ASCO 2015 Melanoma Immunotherapy

Thomas Olencki, DO Division of Medical Oncology

Department of Internal Medicine The Ohio State University Wexner Medical Center

Columbus, Ohio

June 13, 2015

Melanoma Is What Gives Cancer A Bad Name

George Canellos

Adapted from Michael Atkins

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Balch, JCO 19:3635, 2001.

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Survival Curve Of Patients With Metastatic Melanoma

What Are Benchmarks For Treatment Of Metastatic Melanoma ?

• Evaluated – 2100 patients – 70 arms of 42 trials in cooperative groups

• Results – OS

• median - 6.2 mos • 12 mos rate – 26%

– PFS • median – 1.7 mos • 6 mos rate – 15%

Korn, JCO 26:527, 2008

“Clinical benefit” CR+PR+SD

New “Benchmark” for phase 2 trails

High Dose IL-2 In Metastatic Melanoma

Response durations for pts who achieved a CR/ PR

Atkins, JCO 17:2105, 1999

3.7%

High Dose IL-2 In Metastatic Melanoma

Survival for the whole study population (270 patients) OS – 11.4 months at median follow up of 62 mos

Atkins, JCO 17:2105, 1999

Stage IV

Advantages Of Immunotherapy

• Searching for tumor activating mutation less critical

• Immune system may “adapt” to specific tumor characteristics

• Potential for long-term durable response

Immune Therapy

Also Now Known As Checkpoint Inhibitors

Monoclonal Antibody Therapy • Nomenclature for monoclonal Ab:

– CTLA-4

• Ipilimumab (Yervoy®) - BMS – PD -1

• Nivolumab (Opdivo®) – Bristol-Myers Squibb • Pembrolizumab (Keytruda®) - Merck

Ipilimumab

Ipilimumab

Ag presenting Dendritic cell

Or Tumor cell MHC II Ag TCR

CD 28 – T cell stimulation (with IL-2 production) CD 80 B 7.1 CD 86 B 7.2

Activated T Cell

CTLA-4 – T cell inhibition (induction of tolerance) − CD152

Ipilimumab (2)

Ag presenting Dendritic cell

Or Tumor cell MHC II Ag TCR

CD 28 – Unopposed T cell stimulation CD 80 B 7.1 CD 86 B 7.2

Activated T Cell

Unopposed autoimmune effects: - rash and vitiligo - hypopituitarism - diarrhea and colitis - hepatitis

Ipilimumab (3)

• Humanized IgG1k – T1/2 20 - 30 days – administered IV q 3 wks x 4 doses

• Breaks immune system tolerance for the tumor

• Ipilimumab an early check point regulator of T cell Fx

– thought to be active in the lymph node

Phase III Ipilimumab – 2nd Line Tx

R A N D O M I Z E

Ipilimumab 3 mg/kg IV

Ipilimumab 3 mg/kg IV & gp 100

Open 9/2004 – 8/2008 Double blind

(3:1:1; for ipi, ipi & gp100 and gp100 alone)

Hodi, NEJM 363:711, 2010

676 pts with prior Tx

melanoma

70% had M1c poor risk

visceral disease gp 100 vaccine

All drugs q 3 wks x 4 doses

Phase III Ipilimumab – 2nd Line Tx

Ipilimumab alone OS 24% at 2+ yrs

Overall survival

Hodi, NEJM 363:711 2010

Phase III Ipilimumab – 2nd Line Tx

Overall Survival

Hodi, NEJM 363:711 2010

Flat survival curve 24 to 36 mos

Phase III Ipilimumab – 2nd Line Tx • Results ipi ipi and gp100 gp100 Korn PFS 2.8 mos 2.8 mos 2.8 mos 1.7 med OS 10.1 mos 10 mos 6.4 mos 6.2 12 mos 46% 44% 25% 26% 24 mos 24% 22% 14% RR 11% 6% 2% Clin Benefit * 29% 22% 11%

* CR, + PR, + SD Hodi, NEJM 363:711, 2010

Phase III Dacarbazine +/- Ipilimumab 1st Line Tx

R A N D O M I Z E

Ipilimumab 10 mg/kg + DTIC

DTIC

502 pts 1:1 ratio

Robert, NEJM 364:2517, 2011

Open 8/2006 - 1/2008

Phase III Dacarbazine +/- Ipilimumab 1st Line Tx

Robert, NEJM 364:2517, 2011

Overall Survival

Phase III Dacarbazine +/-Ipi 1st Line • Results Ipi and DTIC DTIC Korn PFS NA NA 1.7 med OS 11.2 mos 9.1 mos 6.2 12 mos 47% 36% 26% 24 mos 28% 18% 36 mos 21% 12% RR 15% 10%

Robert, NEJM 364:2517, 2011

Long Term Survival With Ipilimumab

Schadendorf, JCO 33:1889, 2015

OS of 4,846 pts Tx on trial and from Expanded Access Program. Survival plateau starts at 3 yrs and extends to 10 yrs in some pts.

