Immuno-oncology: Where are we now? Wolfram Samlowski, MD Comprehensive Cancer Centers of Nevada Clinical Professor, University of Nevada School of Medicine US Oncology Research (Developmental Therapeutics and GU)

Disclosures • I have served on advisory boards or speakers bureaus for a number of companies: – – – – –

BMS Pfizer Merck Novartis Castle Biosciences

• I plan to discuss off-label uses for new agents ( I will clearly identify these off-label uses)

Objectives Describe the activity of checkpoint inhibitor antibodies in melanoma, lung cancer and RCC. Recognize potential immune-mediated toxicities induced by CTLA, PD-1 and PD-L1 mAb. Identify other potential tumor types that may respond to checkpoint inhibitor mAb treatment. (Off label)

“War on Cancer” • National Cancer Act 1971 (Richard Nixon) – Increased funding for NIH, basic research – Strengthened cooperative cancer research groups • Payoff in 2011 (finally!) – Improved understanding of carcinogenesis • Targeted therapy

– Evasion of immune recognition by cancers • Checkpoint inhibitor mAb

Melanoma as a paradigm

Change in approach to melanoma “The era of targeted therapy is over. The next decade is the decade of immunotherapy” Mario Sznol, MD Yale University

Chemotherapy of melanoma • Metanalysis • 42 phase II trials performed in US cooperative oncology groups from 1975-2005, involving 2100 patients. • There was no apparent improvement in survival over this 30 year time interval • No apparent benefit of multi-agent chemotherapy over single agents • Median 6 month PFS of all trials was 15% • Median 1 year overall survival of all trials was 25% • Performance status, visceral metastases and gender were strongest predictors of PFS and survival Korn E. et al. J Clin Oncol 26:527-534. 2008

Current T cell activation paradigm T-cell activation Inhibitory receptor T cell

Signal 3

Signal 1 TCR MHC

T-cell inhibition

T cell

TCR

Signal 2

APC

MHC

Inhibitory receptor

APC

mAb W. Samlowski; Adapted from O’Day et al. Abstract #4, ASCO 2010.

mAb

Previously Treated Unresectable or Metastatic Melanoma* (N = 676)

R A N D O M I Z ED

Phase III trial of ipilimumab

YERVOY 3 mg/kg + gp100

(n = 403)

YERVOY 3 mg/kg

(n = 137)

gp100

(n = 136)

*Enrolled patients with unresectable or metastatic melanoma previously treated with 1 or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin.

YERVOY [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2011.

Ipilimumab therapy schema

YERVOY [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2011.

Ipilimumab RECIST response rate

Best Overall Response Rate in Pivotal Phase 3 Study1

Best overall response rate 95% CI

YERVOY 3 mg/kg (n = 15 of 137)2

YERVOY 3 mg/kg + gp100 (n = 23 of 403)2

gp100 (n = 2 of 136)2

10.9%

5.7%

1.5%

6.3%, 17.4%

3.7%, 8.4%

0.2%, 5.2%

YERVOY [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2011.

Ipilimumab vs GP100 vaccine phase 3 46% 24% 25%

14% Years

Hodi FS et al. N Engl J Med.363(:711–72, 2010.

Pooled overall survival (OS) data. n = 1,861 10 trials

Dirk Schadendorf et al. J Clin Oncol.56:2736, 2014

Can ipilimumab results be duplicated in a community practice?

Outcome of ipilimumab therapy 31 patients, 2012 Ipilimumab D- or T-Biochemotherapy

Survival (%)

100

70 patients 1999-2006

75 50 25

CR

7

PR

4

SD

4

0 0

200

400

600

Days from start of treatment W. Samlowski, et al. submitted

CTLA4 mAb in metastatic prostate cancer

Ipilimumab in Taxotere refractory prostate CA Patient chracteristics

Kwon et al. Lancet Oncol 15: 700–12, 2014

Ipilimumab in Taxotere refractory prostate CA PFS

Kwon et al. Lancet Oncol 15: 700–12, 2014

Ipilimumab in Taxotere refractory prostate CA

OS

Kwon et al. Lancet Oncol 15: 700–12, 2014

Ipilimumab in Taxotere refractory prostate CA OS Good prognosis (post-hoc analysis)

Hb >11.0 Alk Phos < 5x ULN No visceral metastases

Kwon et al. Lancet Oncol 15: 700–12, 2014

PD-1 mAb in melanoma

Nivolumab and pembrolizumab are FDA approved for 2nd line therapy of melanoma after ipilimumab failure in BRAF mutation negative patients

Nature of patients (melanoma)

Topalian et al., J Clin Oncol 32:1020-1030, 2014

Melanoma response Nivolumab Phase I-II

Topalian et al., J Clin Oncol 32:1020-1030, 2014

Nivolumab Phase I-II-dose response

Topalian et al., J Clin Oncol 32:1020-1030, 2014

Nivolumab vs DTIC PhIII Previously untreated patients

nivolumab

DTIC

Robert et al., N Engl J Med 372:320-30, 2015.

