OS (%)OS (%)

2014.6.21

서울대병원 혈액종양내과 김범석

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PD-1/ PD-L1

CONTENTS

1. What is immune check point 2. PD-1/PD-L1 data

3. Biomarkers for response

4. Tumors with PD-L1 expression

5. Factors influencing PD-L1 expression

6. Response criteria for immunologic agents 7. Toxicity management

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Cancer progression and immunity

3

Therapies that Might Affect the Cancer-Immunity Cycle

Chen DS et al. Immunity. 2013;39(1):1-10.⁴

History of cancer immunotherapy

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Era of immunotherapy comes!!!

Recent success in cancer immunotherapy, can biomarkers or signatures be identified that can serve as predictors or surrogates of therapeutic efficacy

Cancer vaccine

Adoptive immunotherapy

Antibody therapy

Cytokine therapy

Immune check point blockage

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Cytotoxic chemotherapy

Targeted

therapy immunotherapy

What is immune check point

• The ultimate amplitude and quality of the response, which is initiated through antigen recognition by the T cell receptor (TCR), is

regulated by a balance between co-stimulatory and inhibitory signals (that is, immune

checkpoints)

• Immune checkpoints are crucial for the maintenance of self-

tolerance

Drew M. Pardoll Nat Rev Cancer 2012:12;252 7

Multiple promising immune checkpoints!!!

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Immune check point

CTLA-4

(Cytotoxic T-Lymphocyte Antigen 4) ipilimumab

•PD-1 (CD279): Programmed cell death 1

•PD-L1 (B7-H1, CD274): PD-1 ligand 1 Various PD-1 moAb, PD-L1 moAb

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Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle

Chen DS et al. Immunity. 2013;39(1):1-10.¹⁰

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Anti–PD-1 Antibody in Cancer

Objectives

• Primary objective: assess safety and tolerability of BMS-936558 (nivolumab)

• Secondary/exploratory objectives : assess antitumor activity, pharmacodynamics, and molecular markers

Study Design: phase I

Week 0 Week 2 Week 4 Week 6

8wks treatment cycle

Rapid PD or clin. deterioration

Unacceptable toxicity

CR/PR/SD or PD but clin. stable

OFF study

Follow-up every 8wks X 6 Treat to

confirme CR, Worsening PD, Unacceptable toxicity, or 12 cycles

1 cycle

Topalian SL et al. N Engl J Med. 2012 ;366:2443-54. ¹²

Anti–PD-1 Antibody Phase I: patients

Inclusion Criteria Exclusion Criteria

advanced solid tumor age ≥ 18 years

Life expectancy ≥ 12 weeks ECOG PS 0, 1 or 2

Measurable tumor lesion

adequate hematologic, hepatic, renal function

history of one to five systemic treatment regimen

chronic autoimmune disease

prior therapy with antibodies that modulate T-cell function ( anti-CTLA-4, anti-PD-1, anti- PD-L1)

chronic infection (HIV, HBV, HCV)

conditions requiring immunosuppressive medications

• 296 patients

NSCLC(122), Melanoma(104), RCC(34), CRC(19), CRPC(17) 47% had received 3 ≥ prior systemic therapies

Initiated treatment 2008/10- 2012/02

• Dose cohorts (3 to 6 patients per dose level)

MTD not reached (1-3-10mg/kg) >> expansion cohorts enrolled ad 10mg/kg in all histologies Cohorts added for MEL(0.1-0.3-1-3mg/kg), NSCLC(1-3-10mg/kg) and RCC(1mg/kg)

Topalian SL et al. N Engl J Med. 2012 ;366:2443-54. ¹³

(1mg/kg, 27pts)

• Responses were durable and evident by the end of cycle 2 (16wks) of Tx

• Progression-free survival rate was calculated at 24 wk time point

24 wks

Partial tumor regression

Anti–PD-1 Antibody Phase I: duration of response

• BMS-936558 1, 3, or 10 mg/kg every 2 weeks per 8 weeks (up to 2 years, 12 cycles, n=129)

