cco immune checkpoint_inhibitors_in_cancer_care

Immune Checkpoint Inhibitors in Cancer Care: Expert Panel Discussions

This program is supported by an educational grant from Genentech.

Not an official event of the 2015 ASCO Annual Meeting. Not sponsored or endorsed by ASCO or Conquer Cancer Foundation.

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Faculty

Program Director:Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California

Joaquim Bellmunt, MD, PhDDirector, Bladder Cancer CenterDana-Farber Cancer InstituteAssociate Professor, Harvard Medical SchoolBoston, Massachusetts

Charles G. Drake, MD, PhDProfessor, Immunology, Urology, and OncologyCo-Director, Multidisciplinary Prostate Cancer ClinicJohns Hopkins UniversityBaltimore, Maryland

Leora Horn, MD, MSc, FRCPCAssociate Professor of MedicineClinical Director, Thoracic Oncology Research ProgramAssistant Director, Education Development ProgramVanderbilt Ingram Cancer CenterNashville, Tennessee


Faculty Disclosures

Antoni Ribas, MD, PhD, has disclosed that he has served as a consultant for Amgen, GlaxoSmithKline, Merck, and Millennium and has ownership interest in cCAM-Bio, Compugen, Flexus Bio, and Kite Pharma.

Joaquim Bellmunt, MD, PhD, has no real or apparent conflicts of interest to report.


Faculty Disclosures

Charles G. Drake, MD, PhD, has disclosed that he has received royalties from Amplimmune and Bristol-Myers Squibb; consulting fees from Amplimmune, Bristol-Myers Squibb, Compugen, Dendreon, F-star, ImmuneXcite, Lilly, MedImmune, NexImmune, Merck, Potenza, Novartis, Roche/Genentech, sanofi-aventis, and Vesuvius; and funds for research support from Aduro Biotech, Bristol-Myers Squibb, and Janssen.

Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting fees from Genentech and Merck.

Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California

Overview of Immune Checkpoint Blockade


Active immunotherapy

Adoptive cell transferimmunotherapy

IL-2IFNIL-15IL-21

Peptide vaccineDC vaccineGenetic vaccine

OX40

CD137

CD40

PD-1

CTLA-4

T cell cloningTCR or CAR

genetic engineering

General Approaches for Cancer Immunotherapy


CTLA-4: A Brake to the Immune Response to Melanoma

Antigen-MHC : TCR B7 : CD28

B7 : CTLA-4

Modified from Jedd Wolchock, Memorial Sloan Kettering Cancer Center.


Pts at Risk, nIpilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rtio

n A

live

0

0.2

0.4

0.6

0.8

1.0

Mos

0 12 24 36 48 60 72 84 96 108 120

Median OS: 11.4 mos (95% CI: 10.7-12.1)

IpilimumabCensored

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24. Schadendorf D, et al. J Clin Oncol. 2015;[Epub ahead of print].

Ipilimumab: Pooled Survival Analysis From Phase II/III Trials in Advanced Melanoma

3-yr OS rate: 22% (95% CI: 20-24)


CTLA-4 and PD-1/L1 Checkpoint Blockade

Ribas A. N Engl J Med. 2012;366:2517-2519.

Priming phase (lymph node)

Effector phase (peripheral tissue)

T-cell migration

Dendritic cell

T cell

MHC TCR

B7

CD28

CTLA-4

T cell Cancercell

MHCTCR

PD-1

PD-L1

T cellCancer

cellDendritic

cellT cell

B7


100

80

60

40

20

0

CheckMate 066 and KEYNOTE 006: OS

1. Robert C, et al. N Engl J Med. 2015;372:320-330. 2. Robert C, et al. N Engl J Med. 2015;[Epub ahead of print].

OS

(%

)

0 3 6 9 12 15 18Mos

HR for death: 0.42 (99.79% CI: 0.25-0.73; P < .001)

Nivolumab Dacarbazine

Not reached10.8 mos (9.3-12.1)

mOS (95% CI)

Dacarbazine

Nivolumab

Nivolumab vs DTIC in BRAF-negative, previously untreated melanoma[1]

Pembrolizumab vs Ipilimumab in Advanced Melanoma[2]

100

80

60

40

20

0

OS

(%

)

2 4Mos

Ipilimumab

Pembrolizumab q2w

Pembrolizumab q3w

0 8 106 14 1612 18


Clinical Activity of Pembrolizumab

Baseline: April 13, 2012

72-yr-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab

April 9, 2013


Inhibiting PD-1–Mediated Adaptive Immune Resistance

TCRMHC

Melanoma cell

PD-1PD-L1

Interferons

Taube JM, et al. Sci Transl Med. 2012;4:127ra37. Tumeh PC, et al. Nature. 2014;515:568-571.


Inhibiting PD-1–Mediated Adaptive Immune Resistance

Taube JM, et al. Sci Transl Med. 2012;4:127ra37. Tumeh PC, et al. Nature. 2014;515:568-571.

TCRMHC

Melanoma cell

PD-1PD-L1

Interferons

Anti–PD-1Anti–PD-L1


TCRMHC

Melanoma cell

PD-1PD-L1

Interferons

Responder Progression

MHC

Melanoma cell

PD-L1

Tumeh PC, et al. Nature. 2014;515:568-571.

