nd line[5] I No + LAG3
≥ 2nd line[6] I No + lirilumab (KIR)
1st line[7] I No Single agent; + chemotherapy;
+ bevacizumab; + erlotinib; + ipilimumab
1. ClinicalTrials.gov. NCT02041533. 2. ClinicalTrials.gov. NCT01642004. 3. ClinicalTrials.gov. NCT01673867.
4. ClinicalTrials.gov. NCT01721759. 5. ClinicalTrials.gov. NCT01968109. 6. ClinicalTrials.gov. NCT01714739.
7. ClinicalTrials.gov. NCT01454102.
KEYNOTE-001: MK-3475 for Patients With NSCLC
• Treatment: administered IV 2 mg/kg q3w, 10 mg/kg q3w, or 10 mg/kg q2w
• Tumor assessment:
– Imaging q9w
– Primary: RECIST v1.1 (independent central review)
– Secondary: immune-related response criteria (investigator assessed)
• Tumor biopsy
– A new tumor biopsy within 60 days prior to the first dose of MK-3475 was required
Screening
-28 Days
MK-3475
C1D1 CR or PR,
SD
PD, unacceptable
toxicity, or
investigator decision
Continue dosing &
assessments q9w*
Off study Mandatory Biopsy
*Until progression, unacceptable toxicity, or investigator decision.
Garon EB, et al. WCLC 2013. Abstract MO18.02. Reprinted with permission.
4/49
PD-L1 Identifies Pts With NSCLC Most
Likely to Benefit From MK-3475
Strong PD-L1 positive staining was considered ≥ 50% of tumor cells, and weak was
defined as staining between 1% to 49% of positively staining tumor cells. Negative had
no tumor staining for PD-L1.
Re
sp
on
se
Ra
te (
%)
3/42 7/46 15/41 25/129
Gandhi L, et al. AACR 2014. Abstract CT105.
RR-RECIST 1.1
50
40
30
20
10
0
19
37
15
7
Total
1%-49% PD-L1 staining
≥ 50% PD-L1 staining
PD-L1 negative
Re
sp
on
se
Ra
te (
%)
4/53 20/44 28/146
RR-irRC
50
40
30
20
10
0
19
46
8 8
n/N: n/N:
Examples of PD-L1 NSCLC Sample
Immunohistochemical Staining*
PD-L1 Negative PD-L1 Positive
*Clinical trial assay.
Staining
Intensity 0+ 1+ 2+ 3+
PD-L1
Positivity, % 0 2 100 100
Gandhi L, et al. AACR 2014. Abstract CT105
KEYNOTE-001: MK-3475 AEs in Patients
With NSCLC
• 20 patients (53%) experienced ≥1 drug-related AE of any grade
• Drug-related AEs of interest: grade 2 hyperthyroidism (n = 1), grade 2 hypothyroidism (n
= 1), grade 2 pneumonitis (n = 1), and grade 3 pulmonary edema (n = 1)
• No patient experienced treatment-related death
Adverse Event All Grades, n (%) Grades 3-5, n (%)
Rash 8 (21) 0 (0)
Pruritis 7 (18) 0 (0)
Fatigue 6 (16) 0 (0)
Diarrhea 5 (13) 0 (0)
Arthralgia 4 (11) 0 (0)
Back pain 2 (5) 0 (0)
Cough 2 (5) 0 (0)
Decreased appetite 2 (5) 0 (0)
Garon EB, et al. WCLC 2013. Abstract MO18.02.
Ongoing MK-3475 Clinical Trials in
Patients With NSCLC
Line of Therapy Phase PD-L1
Selection
Comparator
Single-agent MK-3475
1st line; ≥ 2nd line[1,2] I/II Both NA
2nd line[3] III Yes Docetaxel
1st line[4] III Yes Chemotherapy
Combination MK-3475
NA[5] I/II No Single agent; + chemotherapy;
+ pemetrexed; + gefitinib; + erlotinib;
