V. Ferraresi Divisione di Oncologia Medica 1

Il parere dell’esperto

Melanoma

MELANOMA and ESMO 2017….what happens?

New data and updates

COMBO IMMUNO/TARGET THERAPIES

….the future……???

IMMUNOTHERAPY

…..two is always better than one??

….. the goal is (again) the CR!!

…. new targets!!

COMBO TARGET THERAPY (COLUMBUS) a confirmation

lesser toxicity?

ADJUVANT THERAPY with CHECKPOINT

INHIBITORS (CA209-238 trial) AND TARGET

THERAPY (BRIM8 and COMBI-AD trials)

….the immediate future

MELANOMA and ESMO 2017….what happens?

New data and updates

COMBO IMMUNO/TARGET THERAPIES

….the future……???

IMMUNOTHERAPY

…..two is always better than one??

….. the goal is (again) the CR!!

…new targets!!

COMBO TARGET THERAPY (COLUMBUS) a confirmation

lesser toxicity?

ADJUVANT THERAPY with CHECKPOINT

INHIBITORS (CA209-238) AND TARGET

THERAPY (BRIM8, COMBI-AD)

…..the immediate future

ESMO 2017 and MELANOMA

IPI10 vs NIVO3

DABR+TRAM vs placebo

VEM vs placebo

OS data immature

COMBI-AD

CA 209-038

BRAF mutated pts: about 40%

SUBGROUP ANALYSES

COMBI-AD CA 209-038

EORTC 18071

No stratification according to BRAF status

HR= 0.86, CI 0.81-0.91; P < 0.00001

HR = 0.90, CI 0.85-0.97; P = 0.003

Only IIIB/IIIC patients

Checkmate-238

Nivolumab vs Ipilimumab

……Is adjuvant checkpoint blockade after resection necessary or it should

be reserved wiht the hope of equal benefit for patients who have a relapse

with unresectale disease after surgery for stage III or IV melanoma….??

An Investigational Immuno-therapy Study of Nivolumab Combined With

Ipilimumab Compared to Nivolumab by Itself After Complete Surgical

Removal of Stage IIIb/c/d or Stage IV Melanoma (NCT 03068455)

CheckMate 915

IPI alone arm eliminated

Recruiting

Italy partecipation pending….

MELANOMA ADJUVANT THERAPY with CHECKPOINT INHIBITORS AND TARGET THERAPY

BRAF inhibitors alone: is there a future…???

BRAFi/MEKi combo (COMBI-AD trial): clear RFS, DMFS and OS benefit

in all stages. The new “standard” for BRAF mutated patients?

anti-PD1: Pending OS data

q2wks NIVO vs q3wks flat PEMBRO

End of adjuvant IPI10mg/kg (FDA approval): more toxic and less active

than NIVO, “light dose” in combo with NIVO in ongoing trials

Differences in population characteristics (stage, BRAF status):

comparisons methodologically not correct

ESMO 2017

Neoadjuvant + adjuvant treatment with combo immuno or combo

target therapy

high % of ORR (80-100%) and pCR (40-50%)

improve locoregional control??

avoid TLND in pts with palpable nodes??

MELANOMA and ESMO 2017….what happens?

New data and updates

COMBO IMMUNO/TARGET THERAPIES

….the future……???

IMMUNOTHERAPY

…..two is always better than one??

….. the goal is (again) the CR!!

…. new targets!!

COMBO TARGET THERAPY (COLUMBUS) a confirmation

lesser toxicity?

ADJUVANT THERAPY with CHECKPOINT

INHIBITORS (CA209-238 trial) AND TARGET

THERAPY (BRIM8 andCOMBI-AD trials)

…..the immediate future

17

CheckMate 067 (ESMO2017)

CheckMate 067 (ESMO2017)

CA 209-067

BRAF mutated pts: 31-32%

CA 209-067

Three-year overall survival data based on PD-L1 expression using

time-dependent ROC for censored survival data

Area- under-the-curve values, as compared with 0.5 (the line of no discrimination), were 0.56

(95% CI, 0.49 to 0.63) in the nivolumab-plus-ipilimumab group (P = 0.09) and 0.57 (95% CI,

0.50 to 0.63) in the nivolumab group (P = 0.04), which indicate that the level of tumor PD-L1

expression alone is a poor predictive biomarker of overall survival

PD-L1: starting point for discussion with patients for combo IPI/NIVO

versus NIVO (if we don’t need the “response” to palliate symptoms

and if you have “favorite” sites of disease……)

BRAF mutation status and combo immunotherapy IPI/NIVO:

we need more data on patients’ characteristics (bias of selection?)

no head-to-head comparison versus combo target therapy

role of subsequent lines of therapy

toxicity as a point for discussion with patients (% G3-4 toxicities)

NIVOLUMAB/IPILIMUMAB combo

What to say……awaiting the regimen?

