BRAF/MEK inhibitors: what can we expect from here · 153 80 233 All 170 93 263 ... T he fit BR AF i...

BRAF/MEK inhibitors: what can we expect from here

Ryan J. Sullivan, MD

Associate Director, Melanoma Program

MGH Cancer Center

Relevant Disclosures

• Advisory Board/Consulting:• Novartis

• Amgen

• Merck

• Array

• Syndax

• Replimmune

• Research Sponsorship:• Amgen

• Merck

1980 2011 20152013

DTIC

High-dose IL-2

Ipilimumab

Vemurafenib (V) Nivolumab

Pembrolizumab

Ipi + Nivo

Dabafenib (D), Trametinib (T)

Binimetinib + Encorafenib

D + T

TVEC

Cobimetinib + V

2017

Advanced Melanoma Treatment Landscape 2018

2018

1980 2011 20152013

DTIC

High-dose IL-2

Ipilimumab

Vemurafenib (V) Nivolumab

Pembrolizumab

Ipi + Nivo

Dabafenib (D), Trametinib (T)

Binimetinib + Encorafenib

D + T

TVEC

Cobimetinib + V

2017

Advanced Melanoma Treatment Landscape 2018

2018

BRAF mutant melanoma:Single-agent BRAF inhibitors are superior to chemotherapy

Dabrafenib

Hauschild et al. Lancet 2012

Vemurafenib

Chapman et al. NEJM 2011

Dual BRAF and MEK inhibition is associated with high response rates and median PFS of 9 to 11 months…

Flaherty et al. NEJM 2012

Ribas et al. Lancet Oncol. 2014

Dabrafenib plus Trametinib

Vemurafenib plus Cobimetinib

And superior survival compared to single-agent BRAF inhibitors (BRAFi)

Long et al. NEJM 2014; Long et al. Lancet 2015.

Dabrafenib + PlaceboMedian PFS 8.8 mo (95% CI:5.9–9.3)

Dabrafenib + TrametinibMedian PFS 11.0 mo (95% CI:8.0–13.9)

HR 0.67 (95% CI: 0.53, 0.84)P < 0.001

Dabrafenib + TrametinibDied: 99 (47%)Med OS = 25·1 mo(95% CI:19.2-NR)Dabrafenib

Died: 123 (58%)Median OS = 18.7 mo(95% CI:15.2–23.7)

HR 0.71 (95% CI: 0.55, 0.92)P = 0.011

Vemurafenib + CobimetinibMedian PFS 12.5 mo (95% CI:9.4–13.4)

Vemurafenib + PlaceboMedian PFS 7.2 mo (95% CI:5.5–7.5)

HR 0.58 (95% CI: 0.46-0.72)P < 0.001

Ove

rall

surv

ival

, %

Time, mo

Vem + PBOVem + cobi

Censored++

HR = 0.70 (0.55-0.90)P = 0.005

VemurafenibMedian OS = 17.4 mo(95% CI:15.0–19.8)

Vemurafenib + ComibmetinibMed OS = 22.3 mo(95% CI:20.3-NR)

Larkin et al. NEJM 2015

Time (mo)

Pro

gre

ss

ion

-Fre

e S

urv

iva

l (%

)

100

0 4 8 12 16 20 24 28

0

20

40

60

80

COMBO450

VEM

192

191

151

101

107

56

87

36

57

23

28

13

4

4

0

0

Patients at risk

COMBO450

VEM

Median PFS in months (95% CI)

COMBO450 VEM

14.9 (11.0–18.5) 7.3 (5.6–8.2)

HR (95% CI), 0.54 (0.41–0.71)P<0.001

And data from most recent combination:Encorafenib and binimetinib versus vemurafenib

Dummer et al. Lancet Oncol 2018

Summary of BRAF-targeted therapy data in 2018

• Single-agent BRAF and MEK inhibitor therapy is associated with improved outcomes (response, PFS, and OS) compared to chemotherapy

• Combined BRAF/MEK inhibitor therapy is associated with improved outcomes (response, PFS, and OS) compared to single agent BRAFi therapy