PD-1 and PD-L1 Expression in Response to CD8 Infiltration and Adaptive Immune Resistance


Predicting Responses in a Validation Set From Gustave RoussyPt CD8+ Density, Invasive

Margin Before TreatmentPredicted Probability

of ResponseBlinded

PredictionClinical Response

(RECIST 1.1)

1 58 0.35 Progression Progression




5 2120 0.75 Response Stable

6 5466 0.98 Response Progression

7 2211 0.76 Response Response






13 5951 0.99 Response Complete response



Tumeh PC, et al. Nature. 2014;515:568-571.


Clinical Development of Anti–PD-1 Checkpoint Inhibitors in Solid Tumors

Antibody Molecule Development Stage

Nivolumab Fully human IgG4

Approved (US): advanced melanoma after previous therapy, advanced squamous NSCLC

after CTPhase III multiple tumors (NSCLC, melanoma,

RCC, HNSCC, GBM, gastric)

Pembrolizumab Humanized IgG4

Approved (US): advanced melanoma after previous therapy

Phase III multiple tumors (HNSCC, NSCLC, melanoma, bladder, gastric/GE)

Pidilizumab Humanized IgG1 Phase II multiple tumors (pancreatic, CRC,

RCC, prostate, CNS)

AMP-224Fc-PD-L2 fusion

protein Phase I


Clinical Development of Anti–PD-L1 Checkpoint Inhibitors in Solid Tumors

Antibody Molecule Development Stage

MEDI4736(durvalumab)

Engineered human IgG1

Phase III multiple tumors (NSCLC, HNSCC)

MPDL3280A(atezolizumab)

Engineered human IgG1

Phase III multiple tumors (NSCLC, bladder, RCC, TNBC)

MSB0010718C(avelumab)

Fully human IgG1 Phase III (NSCLC)


Clinical Development of Other Immune Checkpoint Inhibitors in Solid TumorsTarget Antibody Molecule Development Stage

CTLA-4

Ipilimumab Humanized IgG1

Approved: advanced melanomaPhase III multiple tumors

(melanoma, NSCLC, SCLC, CRPC, GBM, RCC)

Tremelimumab Fully human IgG2Phase III multiple tumors

(HNSCC, NSCLC)

IDO

INCB024360Small-molecule

inhibitorPhase II multiple tumors

(ovarian, melanoma)

NLG919Small-molecule

inhibitorPhase I

B7-H3 MGA271Humanized IgG1kappa

Phase I

LAG-3 BMS-986016 --- Phase I


Anti–PD-1/anti–PD-L1

Generate T cells:

+ Anti–CTLA-4+ Immune-activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ Targeted therapies

Bring T cells into tumors:

VaccinesTCR-engineered ACTCAR-engineered ACT

Management of Cancer in the Post Anti–PD-1/L1 Era


Summary

CTLA-4 blockade can induce long-lasting responses in a subset of patients with metastatic melanoma

PD-1 blockade induces responses by releasing a checkpoint (brake) that limits immune responses to melanoma

When CD8+ T cells blocked by PD-1 are not present in tumors:

– Combine with other immunotherapies, like CTLA-4 blockade

– Combine with targeted therapies

– Create tumor-specific T cells for TCR or CAR ACT

Charles G. Drake, MD, PhDProfessor, Immunology, Urology, and OncologyCo-Director, Multidisciplinary Prostate Cancer ClinicJohns Hopkins UniversityBaltimore, Maryland

What Are the Expected Benefits of Immune Checkpoint Inhibitors


The Immunoediting Hypothesis: Shaping Tumor Development

Dunn GP, et al. Nat Immunol. 2002;3:991-998. Schreiber R, et al. Science. 2011;331:1565-1570.Mittal D, et al. Curr Opin Immunol. 2014;27:16-25.

Elimination Equilibrium Escape

Genetic instability/tumor heterogeneity

Immune selection

CTL

NK

CTL

T reg

T cyto

NKTT reg T reg

CTLNK T reg

CTL


Pembrolizumab Antitumor Activity

1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014. LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al. SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290.

100806040200

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) Melanoma[1] (N = 411)KEYNOTE-001

100806040200

-20-40-60-80

-100

NSCLC[2] (N = 262)KEYNOTE-001

100806040200

-20-40-60-80

-100

HNSCC[3] (N = 61)KEYNOTE-012

100806040200

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Urothelial Cancer[4] (N = 33)

KEYNOTE-012

100806040200

-20-40-60-80

-100

Gastric Cancer[5] (N = 39)

KEYNOTE-012100806040200

-20-40-60-80

-100

TNBC[6] (N = 32)KEYNOTE-012 100

806040200

-20-40-60-80

-100

cHL[7] (N = 29)KEYNOTE-013


Pembrolizumab Antitumor Activity

1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014. LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al. SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290.

100806040200

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) Melanoma[1] (N = 411)KEYNOTE-001

100806040200

-20-40-60-80

-100

NSCLC[2] (N = 262)KEYNOTE-001

100806040200

-20-40-60-80

-100

HNSCC[3] (N = 61)KEYNOTE-012

100806040200

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(%

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Urothelial Cancer[4] (N = 33)

KEYNOTE-012

100806040200

-20-40-60-80

-100

Gastric Cancer[5] (N = 39)

KEYNOTE-012100806040200

-20-40-60-80

-100

TNBC[6] (N = 32)KEYNOTE-012 100

806040200

-20-40-60-80

-100

cHL[7] (N = 29)KEYNOTE-013

Pembrolizumab is FDA approved in unresectable or metastatic melanoma with disease progression following ipilimumab

(and BRAF inhibitor if BRAF V600+) and received Breakthrough Therapy designation for

EGFR/ALK-negative NSCLC and disease progression following platinum-based chemotherapy


Nivolumab Antitumor ActivityMelanoma (n = 272)[1]

1. Weber JS, et al. Lancet Oncol. 2015;16:375-384. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265 3. McDermott DF, et al. J Clin Oncol. 2015;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 2015;372:311-319.