+ ipilimumab
1. ClinicalTrials.gov. NCT02085070. 2. ClinicalTrials.gov. NCT02129556. 3. ClinicalTrials.gov. NCT01905657.
4. ClinicalTrials.gov. NCT02142738. 5. ClinicalTrials.gov. NCT02039674.
BMS 936559: PD-L1 antibody
• 207 patients with advanced solid organ malignancies
– was given every 2 weeks
– 75 p with NSCLC
• 49 evaluable for response
• 5 objective responses (4 non-squamous and 1 squamous)
Brahmer JR NEJM 2012; 366: 2455-65
Phase I Study of MPDL3280A in NSCLC • MPDL3280A: anti–PD-L1 antibody engineered for enhanced safety and efficacy
• Specifically engineered to block the PD1/PD-L1 interaction
• Patients with metastatic solid tumors
– EGFR and KRAS status assessed at baseline
• Study design: MPDL3280A IV every 3 wks x 16 cycles (≈ 1 yr)
• Primary endpoint: safety
• Secondary endpoint: ORR by RECIST v1.1
Characteristics n = 85*
Median age, yrs (range) 60 (24-84)
Sex, male/female, n (%) 48 (56)/37 (44)
ECOG PS, 0 / 1, n (%) 27 (32)/58 (68)
Histology, n (%)
Squamous 20 (24)
Nonsquamouss 65 (76)
*Safety evaluable patients (n = 85) with NSCLC. Data cutoff April 30, 2013. †Systemic regimens administered in the metastatic, adjuvant or neoadjuvant setting. 3% of patients had no previous systemic regimens.
Characteristics, n (%) n = 85*
Previous systemic regimens†
1 or 2 36 (42)
≥ 3 47 (55)
Smoking status
Current/previous 68 (80)
Never 17 (20)
Horn L, et al. WCLC 2013. Abstract MO18.
PD-L1
Status*
(N = 53)
ORR,†
%
(n/N)
Pts With PD,
% (n/N)
IHC 3
(n = 6)
83
(5/6)
17
(1/6)
IHC 2 and 3
(n = 13)
46
(6/13)
23
(3/13)
IHC 1/2/3
(n = 26)
31
(8/26)
38
(10/26)
All patients
(IHC 0/1/2/3
and 7
patients with
diagnostic
unknown;
N = 53)
23
(12/53)
40
(21/53)
Duration of Treatment and Response
Wk
Histology IHC
NS IHC 0
S IHC 3
NS IHC 0
NS IHC 1
NS IHC 0
S IHC 2
NS IHC 3
S IHC 3
NS IHC 3
NS IHC 0
NS IHC 3
NS IHC 1
*PD-LI status determined using proprietary Genentech Roche IHC. †ORR includes investigator-assessed unconfirmed and confirmed (u/c) PR per RECIST 1.1.
Patients first dosed at 1-20 mg/kg by October 1, 2012. Data cutoff April 30, 2013.
MPDL3280A in NSCLC: Best Response by PD-L1
Status and DOT/DOR
Horn L, et al. WCLC 2013. Abstract MO18/Spigel DR. JCO abstract 8080.
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
On study, on treatment
On study, post treatment
Treatment discontinued
Ongoing response
First response
First PD
*ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, 2012. Data cutoff April 30, 2013.
Former/
Current Smokers
Never
Smokers
Response by Smoking Status (ORR*) Smoking Status (NSCLC; n = 53)
Pts
Wit
h P
R (
%)
EGFR
Mutant
EGFR Status (NSCLC; n = 53)
Unknown
Response by EGFR Status (ORR*)
Pts
Wit
h P
R (
%)
KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR*)
Pts
Wit
h P
R (
%)
KRAS
Mutant
Unknown
EGFR WT EGFR Mutant
KRAS WT KRAS Mutant
11/43 1/10
9/40 1/6
8/27 1/10
MPDL3280A Phase Ia: Response by Smoking
and Mutational Status
Horn L, et al. WCLC 2013. Abstract MO18. ASCO/JCO
50
40
30
20
10
0
50
40
30
20
10
0
50
40
30
20
10
0
Former/Current Smokers Never Smokers
26%
10%
23% 17%
30%
10% 51%
30%
19%
76% 13%
11%
81%
19%
KRAS WT
EGFR WT
Current/Former: 20/75: 27% ORR
Never: 0/13
ESMO 2014
[TITLE]
Calles ESMO 2014
MPDL3280A: Treatment-Related Adverse
Events in Patients With NSCLC
• Majority of AEs were grade 1/2 and did
not require intervention
• No MTD or dose-limiting toxicities
• No grade 3-5 pneumonitis observed
• Treatment-related death (cardio-
respiratory arrest) in 1 patient with
sinus thrombosis and large tumor
mass invading the heart at baseline
• Immune-related grade 3.4 AEs: 1
patient with large-cell neuroendocrine
NSCLC (diabetes mellitus, 1%)
*AEs occurring in ≥ 5% of patients. †Grade 3/4 treatment-related AEs listed include treatment-
related AEs for which the any grade occurrence was ≥ 5%
of patients.
Data cutoff April 30, 2013.