• Now three BRAF/MEK inhibitor regimens demonstrating improved outcomes compared to BRAF inhibitor single-agent therapy

• Tolerability of combined BRAF/MEK inhibitor therapy is excellent compared to single-agent therapy

• The median survival is over two years (approaching three years in COLUMBUS)

• And a subset of patient (perhaps a quarter to a third) remain progression free for over three years, others five years

1. Determine optimal sequencing of BRAF-targeted therapy with immunotherapy

2. Identify useful biomarkers

3. Build rationale combinatorial “regimens”

How do we make BRAF targeted therapy better?





BRAF targeted therapy

Immune targeted therapy

This is not an either or choice…

Contemplating the Options

• High response rates

• Transient responses

• Rapid improvement in disease-related symptoms

• Low response rates

• Durable responses

• May take weeks to months to be effective

Immunotherapy BRAF-targeted therapy

Response to BRAFi

No Response to BRAFi

Total

IT first 17 13 30

MAPKifirst

153 80 233

All 170 93 263

Figure 2 MAPKi PFS

IT initially PFS 6.7 mo (CI 4.3-9.1 mo)

MAPKi initially PFS 5.6 mo (CI 4.7-6.8 mo)

p-value 0.43, log rank

Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after targeted therapy

Allison Ackerman*, Oliver Klein*, David F. McDermott, Wei Wang, Nageatte Ibrahim, Donald P. Lawrence, Anasuya Gunturi, Keith T. Flaherty, F. Stephen Hodi, Richard Kefford, Alexander Menzies, Michael B. Atkins, Daniel C. Cho, Georgina Long, Ryan J. Sullivan

Beth Israel Deaconess Medical Center, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA. Brigham and Women’s Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA.

Westmead Hospital, Sydney, NSW, Australia. University of Sydney, Sydney, NSW, Australia. Melanoma Institute Australia, North Sydney, NSW, Australia. Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.

Abstract

In the case of BRAF mutant MM, targeted inhibitors of BRAF selectively

inhibit the mutated protein kinase BRAF and its constitutive activation of

mitogen-activated protein kinase kinase (known as MEK1) in the MAPK

pathway. The first BRAFi vemurafenib is FDA approved, and clinical

trials with second BRAFi dabrafenib as a single agent or in combination

with MEKi for vertical MAPK inhibition have demonstrated efficacy.1,2,3

Clinicians have several options for initial therapy including

immunotherapy (IT) approaches, such as ipilimumab or high-dose

interleukin 2 (IL-2), versus targeted MAPK inhibitors (MAPKi).4,5 IT is

equally effective in BRAF mutant as in BRAF WT populations.6 No

randomized control trials compare targeted MAPKi versus IT

approaches, and there is no data on the optimal initial therapy/

sequencing of these two strategies.

Though targeted MAPKi can lead to impressive responses, these are

typically short-lived (PFS ~6 months),1,7,8 whereas IT can induce durable

remissions albeit only in a small subset of patients.4 Given the strengths

and weaknesses of these two approaches, MAPKi and IT, they might

have complementary roles given in sequence or concurrently.

Here we describe our multicenter experience with the

sequencing of MAPKi before and after IT.

Background

Patient Population: 274 pts with BRAF mutant MM treated in the US

and Australia with MAPKi from 2009-2012, were consecutively

retrospectively identified. Pts who add received prior MAPKi were

excluded. Inclusion required documented BRAF V600E/K and

measurable disease. Other lines of therapy were allowed before or after

treatment, including surgery, radiation, and chemotherapy.

Treatment: All patients received MAPKi with vemurafenib, dabrafenib, or

dabrafenib/trametinib as per clinical trial protocol. Continuation with

MAPKi after progression was allowed, and reinstitution of vemurafenib

following removal from trial feasible after FDA-approval.