Advanced NSCLC(N = 117)[2]

Advanced RCC (N = 34)[3]

Hodgkin’s Lymphoma(N = 23)[4]

125100

7550250

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Pts

AliveDeadConfirmed responders

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1 mg/kg nivolumab10 mg/kg nivolumab

Pts

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Pts

StableDisease

Partial Response

Complete Response


Nivolumab Antitumor ActivityMelanoma (n = 272)[1]

1. Weber JS, et al. Lancet Oncol. 2015;16:375-384. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265 3. McDermott DF, et al. J Clin Oncol. 2015;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 2015;372:311-319.

Advanced NSCLC(N = 117)[2]

Advanced RCC (N = 34)[3]

Hodgkin’s Lymphoma(N = 23)[4]

125100

7550250

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AliveDeadConfirmed responders

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1 mg/kg nivolumab10 mg/kg nivolumab

Pts

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Pts

StableDisease

Partial Response

Complete Response

Nivolumab is FDA approved in unresectable or metastatic melanoma with disease progression following ipilimumab (and

BRAF inhibitor if BRAF V600+) and in metastatic squamous NSCLC on or after progression with platinum-based chemotherapy and

received Breakthrough Therapy Designation for Hodgkin’s Lymphoma


Median time to first response was 42 days (range: 38-85)

Median duration of response: not reached

– IHC (IC) 2 or 3: 0.1+ to 30.3+ wks; IHC (IC) 0 or 1: 0.1+ to 6.0+ wks

Median follow-up: 4.2 mos (1.1+ to 8.5) for IHC 2/3 tumors and 2.7 mos (0.7+ to 3.6) for IHC 0/1 tumors

MPDL3280A: Tumor Burden Over Time in UBC

Powles T, et al. Nature. 2014;515:558-562.


Median time to first response was 42 days (range: 38-85)

Median duration of response: not reached

– IHC (IC) 2 or 3: 0.1+ to 30.3+ wks; IHC (IC) 0 or 1: 0.1+ to 6.0+ wks

Median follow-up: 4.2 mos (1.1+ to 8.5) for IHC 2/3 tumors and 2.7 mos (0.7+ to 3.6) for IHC 0/1 tumors

MPDL3280A: Tumor Burden Over Time in UBC

Powles T, et al. Nature. 2014;515:558-562.

MPDL3280A has received Breakthrough Therapy designation for previously treated metastatic PD-L1–positive urothelial bladder

cancer and PD-L1–positive NSCLC with progression during or after platinum-based CT (and targeted therapy if EGFR or ALK positive)


MEDI4736: Phase I Dose Expansion Preliminary Activity in Multiple Tumor Types Overall grade 3/4 adverse event rate of 6%

Segal NH, et al. ASCO 2014. Abstract 3002.

NSCLCnonsquamous

Melanoma, cutaneous

Gastroesophageal

NSCLCsquamous

Melanoma, uveal

TNBC

Pancreatic adeno

HNSCC

CRCRCCHCC

0 6 12 18 24 30 36 42 48 54 60

Wks Since Treatment Initiation

On treatment


Objective Response Rate to PD-1 Blockade ≈ 25% In KIDNEY Cancer

Drake CG, et al ASCO 2013. Abstract 4514.

Generally tolerable: fatigue, rash, pruritus, diarrhea

– 3 deaths: pneumonitis (non-RCC)

Durable Responses

Even Off Drug

All stopped therapy

Preliminary efficacy in heavily pre-treated patients

– 29% objective responses

– Median PFS 7.3 months


Drake CG, et al ASCO 2013. Abstract 4514.

Case 3: Long-Term Follow-Up of Patients With Metastatic RCC on PD-1 Agent 12/30/2009: Week 32 Imaging = 80% reduction in SLD

On treatment x 2 years total

LT stable PR


Summary

4 patterns of response

– Progression

– Stable disease

– Response

– Psuedoprogression

All discernible in retrospect

NOT easily discernible during treatment


PD-1/PD-L1 Therapy in Solid Tumors: Single-Agent TrialsTumor Type Phase III

Melanoma

Nivo vs chemo (NCT01721772, NCT01721746) Adjuvant nivo vs ipi (NCT02388906) Pembro (2 doses) vs ipi (NCT01866319) Adjuvant pembro vs placebo (high risk) (NCT02362594)

NSCLC

MEDI4736 following adj chemo/CRT (NCT02125461, NCT02273375) MPDL3280A vs chemo (NCT02409355, NCT02409342,

NCT02008227) Nivo vs docetaxel (squamous or nonsquamous) (NCT01642004,

NCT01673867) Nivo vs investigator’s choice chemo (NCT02041533) Nivo x 1 yr vs continuous (2nd line/beyond) (NCT02066636) Pembro vs chemo (PD-L1+) (NCT02142738, NCT02220894) Pembro (2 doses) vs docetaxel (NCT01905657)

Pts with known or suspected autoimmune disease are generally excluded from these trials Bold font = recruiting

Red font = not yet recruitingClinicalTrials.gov.