• ORR: 28% (melanoma), 27% (RCC), 18% (NSCLC)

N Engl J Med 2012;366:2443¹⁴

(1mg/kg, 27pts)

Anti–PD-1 Antibody Phase I: duration of response

• BMS-936558 1, 3, or 10 mg/kg every 2 weeks per 8 weeks (up to 2 years, 12 cycles, n=129)

•Dramatic response

N Engl J Med 2012;366:2443¹⁵

Blockade of immune checkpoints in cancer immunotherapy

• CTLA-4 , PD-1/PD-L1 as a target for cancer immunotherapy

• Optimal combination, cycle, predictive marker, managing adverse event ???

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Pharmacodynamic and Molecular Marker Assessments

18 MEL, 10 NSCLC, 7 CRC, 5 RCC, 2 CRPC

Tumor cell-surface expression of PD-L1 was significantly

correlated with an objective clinical response N Engl J Med 2012;366:2443¹⁷

Anti-PD-1 antibody in melanoma

MK-3475 (Lambrolizumab), a human IgG4 MAB against PD-1

AACR 2014; abstract (#5013)

• Cut-off points > 1%: PD-L1 positive (71.2%, 89/125) vs. PD-L1 negative (28.8%, 36/125)

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PD-L1 expression of tumor

Dong H et al Nat Med 2002:8:793-800¹⁹

PD-L1 expression of tumor

• A variety of tumours, including melanoma, ovarian, renal, hepatocellular and glioblastoma, have been found to express PD-L1 (and occasionally PD-L2).

• PD-L1 expression correlates with poor prognosis

Clin Cancer Res 2007:13(7):2151 Clin Cancer Res 2005;11:2947

Pancreas Esophagus

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PD-1, PD-L1 inducing mechanism

• Oncogenic pathway (PI3K–

AKT or STAT3) induces PD- L1 on tumor cell

• T cell induced PD-L1 upregulation by IFN

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Effect of chemotherapy

PD-L1 (B7-H1) expression in breast cancer cell lines

Ghebeh H et al. Breast Cancer Res. 2010;12(4):R48

•Doxorubicin

downregulates cell surface expression of PD-L1

•Docetaxel cisplatin has no effect on PD-L1 expression

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Tumor Flare Reaction (Pseudoprogression)

• T-cell infiltrate (white arrow) and extensive necrosis (black arrow) with no residual tumor cells.

Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420²³

When tumor flare happen??

Topalian SL et al. N Engl J Med. 2012;366:2443-54 Webet JS et al J Clin Oncol 30:2691-2697

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Case: NSCLC (SqCC) M/55

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Baseline 2weeks 6weeks

irRC: Baseline Assessment

• The sum of the products of diameters (SPD) of all index lesions is documented. (Bi-demensional)

• All index lesions might include 5 lesions per

organ, up to 10 visceral lesions and 5 cutaneous index lesions.

Index lesion1 + Index lesion2 + Index lesion 3

• 기본적으로 WHO와 유사

18 15 30

20

15 11

Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420²⁶

irRC: Subsequent Assessment

• Tumor Burden=SPD

+ SPD

• The SPD of new, measurable lesions:

≥5 x 5 mm, up to 5 new lesions per organ, 5 new cutaneous lesions and 10 new visceral lesions

Index lesion1 + Index lesion2 + Index lesion 3 + Index lesion 4 + ? New

(measurable)

New

(non-measurable)

