inmunoterapia en cáncer de pulmón - seom: sociedad espa · 1-yr os: 42% (48 pts at risk) 2-yr os:...

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


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



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)


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.


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


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


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


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)

inmunoterapia en cáncer de pulmón - seom: sociedad espa · 1-yr os: 42% (48 pts at risk) 2-yr os:...

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