PD-1/PD-L1 Therapy in Solid Tumors: Single-Agent TrialsTumor Type Phase III

RCC Nivo vs everolimus (TKI progression) (NCT01668784)

UBC

MPDL3280A vs chemo (NCT02302807) Pembro vs chemo (NCT02256436) Adjuvant MPDL3280A vs observation for MIBC

(NCT02450331)

Gastric/GEJ Nivo vs placebo (unresectable advanced/recurrent)

(NCT02267343) Pembro vs paclitaxel (NCT02370498)

HNSCC Nivo vs investigator’s choice (NCT02105636) Pembro vs standard therapy (NCT02252042)

Pts with known or suspected autoimmune disease are generally excluded from these trials

ClinicalTrials.gov.

Bold font = recruitingRed font = not yet recruiting


Key Immune Checkpoint Inhibitor Studies Still to Come at ASCO 2015 (Monotherapy)

Abstract Time Disease Setting Study Design

8009Sunday4:30 pm

NSCLC, SQ (salvage)

Nivo vs doc

8010Sunday4:30 pm

NSCLC(salvage)

MPDL3280A vs doc

4500Monday9:45 am

RCC Nivo

4501Monday9:45 am

UBC MPDL3280A

4502Monday9:45 am

UBC Pembro

LBA6008Monday1:15 pm

HNSCC Pembro

Joaquim Bellmunt, MD, PhDDirector, Bladder Cancer CenterDana-Farber Cancer InstituteAssociate Professor, Harvard Medical SchoolBoston, Massachusetts

Recognition and Management of Immunotherapy Related Toxicities


Adverse Events Associated With Checkpoint Inhibitors Are Immune Related

irAE (All Grades), % Ipilimumab + Dacarbazine[1]

(n = 247)Ipilimumab + Placebo[2]

(n = 251)

Total 77.7 61.1 Grade 3/4 41.7 14.5

Dermatologic

Pruritus 26.7 24.4 Rash 22.3 19.1

Gastrointestinal

Diarrhea 32.8 27.5 Colitis 4.5 7.6

Hepatic

Increase in ALT 29.1 1.5 Increase in AST 26.7 0.8 Hepatitis 1.6 0.8

1. Robert C, et al. N Engl J Med. 2011;362:2517-2526. 2. Hodi FS, et al. N Engl J Med. 2010;363:711-723.


Summary of CTLA-4 Blockade Immune-Mediated Toxicities Toxicity related to ipilimumab appears to be dose related

Toxicity-related death occurred in < 1% of cases

Common (> 20%)

Rash, pruritus

Fevers, chills, lethargy

Diarrhea/colitis

Occasional (3% to 20%)

Hepatitis/liver enzyme abnormalities

Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency

Rare (< 2%)

Episcleritis/uveitis

Pancreatitis

Nephritis

Neuropathies, Guillain-Barré, myasthenia gravis

Lymphadenopathy (sarcoid)

Thrombocytopenia

Toxic epidermal necrolysis, Stevens-Johnson syndrome

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].


Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities Toxicity less common than with anti–CTLA-4 but can be fatal

Occasional (5% to 20%)

Fatigue, headache, arthralgia, fevers, chills, lethargy

Rash: maculopapular, pruritus,vitiligo

– Topical treatments

Diarrhea/colitis

– Initiate steroids early, taper slowly

Hepatitis, liver/pancreatic enzyme abnormalities

Infusion reactions

Endocrinopathies: thyroid, adrenal, hypophysitis

Rare (< 5%)

Pneumonitis

– Grade 3/4 toxicities uncommon

– Low grade reversible with steroids and discontinuation

Anemia



Ipilimumab Plus Nivolumab in Untreated Adv Melanoma: Adverse Events

Patients Reporting, % (Select AEs/Organ Category)

NIVO + IPI (n = 94) IPI (n =46)

Any Grade Grade 3–4 Any Grade Grade 3–4

Gastrointestinal select AEs 51 21 37 11Diarrhea 45 11 37 11Colitis 23 17 13 7

Hepatic select AEs 28 15 4 0ALT increased 22 11 4 0AST increased 21 7 4 0

Pulmonary select AEs 12 2 4 2Pneumonitis 11 2 4 2

Renal select AEs 3 1 2 0Creatine increased 2 1 0 0

Endocrine select AEs 34 5 17 4Thyroid disorder 23 1 15 0Hypothyroidism 16 0 15 0Hypophysitis 12 2 7 4

Skin select AEs 71 10 59 0Rash 41 5 26 0Pruritus 35 1 28 0Rash maculo-popular 16 3 17 0

Postow MA, et al. N Engl J Med. 2015;372:2006-2017.