≥5 x 5 mm <5 x 5 mm

Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420 15

9 20

15

20

10 6

9

4

4

X

√ √ √ √

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irRC: Overall Responses

Tumor Burden (index + new

measurable) Non-index New

Non-measurable Overall Response

↓100 Absent Absent irCR

↓100 Stable Any irPR

↓100 Unequivocal progression Any irPR

↓50≤ Absent/Stable Any irPR

↓50≤ Unequivocal progression Any irPR

↓<50 to<25↑ Absent/Stable Any irSD

↓<50 to<25↑ Unequivocal progression Any irSD

↑25≤ Any Any irPD

Two consecutive observations at least 4 weeks apart

Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420

Also need confirmation

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Definition of PD

WHO vs. RECIST 1.1 vs. irRC

WHO RECIST 1.1 irRC

PD

Target

lesion

≥25%

products of the two largest perpendicular diameters of all index lesions

≥20%

≥25%

measurable)

Non- target lesion

Unequivocal

progression of non- index lesions.

Unequivocal

progression of non- target lesions

-

New

lesion Appearance of new

lesions Appearance of new

lesions

new measurable new unmeasurable Time

point Any single time point Any single time point Two consecutive observations at least 4weeks apart

Miller AB, et al. Cancer 47:207–214, 1981

Eisenhauer EA et al. Eur J Cancer. 2009;45:228-47 Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420

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Immune-related response criteria: Summary

Wolchok JD et al.. Clin Cancer Res 2009;15:7412-7420

WHO criteria irRC

Dimension Bi-dimensional Bi-dimensional

Sum LD x SD LD x SD

Tumor burden None SPD_index + SPDnew (measurable)

New lesions

Measurable (≥ 5x5mm) Nonmeasurable (< 5x5mm)

PD PD

Incorporated into tumor burden Do not define progression

Non-index lesions Contribute to define BOR Contribute to define irCR Complete remission Disappearance of all lesions in two consecutive

observations not less than 4 weeks apart Partial remission

↓50% in SPD_index ↓50% in SPD_index+ SPD_new Two consecutive observations not less than 4 weeks apart

Progressive disease ↑25% in SPD_index at any singe time point

↑25% in SPD_index+ SPD_new in two consecutive observations

at least 4 weeks apart

without rapid clinical deterioration₃₀

irRC - 4 Response patterns

(A) Response in baseline lesions (B) Slow, steady decline in tumor volume

(C) Response after initial rapid increase in tumor volume

(D) Tumor volume reduction after new lesions

New lesions

Kaehler KC et al. Semin Oncol. 2010;37(5):485-98

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irRC - 4 Response patterns

O’Regan KN et al. AJR Am J Roentgenol. 2011;197:W241-6.

# Type A response

: Response in baseline lesions : no problem to clinician

# Type B response

: Slow, steady decline in tumor vol.

: usually no problem to clinician

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irRC - 4 Response patterns

O’Regan KN et al. AJR Am J Roentgenol. 2011;197:W241-6.

# Type C response

: Response after initial rapid increase in tumor volume

: chaos to clinician (PD??, clinical deterioration? 25%↑ from nadir?) when to F/U confirm 4wk? 6wk?

# Type D response

: Tumor volume reduction after new lesions

: usually no problem to clinician

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Bi- vs. Uni-dimensional irRC

Bi-dimenstional Uni-dimensional Measurable

Lesion

≥5X5 ㎟ ≥10 mm in the longest

diameter Sum of the

Measurements

All target lesions and new lesions if any

All target lesions and new lesions if any

Response assessment

PD≥ 25% increase PR≥ 50% decrease

PD≥ 20% increase PR≥ 30% decrease

New lesions The presence of new lesions does not define progression.

The measurements of the new lesions are included in the sum of the measurements

Confirmation Confirmation by 2 consecutive observations not less than 4 weeks apart was required for CR, PR, and PD

Nishino et al. Clin Cancer Res 2013;19:3936-43³⁴

Limitation of irRC

• Uni-dimensional vs bi-dimensional

• Made by ipilimumab melanoma based

• Anti PD/PD-L1 Ab? Other cancer?

• What should we do if the patients becomes rapid clinical deterioration with initial PD??

• PD confirmation after 4 week? When?