Statistical Methods: MAPKi PFS and OS were defined from the start of

MAPKi until progression as defined by RECIST criteria or death. Post

MAPKi ipilimumab PFS and OS were defined from start of ipilimumab,

using immune-related response criteria. Fisher's exact test calculated p-

values. The Kaplan-Meier method was used to estimate PFS and OS with

95% CI; and survival curves were analyzed with log rank. Cox

proportional hazards model was used to determine the significance of

prognostic variables in a multivariate model.

Methods

Results

Patient Population: 274 pts, all of whom received MAPKi, were

subdivided: 32 pts received IT initially (IT then MAPKi)

242 pts received MAPKi as initial therapy without prior IT (Figure 1).

Only LDH and choice of MAPKi were statistically different (Table 1).

Background: We previously reported on outcomes of patient (pts) who received immunotherapy (IT) prior to or after BRAF inhibitor (BRAFi) therapy in a cohort of 43 metastatic melanoma (MM) pts. For pts receiving IT following BRAFi, no treatment responses were seen and survival

was dismal. We now report an update and expansion on this analysis which includes a larger cohort of pts, treated with either single agent BRAFi or combination of a BRAFi and a MEK inhibitor (BRAFi/MEKi) for vertical inhibition of the MAP kinase pathway (MAPKi).

Methods: A cohort of 274 BRAF mutant MM pts, treated in the US and Australia with targeted MAPKi in 2009-2012,was retrospectively identified. RR

was evaluated using RECIST criteria. OS and PFS were calculated using Kaplan-Meier estimates in months (mo). A multivariate analysis was performed in the complete cohort with prognostic variables at the time of initiation of therapy, including LDH, stage, ECOG PS, and presence of brain metastases.

All variables are evaluated for the entire cohort, subdivided by immunotherapy (IT) prior to or after MAPKi, with additional subset analysis for BRAFi vs BRAFi/MEKi. RR, OS and PFS were also determined for a cohort receiving ipilimumab after MAPKi discontinuation.

Results: 274 patients were treated with MAPKi. The RR, PFS, and OS to MAPKi following IT initially were 57%, 6.7 mo (CI 4.3-9.1 mo), and 19.6 mo (CI

10.0- mo) respectively; whereas for MAPKi initially were 66%, 5.6 mo (CI 4.7-6.8 mo), and 13.4 mo (CI 10.1-17.0 mo). Results are similar when controlled for prognostic variables. For the 193 pts who discontinued MAPKi, the remaining OS was 2.9 mo (1.8-4.4mo) from day of MAPKi

discontinuation. Of this subgroup, 40 pts subsequently received IT with ipilimumab. Only half could complete 4 doses of ipilimumab. In this setting, ipilimumab PFS was 2.7 mo (CI 1.8-3.1 mo) and OS was 5.0 mo (CI 3.0-8.8 mo).

Conclusions: Within the limitations of a retrospective analysis, prior treatment with IT does not appear to negatively influence response to MAPKi.

Outcomes to IT with ipilimumab following MAPKi discontinuation are poor. Our current data suggests in appropriately selected pts, IT should be considered prior to MAPKi targeted inhibitors.

Figure 1 Patient Population

Table 1 Baseline Characteristics at MAPKi Initiation !

Table 2 MAPKi Outcomes

Response to MAPKi: In univariate analysis based on whether pts

received IT initially prior to MAPKi vs received MAPKi initially, outcomes did

not appear inferior (Table 2, Figure 2, Figure 3).

Since LDH and MAPKi differed between populations, a Cox proportional

hazards model assessed the contribution of initial therapy. Prior IT was not

significant (MAPKi vs IT initially p=.38 and p= .83 for PFS and OS

respectively). LDH and ECOG PS were statistically significant hazards,

which contributes to shorter PFS and OS in Kaplan Meier analysis. No

interaction terms were statistically significant, perhaps because insufficient

pts with elevated LDH or ECOG PS to find associations. The model cannot

control for other potential sources of bias which may have resulted in

physician preference for initial therapy such as disease stability or tumor

size given it was a retrospective analysis of nonrandomized data.

MAPKi Progression/Discontinuation:

193 pts discontinued MAPKi, 176 of which progressed.