Combination Therapy With Ipilimumab and Nivolumab: Toxicity Summary

The safety profile of ipilimumab and nivolumab is characterized by immune related adverse events

There is the potential for increased frequency of drug related adverse events with nivolumab combined with ipilimumab over either agent as monotherapy, in particular for lipase / amylase, AST / ALT

Skin toxicity, uveitis, neurological, renal

No new toxicities have been identified with the combination treatment

Toxicities with the combination have been manageable and reversible following intervention with systemic steroids in alignment with established AE management algorithms


0


Kinetics of Appearance of irAEs With Checkpoint Blockade

Data from pts receiving anti–PD-1 antibodies q2w for ≥ 3 yrs show most irAEs occur by Wk 24 (6 mos)

Toxicities with PD-1/PD-L1 agents may take longer to resolve than with ipilimumab, so long-term surveillance is recommended

Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis

Wks142 4 6 8 10 12

To

xici

ty G

rad

e


Immunotherapy-Related Dermatitis

Ipilimumab: skin toxicity most common irAE

– Rare severe rashes require hospitalization

– Sweet syndrome rarely described

PD-1 inhibitors: oral mucositis and dry mouth more frequent

– Oral corticosteroid rinses and topical lidocaine can be beneficial

Nivolumab: rash (36%) and pruritus (28%) most common skin toxicities; grade 3/4 rare

– Typically maculopapular and managed as outlined for ipilimumab

Howell M, et al. Lung Cancer. 2015;88:117-123.


Skin Toxicity: Learnings!!!

If patient reports rash → visual exam!

High-dose IV steroids for grade 3/4 rash

Long taper upon improvement

Severe reactions are rarely seen. Recently, a case of toxic epidermal necrolysis (TENS) occurred in a nivolumab/ ipilimumab combination study

Educate pts regarding importance of immuno-suppression

Compliance with oral steroids!


Colitis: Immune Checkpoint Inhibitor Toxicity Ulceration in descending colon

Focal active colitis

Alterations in crypt epithelium

Maker AV, et al. Ann Surg Oncol. 2005;12:1005-1016.


Prompt Treatment of Colitis

A retrospective analysis of 836 trial pts showed that early initiation of steroid treatment for colitis led to faster resolution of symptoms than delayed steroid treatment[1]

Several case studies support use of infliximab to further blunt immune response in steroid-refractory colitis[2,3]

Bloody diarrhea uncommon but may indicate more severe colitis[4]

At colonoscopy, colitis typically affects the distal colon with sparing of rectum[4]

1. O’Day S, et al. ASCO 2011. Abstract 8554. 2. Pagès C, et al. Melanoma Res 2013;23:227-230. 3. Merrill SP, et al. Ann Pharmacother. 2014;48:806-810. 4. Howell M, et al. Lung Cancer. 2015;88:117-123.


Pulmonary Toxicities related to Immunotherapy

Several pulmonary inflammatory complications reported with ipilimumab. (sarcoidosis and organizing inflammatory pneumonia)

Pneumonitis rarely in patients treated with PD-1 blocking agents, but with occasional fatal consequence in early trials. (< 3%)

Symptoms of an upper respiratory infection, new cough, or SOB, pneumonitis should be considered and imaging is warranted

In moderate to severe symptoms and/or radiographic findings, bronchoscopy should be considered to exclude infectious processes prior to starting immunosuppression.

In severe cases, treatment with 2 mg/kg of intravenous methylprednisone and consideration of additional immunosuppression including infliximab, mycophenolate mofetil, cyclophosphamide if necessary


Endocrine Toxicities

Following ipilimumab therapy, incidence of hypophysitis 8% and hypothyroidism/thyroiditis 6%; primary adrenal dysfunction rare

Combination of ipilimumab and nivolumab associated with 22% incidence of thyroiditis or hypothyroidism and 9% incidence of hypophysitis

Symptomatic relief for hypophysitis achieved with hormone replacement, although endogenous hormone secretion rarely recovered

– Symptoms can include: headache, fatigue, weakness, memory loss, impotence, personality changes, and visual-field impairment

– Events can occur within wks of beginning treatment but also have been noted to occur many mos (while still on treatment)

Ryder M, et al. Endocr Relat Cancer. 2014;21:371-381.


Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Symptom Management: Hypophysitis

Prompt therapy ameliorates symptoms and permits continued therapy

25% of pts with hypophysitis have normal pituitary MRI

Monitor ACTH and cortisol levels in pts receiving checkpoint inhibitors

Physiologic steroid replacement may be sufficient

– Higher-dose in symptomatic pts (headaches and vision changes)


Less Common Immune-Related Adverse Events Hematologic (hemolytic anemia, thrombocytopenia)

Cardiovascular (myocarditis, pericarditis, vasculitis)

Ocular (blepharitis, conjunctivitis, iritis, scleritis, uveitis)

Renal (nephritis)

Several case reports of rare autoimmune-based toxicities in pts treated with ipilimumab

– Lupus nephritis

– Inflammatory enteric neuropathy

– Tolsosa-Hunt syndrome

Ipilimumab adverse reaction management guide.

– Myocardial fibrosis

– Acquired hemophilia A

– Autoimmune polymyositis


Ipilimumab-Associated Uveitis

Uveitis and episcleritis have been reported in < 1% of pts treated with ipilimumab or anti–PD-1 antibodies

Symptoms typically occur ~ 2 mos following treatment: photophobia, pain, dryness of the eyes, blurred vision

Treatment: topical steroids for grade 1/2 toxicity

For grade ≥ 3 toxicity systemic corticosteroids and discontinuation of immunotherapy is required

Attia P, et al. J Clin Oncol. 2005;23:6043-6053. Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.


irAE Management With Immunomodulatory Medication

Nivolumab + Ipilimumab (n = 94) Ipilimumab (n = 46)

Tx With IMM, %

(n/N)

Resolution After IMM, %

Resolution, Wks

Tx With IMM, %

(n/N)

Resolution After IMM,

%

Resolution, Wks

Skin (any gr)Skin (gr 3/4)