Classifying Cancers Based onT-cell Infiltration and PD-L1 - Melanoma

Teng MWL, Cancer Research 2015

~40% ~40%

~20% ~1%

Potential Role of LAG-3 in T-Cell Exhaustion and Anti–PD-1 Resistance

34

PD-L1

LAG-3

MHC II Effector

CD4+/CD8+

T cell

Acquired

resistance

Tumor or other

infiltrating cell

+ Antigen

PD-1

PD-1

LAG-3 MHC II

PD-L1

PD-1

+Nivolumab + Nivolumab

+ Relatlimab

+ Nivolumab

+ Relatlimab

I-O therapy naive:

LAG-3 may limit I-O

response

I-O therapy

experienced:

LAG-3 may contribute

to resistance

• LAG-3 regulates a checkpoint pathway that limits the activity of T cells1

• LAG-3 and PD-1 receptors are overexpressed and/or co-expressed on tumor-infiltrating lymphocytes in melanoma2,3

Nivolumab

Relatlimab

(BMS-986016/anti–LAG-3)

I-O, immuno-oncology; MHC II, major histocompatibility complex class II; PD-1, programmed death-1; PD-L1, programmed death ligand 1.

1. Grosso JF et al. J Clin Invest. 2007;117:3383‒3392. 2. Goding SR et al. J Immunol. 2013;190:4899–

4909. 3. Taube JM et al. Clin Cancer Res. 2015;21:3969–3976.

Relatlimab (anti-LAG3) + Nivolumab

35

Mel Prior PD-(L)1a

All

n = 61

LAG-3 ≥ 1%b

n = 33

ORR, n (%)c

95% CI 7 (11.5)d

4.7, 22

6 (18)d

7, 35.5

BOR, n (%)c

CR 1 (1.6) 1 (3.0)

PR 6 (9.8)d 5 (15)d

SD 23 (38) 15 (45)

PD 25 (41) 8 (24)

Clinical progressione 6 (9.8) 4 (12)

DCR (CR + PR + SD), n (%)c

95% CI 30 (49)

36, 62

21 (64)

45, 80

PD1/PD-L1 resistant patients (46% PD as

best response, 77% > 2 prior lines)

LAG-3 expression (≥ 1%) enriched for response

Median duration of response was not reached

(range, 0.1+ to 39+)

All Patientsa

N = 270

Any

Grade

n (%)

Grade 3–

4

n (%)

Any TRAEb 137 (51) 27 (10)

TRAEs in ≥ 5% of patients

Fatigue 30 (11) 0

Pruritus 19 (7.0) 0

Diarrhea 18 (6.7) 3 (1.1)

Arthralgia 17 (6.3) 0

Infusion-related reaction 15 (5.6) 0

Any serious TRAEb 18 (6.7) 12 (4.4)

Serious TRAEs in > 1 patient

Colitis 4 (1.5) 3 (1.1)

Pneumonitis 2 (0.7) 2 (0.7)

Myocarditisc 2 (0.7) 0

Pyrexia 2 (0.7) 0

Any TRAE leading to discontinuationb 11 (4.1) 8 (3.0)

PD-1/PD-L1 resistant/refractory melanoma pts t

37

Pink: PD-L1 ≥ 1% Blue: PD-L1 < 1% Gray: PD-L1 unknown

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

37

45% with

tumor

reduction

24% with

tumor

reduction

13% with

tumor

reduction

Best

perc

en

t c

han

ge i

n s

um

of

targ

et

lesio

n d

iam

ete

rs f

rom

baselin

ea,b

aSix patients with clinical progression prior to their first scan and 1 with PD due to a new symptomatic brain metastasis prior to getting full

scans were not included. bOne patient with best change from baseline > 30% had a best response of SD.

LAG-3 ≥ 1% n = 29

LAG-3 < 1% n = 17

LAG-3

Unknown n = 8

RELATLIMAB – PD-1/PD-L1 resistant/refractory melanoma pts

Best Change in Target Lesion Size by LAG-3 and PD-L1 Expression

BRAF mut: 29%; M1c; 55%; Liver: 40%

ECHO-202/KEYNOTE-037

ECHO-301/KEYNOTE 352 phase III trial ongoing (fully accrued)

MELANOMA and ESMO 2017….what happens?

New data and updates

COMBO IMMUNO/TARGET THERAPIES

….the future……???

IMMUNOTHERAPY

…..two is always better than one??

….. the goal is (again) the CR!!

… . new targets!!

COMBO TARGET THERAPY (COLUMBUS) a confirmation

lesser toxicity?