30 pts on MAPKi despite progression.

Following discontinuation of MAPKi, median time elapsed

before death was 2.9 mo (CI 1.8-4.4 mo). Initial ECOG PS

and progression were significant hazards (data not shown).

Post MAPKi Ipilimumab:

40 of the 193 pts were subsequently treated with ipilimumab.

LDH and ECOG PS were elevated (Table 4).

Responses were poor (Table 5, Figure 4, Figure 5).

Due to clinical deterioration, 4 doses received in only 50% pts.

Table 4 Characteristics at Ipi initiation

Table 5 Post MAPKi Ipilimumab Outcomes

Figure 4 Post MAPKi Ipilimumab PFS

PFS 2.7 mo (CI 1.8-3.1 mo)

Figure 5 Post MAPKi Ipilimumab OS

Time (mo)

PF

S (

pro

babili

ty)

Conclusions This retrospective cohort analysis of a heterogeneous population can

only be hypothesis-generating. Our review of experience with MAPKi

before and after immunotherapy provides the following insights:

1. In appropriately selected patients immunotherapy should be

considered prior to targeted agents.

2. Although confounding bias cannot be excluded, prior treatment with

immunotherapy does not adversely influence response to MAPKi.

3. Outcomes to treatment with ipilimumab following MAPKi are poor. In

the setting of rapid deterioration, pts may not complete the full

course of an immunotherapy with delayed response.

4. A randomized control trial of ipilimumab versus vemurafenib with

crossover to determine the ideal sequence of therapies is being

planned through the Eastern Cooperative Oncology Group (E1612).

Concurrent therapy is also being explored (NCT01400451).

5. Clinical deterioration may be rapid following discontinuation of

MAPKi. In setting of post-MAPKi ipilimumab, prolonged OS is

primarily seen with resumption of MAPKi.

References

1. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N

Engl J Med. 2011 Jun 30;364(26):2507-16 2. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openl abel,

phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65

3. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl

J Med. 2012 Sep 29. [Epub ahead of print]

4. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. N Engl J Med. 2012 Feb 23;366(8):707-14.

5. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma:

analysis of 270 patients treated between 1985 and 1993. JCO 1999 Jul;17(7):2105-16.

6. Shahabi V, Whitney G, Hamid O,et al: Assessment of association between BRAF-V600E mutation status in melanomas and

clinical response to ipilimumab. Cancer Immunol Immunother. 2012 May;61(5):733-7. 7. Ribas, A, Kim KB, Schuchter LM, et al: BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously

treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol 29: 2011

8. Sosman JA, Kim KB, Schuchter L, et al: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N

Engl J 2012 Feb 23;366(8):707-14

IT initially (N=32)

MAPKi initially (N=242)

Total (N=274) p-value

MAPKi

Vem 27 92 119 0

Dab 0 99 99

Dab/Trem 5 51 56

ECOG PS

0 14 135 149 0.544

1 14 83 97

2 3 17 20

3/4 1 7 8

Stage

III 0 6 6 0.689

IVA 4 19 23

IVB 2 21 23

IVC 24 191 215

LDH

normal 29 141 170 0

elevated 1 87 88

Brain Mets

yes 2 51 53 0.186

no 23 188 264

IT initially (N=32)

MAPKi initially (N=242)

Total (N=274)

Response

CR 0 9 9

PR 17 144 161

SD 7 54 61

PD 6 26 32

Progression on MAPKi

No 11 57 68

Yes 21 185 206

Off MAPKi

No 13 68 81

Yes 19 174 193

Death

No 17 113 130

Yes 15 129 144

274 pts in analysis

IT initially MAPKi initially

242 pts MAPKi

(92 pts Vem, 99 pts Dab, 56 pts Dab/MEKi)

33 pts Ipi

4 pts PD-1

14 pts MAPKi

2 pts CT, 1 pts mult

7 pts E7080

32 pts IT

(15 pts IL-2, 10 pts Ipi, 6 pts IL-2+mAb, 1pt

PD-1)