61 (41/67)100 (9/9)

6989

18.66.1

50 (13/26)0

850

8.6NE

GI (any gr)GI (gr 3/4)

65 (31/48)85 (17/20)

9388

4.74.3

65 (11/17)100 (5/5)

7880

5.03.6

Endo (any gr)Endo (gr 3/4)

44 (14/32)80 (4/5)

1425

NENE

38 (3/8)100 (2/2)

3350

NENE

Hep (any gr)Hep (gr 3/4)

50 (13/26)86 (12/14)

8583

14.18.3

00

00

NENE

Pul (any gr)Pul (gr 3/4)

73 (8/11)100 (3/3)

7567

6.19.0

100 (2/2)100 (1/1)

100100

3.23.6

Renal (any gr)Renal (gr 3/4)

67 (2/3)100 (1/1)

100100

0.40.6

00

00

NENE



Toxicity Guidelines

TFTs, CBCs, LFTs and metabolic panels should be obtained at each treatment and q6-12 wks for 6 mos posttreatment in all pts receiving checkpoint protein antibodies

ACTH, cortisol should also be checked in pts with fatigue and nonspecific symptoms, plus testosterone in men

Frequency of follow-up testing should be adjusted to individual response and AEs that occur

Corticosteroids can reverse nearly all toxicities associated with these agents, but should be reserved for grade 3/4, or prolonged grade 2, irAEs

Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].


Management of Drug-Related AEs

The majority of both nivolumab- and ipilimumab-related AEs to date have been reversible and manageable by delaying study drug ± administration of corticosteroids; other immunosuppressants may also be needed

The following categories of AEs, requiring greater vigilance and early intervention:

– Pulmonary

– Hepatic

– Renal

– GI

– Endocrine

– Neurological

– Skin


Summary

Toxicity is mostly low grade and can be managed with supportive treatment

A concerted effort to educate the whole multidisciplinary team needs to take place and development of accessible algorithms to ensure minimized risk with toxicity

The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient–provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs

The majority of both nivolumab and ipilimumab related AEs to date have been reversible and manageable by delaying study drug ± administration of corticosteroids; other immunosuppressants may also be needed

The following categories of AEs, requiring greater vigilance and early intervention: pulmonary, hepatic, renal, GI, endocrine, neurological, skin

Leora Horn, MD, MSc, FRCPCAssociate Professor of MedicineClinical Director, Thoracic Oncology Research ProgramAssistant Director, Education Development ProgramVanderbilt Ingram Cancer CenterNashville, Tennessee

Immune Checkpoint Inhibitors: Who Will Benefit?


Things to Consider

What is the best marker?

– What is the best assay?

What stage of disease?

– What line of therapy?

In what sequence?

What type of pt?

Image courtesy of Cliparts.co.


What Is a Marker?

Predictive marker

– Provide information on the likely benefit from therapy

Prognostic marker

– Provide information on outcome regardless of therapy


PD-L1 Testing Is Controversial

Different assays have not been compared

Each assay has a different cut point that defines PD-L1 positive

What is better – archival or fresh tissue?

Where do you biopsy – the primary tumor or a metastatic site?

Is tissue from a core biopsy the only way to evaluate for PD-L1 expression?


PD-L1 as a Prognostic Marker

PD-L1 expression has been identified as a negative prognostic marker

– More aggressive phenotype in melanoma[1]

– Increased risk of metastasis and death in RCC and lung cancer[2,3]

– Increased risk of metastatic disease in gastric cancer [4]

1. Massi D, et al. Ann Oncol. 2014;25:2433-2442. 2. Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:17174-17179. 3. Mu CY, et al. Med Oncol. 2011;28:682-688. 4. Zheng Z, et al. Chin J Cancer Res. 2014;26:104-111.


Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.

PD-L1 as a Predictive Marker: Response Based on PD-L1 Expression

P = .006 for association by Fisher’s exact test

9 (21)33 (79)

42

Total

Objective responseNo objective responseAll

9 (36)16 (64)

25

017 (100)

17

PD-L1Positive

PD-L1Negative

Response Status, n (%)

PD-L1 Status

1.0

0.8

0.6

0.4

0.2

0Positive(n = 25)

Negative(n = 17)

9/25

16/25

17/17

0/17

Objective responseNo objective response

n/N =

Pro

po

rtio

n o

f P

ts

Association Between Pretreatment Tumor PD-L1 Expression and Clinical Response


PD-L1 Prevalence and Expression

Herbst RS, et al. Nature. 2014;515:563-567.

PD-L1 Prevalence Determined With Anti–PD-L1 IHC Assay

Indication NPD-L1 Positive

(IC), %PD-L1 Positive

(TC), %

NSCLC 184 26 24

RCC 88 25 10

Melanoma 58 36 5

HNSCC 101 28 19

Gastric cancer 141 18 5

Colorectal cancer 77 35 1

Pancreatic cancer 83 12 4



IHC 3

IHC 2

IHC 1

IHC 0

All

IHC 3

IHC 2

IHC 1

IHC 0

All

0 20 40 60 80 100

0 20 40 60 80 100

020406080100

020406080100

Pts (%)

Pts (%)

IHC 3, n = 8; IHC 2, n = 1; IHC 1, n = 3; IHC 0, n = 34; Unknown, n = 7; All, n = 53


All

Tu

mo

r T

ype

P

ts –

IH

C (

TC

)P

ts W

ith

NS

CL

C –

IH

C (

TC

)