Adverse Event
(n = 85)
Treatment Related, % (n)
Any Grade* Grade 3/4†
Any AE 66 (56) 11 (9)
Fatigue 20 (17) 2 (2)
Nausea 14 (12) 1 (1)
Decreased appetite 12 (10) 0
Dyspnea 9 (8) 1 (1)
Diarrhea 8 (7) 0
Asthenia 7 (6) 0
Headache 7 (6) 0
Rash 7 (6) 0
Pyrexia 6 (5) 0
Vomiting 6 (5) 1 (1)
Upper respiratory tract
infection
5 (4) 0
Horn L, et al. WCLC 2013. Abstract MO18. Reprinted with permission.
Vaccine therapy
Vaccine Antigen Specific
Phase trial stage/pop
Nº Trial design Results
MAGE 3 present in numerous tumors
JCO 2013
Proof-of-concept MAGE A3 positive Stage IB Phase II vaccine vs placebo
122 Recurrence 35% MAGE A3 arm vs 43% placebo Disease Free Interval: HR: 0.75; p:0.25 Disease Free Survival: HR: 0.76; p:0.24 OS: HR: 0.81; p:0.45
MAGE-A3 ESMO 2014
MAGRIT Stage IB, II and IIIA + MAGE-3 gene placebo vs vaccine
2312 Stopped Did not meet primary end points, including DFS
Vaccine Phase trial stage/pop
Nº Results
MUC-1 Membrane-associated Glycoprotein MUC-1 is increased in cancer cell 60% NSCLC Role not clear Peptide based vaccine- Liposomal BLP-25 (L-BLP25) Butts C. JCO 2005
Phase II IIIB and IV stable after ChT or RT
171 Eight weekly sc imm L-BLP25 vs BSC Median Survival: 17.4 m vs 13 m (HR: 0.73; p: 0.11) 3-year survival rate was: 31% L-BLP25 vs 17% (p:0.035) A post hoc analysis: benefit in stage IIIB (3-y: 49% vs 27%; p: 0.07)
MUC-1 L-BLP-25
START Stage III unresectable vaccine vs ctx vs placebo
1513 After ChemoRT; placebo vs Vaccine Did not meet primary end point OS: 0.88; median OS: 25.6 vs 22.3; p:0.123
Vaccine Phase trial stage/pop
Nº Results
TG 4010 glycoprotein based pox virus Encoding for MUC-1 and IL-2 Ramlau R. JTO 2008
Phase II Stage IIIB/IV 1st line with CDDP-VNR
67 Concurrent arm: 35% and OS: 12.7
TG4010 MUC positive Lancet Oncol 2011
Phase IIB IIIB/IV cis-gem alone vs Cht + vaccine
148 PFS: TG40101: 43.2% ChT: 35.1% (p:0.307) OS: TG4010: 10.7 m ChT: 10.3 m
TG 4010 glycoprotein MUC-1
Stage IV ongoing
placebo vs vaccine Primary end point: OS
Vaccine Phase trial stage/pop
Nº Results
CIMAvax EGF Recombinat Human Epidermal Growth Factor Neninger E. JCO 2008
Phase II Stage IIIB/IV 1st line following BSC vs vaccine
80 Median OS: 11.7m with good EGFR antibody response
Bec2 combined with BCG anti-idiotypic antibody GD3 JCO 2005
Phase III SCLC after induction
551 No improvement in OS, PFS or QoL OS median 16.4 vs 14.3 m
Belagenpumatucel antisense gene –TGF-B2 AACR 2013
Phase II Stage IV
75 OS: 44.4 m
Immunocompetent Mice Reject Tumors Originating in Immunodeficient Mice
Shankaran V, et al. Nature. 2001;410:1107-1111.
In other words, competent immune
systems force the tumors to figure
out how to survive in hostile
environments
Conclusions
Next frontier of treatment of lung cancer
The cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitory checkpoint pathway is important in
regulating early T-cell activation.
Brahmer J R JCO 2013;31:1021-1028
©2013 by American Society of Clinical Oncology
Safety and response with nivolumab/erlotinib in p with advanced mutant EGFR (NCT01454102)
Rizvi 14, poster, abstr 8022
PD
Key patient inclusion criteria
•Stage IIIB/IV NSCLC
•Non-squamous
•EGFR+
•CT naïve
(n=21)
nivolumab 3 mg/kg q2w
+ erlotinib 150 mg/day
• Key results:
– 21 p (20 prior treatment with erlotinib)
– Grade 3 AEs occurred in 24% of p (no grade 4 reported)
– ORR 19% / 45% SD
– PFS 29.4 weeks (4.6-81.7), OS NR (10.7-86.9)