Nivolumab vs DTIC PhIII

OS

Previously untreated patients

Robert et al., N Engl J Med 372:320-30, 2015.

PFS

Lambrolizumab Ph I-II

• Treatment: 10 mg/kg IV Q2W, 10 mg/kg IV Q3W, or 2 mg/kg IV Q3W • Prior ipilimumab allowed • Response assessment • Primary: irRC per investigator assessment • Secondary: RECIST 1.1 independent radiology review Hamid et al. N Engl J Med 369;135-144, 2013

Lambrolizumab waterfall plot Hamid et al. N Engl J Med 369;135-144, 2013

Lambrolizumab response duration

Hamid et al. N Engl J Med 369;135-144, 2013

PD-1 mAb in NSCLC

Nivolumab is FDA approved for 2nd line therapy of squamous histology NSCLC after failure of initial therapy

Nivolumab in Squamous NSCLC

Rizvi, et al. Lancet Oncol 16: 257–65, 2015

Nivolumab in Squamous NSCLC

Rizvi, et al. Lancet Oncol 16: 257–65, 2015

Nivolumab in Squamous NSCLC

Rizvi, et al. Lancet Oncol 16: 257–65, 2015

Nivolumab in Squamous NSCLC Objective responders

Stable disease

Up to 1 year follow-up Rizvi, et al. Lancet Oncol 16: 257–65, 2015

Nivolumab in Squamous NSCLC

PFS

Rizvi, et al. Lancet Oncol 16: 257–65, 2015

Nivolumab in Squamous NSCLC

OS

Rizvi, et al. Lancet Oncol 16: 257–65, 2015

PD-1 mAb in other tumor types

Checkpoint mAb in other tumors

Renal Cancer SCCHN Gastric

PD-1 Ovarian ER/PR/Her2– breast Hodgkins/NHL PD-L1

Bladder Lung Melanoma

Combinations of Checkpoint Inhibitors

Generation and regulation of antitumor immunity 2.

Lymph Node

CTLA-4 “tolerance”

1. 3.

4.

5. “anergy”

Tumor

PD-1/PD-L1

6. Modified from Mellman et al. Nature 480:480-489, 2011

Ipilimumab + nivolumab Ph I

New Engl J Med June 10, 2013

Ipilimumab and nivolumab Bar-plot of responses

New Engl J Med June 10, 2013

Ipilimumab and nivolumab Spider plot of responses New Engl J Med June 10, 2013

International randomized phase III Ipilimumab and nivolumab

Toxicity of Checkpoint Inhibitor mAb

Keys to managing toxicity Toxicity of Checkpoint inhibitor mAb: a) Novel to most oncologists b) Represent overactivation of immune system c) Require novel management paradigm d) “manageable” Management principles: 1) Prompt recognition 2) Rapid intervention 3) Early treatment intensification

Keys to managing toxicity (2) Toxicity of Checkpoint inhibitor mAb: a) Patient education b) Nursing staff/physician education c) Direct means of communicating toxicity d) Early decisive intervention Treatment principles: (stop, drop and roll) 1) High dose steroids (1 mg/kg) 2) A brief period of observation/slow taper (1 week) 3) Early addition of 2º immunosuppressive agents

Select Important Safety Information: Adverse Reactions • Adverse reactions from the pivotal phase 3 study, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3-5 events Selected Adverse Reactions in the Pivotal Phase 3 Study Patients, %a YERVOY 3 mg/kg (n = 131) System Organ Class/ Preferred Term

YERVOY 3 mg/kg + gp100 (n = 380)

gp100 (n = 132)

Any Grade

Grade 3-5

Any Grade

Grade 3-5

Any Grade

Grade 3-5

Diarrhea

32

5

37

4

20

1

Colitis

8

5

5

3

2

0

Gastrointestinal Disorders

Skin and Subcutaneous Tissue Disorders Pruritus

31

0

21