All T

um

or T

ype

P

ts – IHC

(TC

)P

ts With

NS

CL

C –

IHC

(TC

)

IHC 3

IHC 2

IHC 1

IHC 0

All

IHC 3

IHC 2

IHC 1

IHC 0

All

CR/PR SD PD

Association of MPDL3280A Response With PD-L1 IHC (Tumor Cell) Status


Association of MPDL3280A Response With PD-L1 IHC (Immune Cell) Status


IHC 3

IHC 2

IHC 1

IHC 0

All

IHC 3

IHC 2

IHC 1

IHC 0

All

0 20 40 60 80 100

0 20 40 60 80 100

020406080100

020406080100

Pts (%)

Pts (%)



All

Tu

mo

r T

ype

P

ts –

IH

C (

IC)

Pts

Wit

h N

SC

LC

–

IHC

(IC

)

All T

um

or T

ype

P

ts – IHC

(IC)

Pts W

ith N

SC

LC

– IH

C (IC

)

CR/PR SD PD

IHC 3

IHC 2

IHC 1

IHC 0

All

IHC 3

IHC 2

IHC 1

IHC 0

All


KEYNOTE-001: Pembrolizumab Efficacy By PD-L1 StatusCohort N ORR*, %

All patients 495 19.4

Percent PD-L1 tumor cell staining≥ 50%1% - 49%< 1%

7310328

45.216.510.7

Garon EB, et al. N Engl J Med. 2015; 372:2018-2028.

*per RECIST

Proportion score (PS): membranous PD-L1 expression of tumor cells

0 4 8 28242016120

20

40

60

80

100

Mos

11916176

9211955

565833

000

300

440

560

22158

PS ≥50%PS 1-49%PS <1%

No. at RiskO

vera

ll S

urv

ival

(%

)

PS 1-49%

PS ≥50%

PS <1%


Intratumoral PD-L1 as a Predictive Marker

Mahoney KM, et al. Oncology. 2014;28:39-48.

Setting TreatmentObjective Response Rate, %

Assay (mAb)Unselected PD-L1+ PD-L1–

Solid tumors (n = 42) Nivo 21 36 0 Tumor (5H1)

Melanoma (n = 44) Nivo 32 67 19 Tumor (28-8)

Tumor (28-8)Melanoma (n = 34) Nivo 29 44 17

Melanoma (n = 113) Pembro 40 49 13 Tumor (22C3)

NSCLC (n = 129) Pembro 19 37 11 Tumor (22C3)

HNSCC (n = 55) Pembro 18 46 11 Tumor (22C3)

Melanoma (n = 411) Pembro 40 49 13 Tumor (22C3)

Solid tumors (n = 94) MPDL 21 36 13 TIL

Melanoma (n = 30) MPDL 29 27 20 TIL

NSCLC (n = 53) MPDL 23 46 15 TIL

Bladder (n = 65) MPDL 26 43 11 TIL

Solid tumors (n = 179) MEDI 11 22 4 NR (SP263)


Mutational Burden in Human Cancers

National Cancer Informatics Program.


Frequency of Driver Mutations in NSCLC, %

AKT1 1

ALK 3-7

BRAF 1-3

EGFR 10-35

HER2 2-4

KRAS 15-25

MEK1 1

NRAS 1

PIK3CA 1-3

RET 1

ROS1 1

BRAFHER2

MEK1

AKT1

ALK

PIK3CA

NRAS

ROS1

RET

www.mycancergenome.org.

Molecular Subsets of Lung Cancer Defined by Driver Mutations

UnknownKRAS

EGFR


*ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, 2012.

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*)P

ts W

ith

PR

(%

)

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 MO18.01.

5040302010

0

5040302010

0

5040302010

0

Former/Current Smokers Never Smokers

26%

10%

23%17%

30%

10%51%

30%

19%

76%13%

11%

81%

19%

KRAS WT

EGFR WT


Immune Therapy in NRAS Melanoma

Johnson DB, et al. Cancer Immunol Res. 2015;3:288-295.

*Pearson χ2 test P value for NRAS-mutant vs non-NRAS-mutant pts.


Immune Therapy in NRAS Melanoma

Response, n (%) NRAS Mutant BRAF Mutant Wild Type

Anti–PD-1/PD-L1 (n = 11) (n = 14) (n = 23)

Objective response 7 (64) 3 (21) 8 (35)

Clinical benefit 8 (73) 3 (21) 10 (43)

Ipilimumab (n = 43) (n = 31) (n = 95)


Clinical benefit 18 (42) 5 (16) 19 (20)

IL-2 (n = 15) (n = 29) (n = 19)


Clinical benefit 5 (33) 11 (34) 7 (37)Owing to many pts receiving multiple lines of therapy, no formal analysis to compare ORR between groups was performed



In What Sequence?

Severe cutaneous and neurologic toxicity in melanoma pts during vemurafenib administration following anti–PD-1 therapy



What Line of Therapy?

Tumor Type Line of Therapy

Melanoma Phase I: heavily treated; second line; first line (BRAF mutation negative); adjuvant

Renal cell Phase I: heavily treated; second line

Lung cancer Phase I: heavily treated; second line, PD-L1 positive or unknown; first line, PD-L1 positive (EGFR and ALK negative); adjuvant

Bladder Phase I: second line

Breast cancer Phase I: second line or beyond

Pancreatic cancer Phase I: first line; adjuvant, neoadjuvant

HCC Phase I

Ovarian cancer Phase I: platinum refractory

Gastric cancer Phase I


What Line of Therapy?

