melanoma asco review update 2016

ASCO 2016 Melanoma Update

Thomas Olencki, DO Division of Medical Oncology

Department of Internal Medicine The Ohio State University Wexner Medical Center

Columbus, Ohio

June 18, 2016

p <0.0001 15 14 13 12 11 10

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

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 checkpoint

inhibitors: – CTLA-4 – early inhibitor and most active in lymph node

•  Ipilimumab (Yervoy®) – BMS

– PD -1 – later inhibitor in peripheral blood or tumor •  Nivolumab (Opdivo®) – Bristol-Myers Squibb •  Pembrolizumab (Keytruda®) - Merck

Ipilimumab

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 à q 3 wks x 4 doses


Ipilimumab alone OS 24% at 2+ yrs

Overall Survival

Hodi, NEJM 363:711 2010

OS at 1 yr 46%


Overall Survival

Hodi, NEJM 363:711 2010

Flat survival curve 24 to 36 mos

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. Median OS was 9.5 mos

3 yr OS of 21%

LDH May Be Most Accurate Predictor Of Response To Ipilimumab

Kelderman, Cancer Immuno Immunother 63:449. 2014

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

•  LDH may predict who will respond Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015

Nivolumab or Pembrolizumab

Brief Review Of 3 Trials

•  Nivolumab - Phase 1

•  Pembrolizumab vs ipilimumab

•  Nivolumab and Ipilimumab

Phase I Nivolumab Dose Finding Study

•  All 107 pts had to have had prior therapy

•  62% had 2 or more different therapies

•  These were real world patients with bulky disease

•  Stable brain metastasis were acceptable

•  This is the 1st long-term follow-up study of the nivolumab therapy

Hodi, AACR April, 2016

Hodi, AACR April, 2016

34% 5 yr OS

Phase I Nivolumab 5 Year OS Results

Pembrolizumab vs Ipilimumab Keynote-006

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 ≤ 1 therapy

Robert, NEJM 372:320, 2015; Schachter, ASCO 2016 # 9504

Open 9/2013 - 3/2014

Pembrolizumab 10 mg/kg q 2 wks

Median FU – 23 mos


•  Response (23 mos median follow up) pembrolizumab (q3wk) ipilimumab

ORR 36% 13% CR 13% 5% PR 23% 8% SD 16% 18% PD 42% 49% Not eval 6% 18%

Schachter, ASCO 2016 #9504



Median PFS



Median OS

Median OS


•  In this study, ipilimumab pts faired better than in prior studies •  No difference in PFS or OS was seen with the different

pembrolizumab schedules •  Pembrolizumab (40% OS) found to be more effective than ipi

(22% OS) at 3 yr. OS in all subgrps. analyzed •  Pembrolizumab PFS curve flattens at 20 months

•  Pembrolizumab ( anti-PD-1 Tx) represents a new “standard of care” over ipilimumab for metastatic melanoma patient’s


Combination PD-1 Inhibition And Anti-CTLA-4

Or Nivolumab And Ipilimumab

(CheckMate 067)

Phase III Nivolumab And Ipilimumab Or Monotherapy (CheckMate 067)

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 373:23, 2015 ; Wolchok, ASCO 2016 #9505

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 373:23, 2015; Wolchok, ASCO 2016 #9505

Nivolumab 6.9 mos

Median PFS – CheckMate 067 Median 20.7 mos Follow-up

Nivo and Ipi 11.5 mos

Ipilimumab 2.9 mos

Nivo 6.9 mos

Wolchok, ASCO 2016 #9505

Phase III Nivo And Ipi Or Monotherapy •  Response results – at 20.7 mos FU

Ipi and Nivo Nivo Ipilimumab ORR 58% 44% 19% CR 12% 10% 2% PR 46% 34% 17% SD 13% 11% 22% PD 23% 38% 49% Unknown 7% 8% 10% Med resp dur NR 22 mos 14 mos Ongoing resp 73% 72% 52%


Tumor-burden change

from baseline

Nivo

Nivo & Ipi

Ipi

35%↓

52%↓

6%↑ Larkin, NEJM 373:23, 2015

Wolchok, ASCO 2016 #9505

Median PFS In PD-L1 + Tumors

Ipi and Nivo 14 mos

Ipilimumab 3.9 mos

Nivolumab 14 mos

Now NR

Now 20 mos


Median PFS In PD-L1 Negative Tumors

Ipi and Nivo 11.2 mos

Ipilimumab 2.8 mos

Nivolumab 5.3 mos


Phase III Nivo And Ipi Or Monotherapy

•  Response by PD-L1 status Nivo & Ipi Nivo Ipi

PD-L1 ≥ 5% 72% 58% 21% PD-L1 < 5% 55% 41% 18% •  69% of pts who DC’ed combination Tx due to AE developed

a response. •  50% of those responses were after Tx ended. Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505