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Immune related AEs may be associate with PD-1/PD-L1 blockade

Confirmed immune-related AEs

• Flu like febrile sense

• Autoimmune hepatitis, elevated transaminases

• Colitis/duodenitis

• Rash

• Myositis/myasthenia gravis

• Pneumonitis

• Hypothyroidism

• Pan hypopituitarism (endocrinopathy)

• Pancreatitis

• Type 1 diabetes mellitus

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General Principles for irAE

• Down-modulating PD-1/PD-L1 signaling may permit emergence of auto-reactive T cells and clinical autoimmunity

• Adverse events consistent with autoimmune etiology are termed immune-related adverse events (irAEs)

• Please contact the medical monitor for guidance on management of clinically significant potential immune related adverse events

Diagnosis

• Monitor for evidence of clinically significant systemic or organ-specific irAE*

• Try to rule out neoplastic, infectious,

metabolic, toxin, or other etiologic causes Prior to labeling an AE as an irAE

• Support diagnosis of immune-mediated toxicity by use of serological, immunological, and histological (biopsy) data

Management:

• Suggested workup procedures for suspected irAEs are

included in Protocol

• Initial conservative management

• Consider corticosteroid therapy if clinically necessary

*Examples

• Systemic Lupus erythematosus-like diseases

• Organ-specific: rash, colitis, uveitis, hepatitis, or thyroid disease

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Timing of immune-related adverse events lessons from Ipilimumab

Webet JS et al J Clin Oncol 30:2691-2697

Frequency 시기 임상/병리학적 양상

Skin/mucosa 47-68% 3-6 주 - Diffuse, maculopapular rash, pruritus - CD4⁺ and melan-A-specific CD8⁺ T cells

Diarrhea/colitis 44% 6-7 주

-Diarrhea, abdominal pain, bloody or mucous stool, bowel perforation, peritoneal signs, ileus

-Neutrophilic (46%), lymphocytic (15%), or mixed (38%) infiltrations

Hepatotoxicity 3-9% 6-7 주 - Asymptomatic increase of bilirubin and transaminases - Diffuse T-cell infiltration

Hypophysitis 1-6% 6 주

- Headache, nausea, vertigo, behavior change, visual disturbance

- Enlarged or inhomogenous pituitary gland on MRI

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What is known

• Immune check point is important

• Anti-PD1 Ab/ anti-PD-L1 Ab are effective and have a long duration of response

• Expression of PD-L1 on tumor cell can be predictive marker

• PD-L1 positive tumor has poor prognosis

• Tumor flare phenomenon can happen

• Different response criteria should be used

• Immune related AE (autoimmune)

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What is unknown

• Single vs combo, Optimal combo?

• Optimal candidate disease?

• Predictive factor other than PD-L1 (who is responding, not responding)

• PD-L1/PD-1 related pathway?

• What inducing PD-L1? (PI3K, STAT3, PTEN)

• Inducing strategy of PD-L1 can enhance the efficacy of Anti-PD1 Ab/ anti-PD-L1 Ab?

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Hodi FS, et al. N Engl J Med. 2010;363:711-723.

Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

OS (%)

Mos 0

0 100

48 80

60 40 20

40 32 24 16

8 56

OS (%)

Mos 0

0 100

10 80

60 40 20

8 6

5 3

1 2 4 7 9 1112

HR: 0.37 (95% CI:

0.26-0.55; P < 0.001) Dacarbazine (n = 336)

Vemurafenib (n = 336)

Yrs

Immunotherapy Targeted Therapy

Percent Alive Percent Alive

1 2 3

0 0 1 2 3

Yrs

Combination

Percent Alive

1 2 3

0

Yrs

?

Combining Immunotherapy and Targeted Therapy for Melanoma?

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Biomarker efforts to study tumor immune biology

Circulating cells

Gene expression chip

Target expression Serum protein

(cytokineO) Tumor immunology

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