27 pts Vem

5 pts Dab/MEKi

3 pts Vem

1 pt MEKi

1 pt BRAFi/MEKi

1 pt Vem, 1 pt PD-1

1 pt E7080 -> Vem

1 pt E7080

2 pt PD-1

2 pt BRAF-DT

1st line

2nd line

7 pts Ipi

OS 5.0 mo (CI 3.0-8.8 mo)

long term survivors all treated with additional MAPKi

OS

(p

robab

ility

)

Time (mo)

Table 3 Cox Proportional Hazards Model of MAPKi PFS and OS

Post MAPKi Ipi (N=40)

ECOG PS

0 8

1 9

2 8

3/4 2

LDH

normal 11

elevated 16

Post MAPKi Ipi (N=40)

Response

CR 0

PR 0

SD 2

PD 34

Progression on Ipi

No 4

Yes 36

#Doses received

1 6

2 8

3 6

4 20

Death

No 16

Yes 24

Figure 3 MAPKi OS

IT initially OS 19.6 mo (CI 10.0- mo)

MAPKi initially OS 13.4 mo (CI 10.1-17 mo)

p-value 0.40, log rank

MAPKi Initially

IT Initially

OS

(pro

babili

ty)

Time (mo)

PF

S (

pro

babili

ty)

Time (mo)

MAPKi Initially

IT Initially

PFS HR p values OS HR p values

MAPKi vs IT initially 0.8 0.38 0.9

Dabrafenib vs Vemurafenib 1.4 0.07

Dabrafenib/MEKi vs Vemurafenib 1.1 0.77

Elevated LDH 1.7 0.01

Presence of Brain Mets 1.1 0.60

ECOG PS 1 2.0 0.00

2 2.2 0.03

3/4 49 0.00

Stage IVA 1.3 0.63

IVB 0.9 0.79

IVC 1.6 0.32

Ackerman et al. Cancer 2014

BRAF-targeted therapy is usefulafter ipilimumab (or high-dose IL-2),ipilimumab is not particularly usefulafter BRAF-targeted therapy







Immunotherapy BRAF-targeted therapy

Overall survival improved in patientstreated with ipilimumab firstcompared with those treated withBRAF inhibitors first.

Ascierto et al. ASCO 2013








Anti-PD1 therapy BRAF-targeted therapy

Treatment RR PFS (med) OS (med/2-yr)

Single-agent BRAFi 50% 6-8 mo 18.7 mo / ~40%

Combo BRAFi & MEKi 65-70% 10-12 mo 26 mo / 53%

Ipilimumab (IPI) 10% 2-3 mo 12 mo / 30+%(20% 5 yr survival)

Anti-PD1 mAb(NIVO or PEMBRO)

40-45% ~5-7 mo ~ 32-36+ mo / ~55-60%

Combo IPI & NIVO ~60% 11-12 mo UNK / 64%


Treatment RR PFS (med) OS (med/2-yr)

Single-agent BRAFi 50% 6-8 mo 18.7 mo / ~40%

Combo BRAFi & MEKi 65-70% 10-12 mo 26 mo / 53%

Ipilimumab (IPI) 10% 2-3 mo 12 mo / 30+%(20% 5 yr survival)

Anti-PD1 mAb(NIVO or PEMBRO)

40-45% ~5-7 mo ~ 32-36+ mo / ~55-60%

Combo IPI & NIVO ~60% 11-12 mo UNK / 64%








COMBI-D/V PFS

Schadendorf et al. Eur J Cancer 2017









Flaherty et al. NEJM 2010

Baseline Week 12

Sullivan and Flaherty. Clin Cancer Res 2015

Baseline Week 3

Chapman et al. NEJM 2015









Johnson et al. J Immunother. 2017


Variable Anti-PD-1 first (n=56) BRAFi first (n=58) p-value

Number (%) Number (%)

Brain Metastases

Yes 5 (9) 14 (24) 0.05

Lactate Dehydrogenase

Normal 40 (74) 27 (54) 0.05

Anti-PD-1 agent

Nivo or pembro 34 (61) 53 (92)