3 yr surv of 21%

Conclusions Regarding Ipilimumab • Tolerable to wide range of pt’s

– borderline PS − elderly – treated brain mets − uveal and mucosal primaries

• Combination with chemo Tx may not improve efficacy • Associated with

– RR 10-15% – PFS of about 3 mos – Stable OS of 21% at 3 yrs extending to 10 years in some pts

• Benefit of ipilimumab – increase in overall survival

Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015

Nivolumab or Pembrolizumab

PD-1 / PD-L1 Interaction

Tumor

MHC II Ag TCR

Activated T Cell

(B7-H1) PD-L1 PD-1 - T cell inhibition

PD-1/PD -L1 is a regulator of T cell function in the tumor and peripheral blood

PD-1 / PD-L1 Interaction

Tumor

MHC II Ag TCR

Activated T Cell

B7-H1 – PD-L1 PD-1 - T cell inhibition

Nivolumab / Pembrolizomab

Brahmer, JCO 28:3167, 2010

Induction of tolerance

Results: PR and SD with few side effects

Brief Review Of 3 Trials

• Nivolumab 1st line

• Pembrolizumab vs ipilimumab

• Nivolumab and Ipilimumab

Phase III Nivolumab vs DTIC As 1st Line Therapy

R A N D O M I Z E

Ipilimumab 3 mg/kg

DTIC 1000 mg/m2

418 pts 1:1 ratio

Robert, NEJM 372:320, 2015

Open 1/2013 - 2/2014 All patients BRAF

wild type

Phase III Nivolumab vs DTIC As 1st Line Therapy

• Results Nivolumab DTIC PFS 5.1 mos 2.2 mos med OS not reached 10.8 mos 12 mos 73% 40% RR 40% 14%

• Conclusions: Trial significant for ↑ PFS, OS & RR

Robert, NEJM 372:320, 2015

Phase III Nivolumab vs DTIC As 1st Line Therapy - OS

Robert, NEJM 372:320, 2015

Phase III Nivolumab vs DTIC As 1st Line Therapy - PFS

Robert, NEJM 372:320, 2015

Pembrolizumab vs Ipilimumab

R A N D O M I Z E

Pembrolizumab 10 mg/kg q 3 wks

Ipilimumab 3 mg/kg q 3 wks

834 pts 1:1:1 ratio

Robert, NEJM 372:320, 2015

Open 9/2013 - 3/2014

Pembrolizumab 10 mg/kg q 2 wks

Pembrolizumab vs Ipilimumab

Robert, NEJM 2015

Ipilimumab

Pembrolizumab

Progression free survival

Pembrolizumab vs Ipilimumab

Robert, NEJM 2015

Ipilimumab

Overall survival

Pembrolizumab vs Ipilimumab

• Results pembrolizumab (q3wk) ipilimumab PFS 4.1 mos 2.8 mos med OS not reached not reached 12 mos 68% 58% RR 33% 12% • Conclusions: Trial stopped early by the DSMB because of

superiority of pembrolizumab

Robert, NEJM 372:320, 2015

Combination PD-1 Inhibition And Anti-CTLA-4

Or Nivolumab And Ipilimumab

Phase III Nivolumab And Ipilimumab Or Monotherapy

R A N D O M I Z E

Ipi 3 mg/kg & Nivo 1 mg/kg IV

Ipilimumab 3 mg/kg I

Open 7/2013 – 3/2014 Double blind

Larkin, NEJM May 31, 2015 Epub

945 pts with No prior Tx

58% had M1c poor risk

visceral disease

Nivolumab 3 mg/kg

1:1:1 randomization

Median PFS In Intention To Treat Pts

Nivo and Ipi 11.5 mos

Ipilimumab 2.9 mos

Larkin, NEJM May 31, 2015 Epub

Nivolumab 6.9 mos

Phase III Nivo And Ipi Or Monotherapy • Response results Ipi and Nivo Nivo Ipilimumab ORR 58% 44% 19% CR 12% 9% 2% PR 46% 35% 17% SD 13% 11% 22% PD 23% 38% 49% Unknown 7% 8% 10%