Early Phase 2 Randomized Study Of Nivolumab And Ipilimumab vs Ipilimumab

•  Pt numbers small - 95 in combination and 47 in Ipi

•  Follow-up is short at 2 years

•  All patients previously not treated

Postow, AACR April 2016

Postow, AACR, 2016

Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab

Postow, AACR 2016 months

Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab

Phase III Nivo And Ipi Or Monotherapy •  Adverse events:

–  combination arm •  rash/ pruritis – 60% •  diarrhea - 45% •  hepatic – 32% •  pulmonary – 7% •  renal – 6% •  incidence of Gr 3 and 4 – 56% •  39% of pts had AE that led to DC of TX •  NO patient deaths


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

•  Nivo/ipi active in any sub grp. including ≥ 2 x LDH

•  Responses and Overall Survival durable

•  Toxicity moderate to severe but manageable –  should not use in pts with “minimal reserve”

Predictors Of Response And

Resistance

Mutational Density As A Predictor Of Response

Alexandrov, Nature 500:415, 2013

Factors Affecting Response And Resistance

Charen, ASCO 2016 Special Session - Rathmell

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 maybe different on primary versus metastatic sites

•  Should not be used at this time for clinical decisions

Adapted from Atkins, Plenary Session, ASCO 2015

What About The Pt With Borderline PS?

What About Grandma? •  Pts who may not tolerate combination therapy include:

–  poor social support –  living a long distance from medical care –  poorly controlled diabetes –  deconditioned elderly

•  Sequential use of checkpoint inhibitors is often better tolerated and safer than combination Tx

•  Is there a preferred sequence? –  PD-1 inhibitor followed by ipilimumab –  Ipilimumab followed by a PD-1 inhibitor

•  CheckMate 064 addressed this issue

Weber, Lancet Oncol pub online June 4, 2016

CheckMate 064 – Phase 2

R A N D O M I Z E

Nivolumab

Open 4/2013 – 7/2014


140 pts

≤ 1 prior Tx

Nivolumab

Ipilimumab

Ipilimumab

RR – 41% OS – NR

RR – 20% OS – 16.9 mos

Median follow-up of 19.8 months

12 wks

CheckMate 064 - OS


Nivo-Ipi

Ipi-Nivo

CheckMate 064 •  Results

–  Overall survival follow-up is ongoing

•  Given the opportunity, nivolumab followed by ipilimumab sequence may provide > clinical benefit to pts

•  Toxicity comparable between both arms at 12 weeks, but greater in the Nivo à Ipi arm the latter 12 weeks

•  Hazard ratio 0.57 in favor of Nivo à Ipi arm

•  All prior assigned grps did better on Nivo à Ipi arm

Weber, Lancet Oncol pub online June 4,2016

The B raf Mutation Pt

What Is The Best Way To Tx Pts With B raf Mutation + Melanoma?

•  No one really knows

•  Emotional topic with no firm data

•  Phase 3 study recently opened EA6134

•  Optimal therapy may include up front: B raf, MEK and PD-1 inhibitor simultaneously

EA 6134 - Intergroup

R A N D O M I Z E

B raf V600

mutation positive

Nivo and Ipi

Dabrafenib and tremetinib

PD

PD

C R O S S O V E R

Nivo and Ipi

Dabrafenib and tremetinib

OSU Contact: Joanne Jeter MD 614-293-4320

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

those pts who need a resp. and can tolerate the toxicity

•  Single agent PD-L1 therapy indicated when toxicity a concern

•  Nivolumab & ipilimumab are more effective than nivo alone

•  Nivo/ Pembro alone or with ipilimumab are both more active than ipilimumab alone

•  Nivo/ Pembro and nivolumab with ipilimumab represent a “new standard of care”


Conclusions (2) •  Steroids to Tx toxicity does not negate therapeutic effect •  B raf mutation status does not predict for response to

checkpoint blockade therapy •  The most effective Tx (targeted vs immune vs combination)

for B raf mutation pt’s remains to be determined •  High LDH (≥ 2 x nl) is not a negative indicator of response

to combination 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 2016 #e21006)


Summary Therapy Resp. Rate OS (5 yr) High dose IL-2 15% 6% Ipilimumab 10 - 20% 20% Nivo/pembro 30 – 40% 34% Nivo/Ipi 55 - 60% 64% (at 2 yrs)

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melanoma asco review update 2016

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