<0.001Atezolizumab 3 (5) 3 (5)

Ipi + Nivo 19 (34) 2 (3)

BRAF inhibitor

BRAFi monotherapy 13 (23) 26 (45)

*BRAFi + MEKi 9 (16) 32 (55)

None 34 (61) 0

Prior therapy

Prior ipilimumab 12 (21) 16 (28)

0.86Prior IL-2 12 (21) 12 (21)

Prior chemotherapy 3 (5) 4 (7)

BRAF targeted therapy after progression on anti-PD1/PDL1 therapy is not particularly effective









Improving patient selection for BRAF/MEKi therapy

is a major unmet need

PFS

Long et al. Lancet 2015

Miller and Oudin et al. Cancer Discovery 2016

How does this work?

Does this make sense?

Genetic mechanisms of acquired resistance are

diverse

Multiple genetic ways of reactivating the MAPK

pathway

Shi et al. Cancer Discovery 2014

Mechanisms of intrinsic resistance are less diverse

One of the major drivers of intrinsic

resistance seen in AXL-high at baseline

Konieczkowski et al. Cancer Discovery 2014

Where do we go from here?

• Analytical development in CLIA-certified lab

• Clinical validation in larger sample set

• Develop trials incorporating the assay

BRAF mutant melanoma (Stage IV)

2-4 weeks of BRAF-targeted therapy

Biomarker Reassuring:Continue BRAF-targeted therapy

Biomarker Concerning:“Triplet” Therapy





1. Increase antigen expression 2. Decreased immunosuppresive cytokine production

3. Increase CD8+ T-cell infiltration

4. Increase T-cell clonality (Adaptive Biotechnologies) 5. Increased PD-L1 expression

BRAFi effects on tumor microenvironment predict optimal combination is with anti-PD1/PDL1 inhibition

Frederick et al. Clin Cancer Res 2013

Cooper et al Cancer Immunol Res 2014

Preclinical data predicts synergy between MAPK targeting and PD1/PDL1 inhibition

↑ MHC and melanoma antigen expression3

Antitumor activity of combined BRAFi+MEKi plus

anti-PD-13

Hu-Lieskovan et al. Sci Transl Med 2015.

Screening Atezo + Vem combinationVem run-in

C1 C2+Up to 28 d

Vem (PO BID)960 mg 720 mg 720 mg

Atezo (IV q3w)

starting C1D115 mg/kg

Screening Atezo + Vem combination (concurrent start)

C1 C2 C3 C4+Up to 28 d

Vem (PO BID)

Atezo (IV q3w)

720 mg

20 mg/kg

Cohort 1

Cohort 2

Screening Atezo + Vem combinationVem run-in

960 mg 720 mg 720 mg

Atezo (IV q3w)

starting C1D11200 mga

C2 C3+Up to 28 d 28 d C1

Vem (PO BID)

Cohort 3

56 d

All N = 17

Concurrent atezo + vem

Staggered atezo + vem

C1n = 3

C2n = 8

C3n = 6

Median safety follow-up, mo 12.3 6.5 10.6 14.2

All treatment-emergent AEs 100% 100% 100% 100%

Grade 3 atezo-related AEs 41% 67% 38% 33%

Grade 3 vem-related AEs (during combination period)

59% 100% 50% 50%

Hamid et al. SMR 2015

Best overall response (confirmed, RECIST v1.1)

• 16/16 (100%) patients evaluable for tumor response had reduction in target lesionsa

Maxim

um

SLD

reductio

n fr

om

baselin

e, %

-100

-80

-60

-40

-20

20

40

0

Complete response

Partial response

Stable disease

Progressive disease

Time on study, mo

Ch

an

ge

in S

LD

fro

m b

ase

lin

e, %

Progressive disease

PR/CRa

Stable disease

Discontinued study

New lesion

Vemurafenib plus atezolizumab

Screening

Atezo + Cobi + Vem

Atezo 800 mg, cobi 60 mg, vem 720 mg

Cobi + Vem

Days1-21: Cobi 60 mg,

vem 960 mg

Days 22-28: Vem 720 mg

C1Up to 28 d 28 days C2+

Atezo (IV q2w)800 mg

Vem (PO BID)960 mg 720 mg

Cobi (PO QD, 21/7)60 mg

Best Objective Response

(RECIST v1.1)