Larkin, NEJM May 31, 2015 Epub

Tumor-burden change

from baseline

Nivo

Nivo & Ipi

Ipi

35%↓

52%↓

6%↑

Larkin, NEJM May 31, 2015 Epub

Median PFS In PD-L1 + Tumors

Ipi and Nivo 14 mos

Ipilimumab 3.9 mos

Nivolumab 14 mos

Larkin, NEJM May 31, 2015 Epub

Median PFS In PD-L1 Negative Tumors

Ipi and Nivo 11.2 mos

Ipilimumab 2.8 mos

Nivolumab 5.3 mos

Larkin, NEJM May 31, 2015 Epub

Phase III Nivo And Ipi Or Monotherapy

• Response by PD-L1 status Nivo & Ipi Nivo Ipi PD-L1 ≥ 5% 72% 57% 21% PD-L1 < 5% 54% 41% 18% 67% of pts who DC’ed combination Tx due to AE developed a response. One half of those responses were after Tx ended. Only about 25% pts are PD-L1+ (BMS testing)

Larkin, NEJM May 31, 2015 Epub

Phase III Nivo And Ipi Or Monotherapy • Adverse events:

– combination arm • diarrhea- 44% • fatigue – 35% • puritus – 33% • incidence of Gr 3 and 4 – 55% • 36% of pts had AE that led to DC of TX – diarrhea & colitis • NO patient deaths

– use of steroids did NOT prevent responses – absolutely need to wean steroids over a minimum of 4 wks

Larkin, NEJM May 31, 2015 Epub Atkins, Plenary Session, ASCO 2015

Phase III Nivo And Ipi Or Monotherapy • Combination Tx with Nivo and Ipi represents a

dramatic therapeutic breakthrough for pts • In PDL-1 status

– for PDL1+ Nivo = Nivo & Ipi PFS – for PDL1− Need Nivo and Ipi for PFS benefit

• Response and PFS presented today • Overall survival pending longer follow up • Toxicity moderate to severe but manageable

Mutational Density As A Predictor Of Response

Alexandrov, Nature 500:415, 2013

Predictors Of Response • Primed tumor – CD8 infiltrate within tumor

– Can be primed by prior or concurrent therapy with ipilimumab

– Increased number of T reg cells and expression of suppressive IDO (surrogate for immune infiltrate)

• Absolute lymphocyte count at beginning of 2nd course of > 1,000 (for ipilimumab) Allison, Plenary Session of ASCO 2015

Postow, JCO 33:1974, 2015

Predictors Of Response – PD-1 • PD-L1 level evaluation

– Technically difficult – Tumor heterogeneity limits reliability – Expression inducible by PD-1 therapy – No standard assay comparable between companies – Significant variability

• Tumor versus CD8 PD-1 levels • Levels different on fresh versus frozen versus archival tissue • Levels different on primary versus metastatic sites

• Should not be used at this time for clinical decisions Adapted from Atkins, Plenary Session, ASCO 2015

Other T Cell/Tumor Interactions

Allison, Plenary Session of ASCO 2015

Conclusions (1) • Combination Tx with nivolumab and ipilimumab indicated for

those pts who need a resp. and can the tolerate toxicity • Single agent PD-L1 therapy indicated when toxicity a

concern • Nivolumab & ipilimumab are more effective than nivo alone • Nivo/ Pembro or nivolumab with ipilimumab are both more

active than ipilimumab alone • Nivo/ Pembro and nivolumab with ipilimumab represent a

“new standard of care”

Adapted from Atkins, Plenary Session, ASCO 2015

Conclusions (2) • Use of steroids to treat toxicity does not negate therapeutic

effect • B raf mutation status does not predict for response to

checkpoint blockade therapy • High LDH may not be an absolute negative indicator of

response to checkpoint therapy • HD IL-2 may be safely and effectively administered to those

pts that progress on any checkpoint inhibitor therapy (Buchbinder and McDermott, ASCO 2015)

Adapted from Atkins, Plenary Session, ASCO 2015

Melanoma Is What Gives Cancer A Bad Name

But now we can do something about it!