Tumor Type Line of Therapy

Melanoma Phase I: heavily treated; second line; first line (BRAF mutation negative); adjuvant

Renal cell Phase I: heavily treated; second line

Lung cancer Phase I: heavily treated; second line, PD-L1 positive or unknown; first line, PD-L1 positive (EGFR and ALK negative); adjuvant

Bladder Phase I: second line

Breast cancer Phase I: second line or beyond

Pancreatic cancer Phase I: first line; adjuvant, neoadjuvant

HCC Phase I

Ovarian cancer Phase I: platinum refractory

Gastric cancer Phase I

All Lines of Therapy


Which Pts Do We Avoid?

Exclusion criteria in previous studies:

– Performance status ≥ 2

– Autoimmune disease

– Recent data suggest ipilimumab can be given safely

– Hepatitis, HIV

– Recent data suggest ipilimumab can be given safely

– Brain metastases

– PD-L1 negative

– Interstitial lung disease

– On “higher dose” steroids

Extreme caution should be taken in treating pts with recent or ongoing autoimmune conditions

– Particularly inflammatory bowel disease


Summary

PD-L1 is a negative prognostic marker in multiple tumor types

PD-L1 expression is associated with an increased response rate to therapy with PD-1/PD-L1 inhibitors

Response to immune checkpoint inhibitors has not been associated with current known mutations

Increased mutation burden is associated with response to immune checkpoint inhibitors

PD-1/PD-L1 inhibitors are active and being explored in all lines of therapy

The safety of PD-1/PD-L1 inhibitors in select clinical cohorts needs to be explored

Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California

Future Directions: Combinations and Resistance


Management of Cancer in the Post Anti–PD-1/PD-L1 Era

Anti–PD-1/anti–PD-L1

Generate T cells:

+ Anti–CTLA-4+ Immune-activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ Targeted therapies

Bring T cells into tumors:

VaccinesTCR-engineered ACTCAR-engineered ACT


Ipilimumab ± Nivolumab in Previously Untreated Metastatic Melanoma


100908070605040302010

0

PF

S (

% o

f P

ts)

0 3 6 9 12 15 18Mos

Nivolumab plus ipilimumab (n = 72)

Ipilimumab (n = 37)

Death or DiseaseProgression, n/N

30/7225/37

Median PFS, Mos (95% CI)

NR4.4 (2.8-5.7)

Nivolumab plus ipilimumabIpilimumab

HR: 0.40 (95% CI: 0.23-0.68; P < .001)


Immunotherapy Effects of BRAF Inhibitors

↑ CD8+ TILs[1]

↑ Melanoma antigen expression[1]

Antitumor activity of combined BRAFi + MEKi plus anti–PD-1[2]

↑ MHC and melanoma antigen expression[2]

1. Frederick DT, et al. Clin Cancer Res. 2013;19:1225-1231. 2. Hu-Lieskovan S, et al. Sci Transl Med. 2015;7:279ra41.


Immune Checkpoint Therapy: What Is Next?

Anti–PD-1/PD-L1

Your favorite

treatmentThe future of cancer therapy


Checkpoint Inhibitor Therapy: Select Phase III Combination TrialsTumor Type Phase III (Unless Otherwise Indicated)

Melanoma Nivo vs ipi vs ipi/nivo (NCT01844505) Nivo/ipi + GM-CSF vs nivo/Ipi (NCT02339571)

RCC Nivo/ipi vs sunitinib (NCT02231749) MPDL + bev vs sunitinib (NCT02420821)

NSCLC Ipi + pac/carbo vs pac/carbo (NCT02279732) MPDL + CT (± bev) vs CT (+ bev) (NCT02367794,

NCT02367781, NCT02366143)

HNSCC MEDI4736 + treme vs SOC (NCT02369874)

GBM Nivo/Ipi vs nivo vs bev (NCT02017717)

TNBC MPDL/nab-pac vs nab-pac (NCT02425891)

Pts with known or suspected autoimmune disease are generally excluded from these trials

ClinicalTrials.gov.


Conclusions

PD-1 blockade induces responses by releasing a checkpoint (brake) that limits immune responses to melanoma and other tumors

When CD8+ T cells blocked by PD-1 are not present in tumors

– Combine with other immunotherapies, like ipilimumab

– Combine with targeted therapies

– Create tumor-specific T cells for TCR or CAR ACT


Select Checkpoint Inhibitor Combination Studies Still to Come at ASCO 2015

Abstract Time Disease Setting Study Design

LBA1Sunday1:00 PM

Melanoma(first line)

Nivo ± ipi vs ipi

3003Monday1:15 PM

MelanomaMEDI4736 ± dabrafenib ±

trametinib

8011Sunday4:30 PM

NSCLC(second line)

Pembro + ipi

8030Monday8:00 AM

NSCLC(first line)

MPDL3280A + doublet CT

8031Monday8:00 AM

NSCLC(first line)

Pembro + doublet CT

Go Online for More CCO Coverage of Cancer Immunotherapy!

Downloadable slidesets of key studies from ASCO 2015 selected by expert faculty

Expert Analysis of key ASCO 2015 abstracts

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

cco immune checkpoint_inhibitors_in_cancer_care

Documents

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