ADJUVANT THERAPY with CHECKPOINT

INHIBITORS (CA209-238 trial) AND TARGET

THERAPY (BRIM8 andCOMBI-AD trials)

……the immediate future

BRAF + MEK Inhibitor Combination Treatment Phase 3 Studies: Adverse Events of Special Interest

COMBI-d1 COMBI-v2 coBRIM3

Study Agent(s) Dabrafenib + Trametinib

Dabrafenib Dabrafenib + Trametinib

Vemurafenib Vemurafenib +

Cobimetinib Vemurafenib

Patients, n (study arm) 209 211 350 349 254 239

AEs of interest, %

CuSCC/KA 2 9 1 18 3 11

Skin papilloma 1 21 2 23 --- ---

Hyperkeratosis 3 32 4 25 10 28

Photosensitivity reaction --- --- 4 22 28 15

Decreased ejection fraction 4 2 8 0 7 3

Hypertension 22 14 26 24 --- ---

Chorioretinopathy < 1 < 1 1 < 1 12 < 1

Hand-foot syndromeb 5 27 4 25 --- ---

Increased ALT 11 5 14 17 24 18

Increased AST 11 3 11 13 22 13

Retinal detachment --- --- --- --- 8 0

QT interval prolongation --- --- --- --- 4 5

COLUMBUS ESM0 2017

- Lower incidence of pyrexia and dermatological toxicity - Higher incidence of hepatic toxicity not confirmed in phase III trial

(1% due to tox)

MELANOMA and ESMO 2017….what happens?

New data and updates

COMBO IMMUNO/TARGET THERAPIES

….the future……???

IMMUNOTHERAPY

…..two is always better than one??

….. the goal is (again) the CR!!

…new targets!!

COMBO TARGET THERAPY (COLUMBUS) a confirmation

lesser toxicity?

ADJUVANT THERAPY with CHECKPOINT

INHIBITORS (CA209-238 trial) AND TARGET

THERAPY (BRIM8 andCOMBI-AD trials)

……the immediate future

TARGETED THERAPIES AND IMMUNOTHERAPIES

HOW TO USE THESE AGENTS TOGETHER?

SEQUENCES???

after progression?

at predefinite time?

CONCURRENT COMBINATIONS???

METASTATIC MELANOMA

BRAF MUTATED DISEASE

BRAF inhibitors and immune system

KEYNOTE022 Phase 2: Combination Pembrolizumab + Dabrafenib + Trametinib Study Design

Key eligibility criteria • Unresectable or metastatic

stage IV BRAF V600E/K–

mutant melanoma

• No prior therapy

• ECOG performance status

0-1

N = 120

Randomised 1:1

Pembrolizumab 2 mg/kg Q3W +

dabrafenib 150 mg BID +

trametinib 2 mg QD

Placebo Q3W +

dabrafenib 150 mg BID +

trametinib 2 mg QD

Treatment until disease

progression, intolerable toxicity,

investigator decision, or (for

pembrolizumab) 24 monthsa

Primary endpoint: PFS

Secondary endpoints: ORR,

DOR, OS

Stratified by:

ECOG performance status (0 vs 1)

LDH: > 1.1 × ULN vs ≤ 1.1 × ULN

ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; ULN, upper limit of normal.

a Patients experiencing a confirmed CR after ≥ 6 months may discontinue pembrolizumab after receiving ≥ 2 doses beyond initial CR but may continue treatment with dabrafenib and trametinib.

Long GV, et al. J Clin Oncol. 2016;34(suppl) [abstract TPS9596].

Immunotherapies:

• Limited by non-responders

• Long-term plateau of OS

demonstrated for anti-CTLA4 and anti-PD-1

• Efficacy possible beyond discontinuation

• No condition identified for efficacy (PD-L1)?

Targeted therapies:

• Efficacy conditioned on mutation BRAF

• 3 years OS plateau demonstrated for D T

• Limited by resistance

• No clear demonstration that can be

discontinued

So far…

• No predictive marker for choice of frontline treatment

• No marker for safe discontinuation

• No marker for best selection of combination, or order of sequencing

(ONGOING TRIALS)

• Optimal scheduling for combo immunotherapies awaiting (IPI light )

Different Profiles of Treatment: Facts on Efficacy

Immunotherapies:

• “Natural”: exploit endogenous immune

system to eradicate cancer

• Slow

• Exclude fast progressions

• Long response

Targeted therapies:

• “Artificial”: precision/perzonalized medicine

• Fast

• More active in case of fast progression

• Resistance sooner or later

Different Profiles of Treatment: Perceptions....... Truth is different than perception

• All treatments are less active when the disease is

aggressive and fast (eg, high LDH)

• Anti-PD-1+CTLA4 inhibitors work nearly as fast as

targeted therapies

• Targeted therapies can provide very long survival

• Different profiles of toxicities (…and combo

TT/IT)

• What to do? AWAIT THE RESULTS OF CLINICAL

TRIALS!

• Outside an investigational trial we must still be

guided by patients and disease characteristics

Grazie

Melanoma treatment