N = 38

n (%) 95% CI

ORRa 31

(81.6%)65.7, 92.3

CR7

(18.4%)7.7, 34.3

PR24

(63.2%)46.0, 78.2

SD 3 (7.9%) 1.7, 21.4

PD 2 (5.3%) 0.6, 17.8

NEb 2 (5.3%) −

Vem/Cobi/Atezo

Sullivan et al. SMR 2016; updated ASCO 2017

Safety Summary

Safety during triple combination N = 39; n (%)

Treatment-emergent AEs during combination period

All grade atezo- and/or cobi- and/or vem-related AEs 37 (95%)

Grade 3-4 atezo- and/or cobi- and/or vem-related AEs 16 (41%)

Grade 3-4 atezo-related AEs 11 (28%)

Treatment-related SAEs 6 (15%)

All treatment discontinuations 6 (16%)

• The triple combination treatment was generally well tolerated; no

unexpected AEs occurred

• No Grade 5 AEs occurred

• All AEs were manageable and reversible with dose interruption

and/or reduction

• Treatment-related SAEs:

• All six patients continued with treatment after study drug

interuption

All-Grade AEs

(≥ 20% incidence)

N = 39

n (%)

Arthralgia 19 (48.7)

Diarrhea 17 (43.6)

AST increased 16 (41)

Fatigue 16 (41)

Photosensitivity reaction 16 (41)

Nausea 16 (41)

Pyrexia 15 (38.5)

ALT increased 14 (35.9)

Pruritus 14 (35.9)

Influenza-like illness 11 (28.2)

Rash - maculopapular 10 (25.6)

Grade 3-4 AEs^^N = 39

n (%)

ALT increased 5 (12.8)

AST increased 4 (10.3)

Hypophosphatemia 3 (7.7)

Blood creatinine phosphokinase

increased2 (5.1)

Diarrhea 2 (5.1)

Blood bilirubin increased 2 (5.1)

Rash 2 (5.1)

^^1 each of the following: Nausea, vomiting, stomatitis, pyrexia, lubmar spinal stenosis, hyponatremia, anemia, bilateral UE rash, sepsis, hypertension, autoimmune hepatitis, diverticulitis


Summary of Vem/Cobi/Atezo

• Atezo + cobi + vem treatment is relatively safe

• The triple combination demonstrated promising

antitumor activity

− Unconfirmed response rate was 81.6%

• Increased tumor CD8+ T-cell accumulation

after cobi + vem treatment may result in

enhanced immunotherapy responsiveness and

supports the mechanistic rationale for this

study

• A dosing schedule that includes a cobi and

vem lead-in was safe and efficacious, and

merits further investigation

• A Phase III study evaluating atezo +

cobi + vem vs placebo + cobi + vem

in patients with BRAF V600 mutant

advanced melanoma is planned

(NCT02908672)

• Key study objectives

− Primary: investigator-assessed

PFS

− Secondary: PFS (IRF-assessed),

OS, ORR, DOR, Safety, PK

R 28 days Treatment until PD or toxicity

Previously Untreated

Advanced Melanoma

• BRAF V600 mutation

• ECOG PS 0-1

• Measurable disease

• No significant history of liver disease

N = 500

Vem 960mg BIDa

Cobi 60mg QDb

Atezo 840mg q2wVem 720mg BID + Vem Placebo 240mg BID

Cobi 60mg QDb

Vem 960mg BIDa

Cobi 60mg QDb

Placebo q2wVem 960mg BID

Cobi 60mg QDb


Conclusions

Great successes with combined BRAF/MEK inhibition

However there is a mandate to do better for our patients…

Obrigado!

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