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(1)

V. Ferraresi

Divisione di Oncologia Medica 1

Il parere dell’esperto

Melanoma

(2)

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

(3)

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

(4)

ESMO 2017 and MELANOMA

IPI10 vs NIVO3

DABR+TRAM vs placebo

VEM vs placebo

(5)
(6)

OS data immature

COMBI-AD

CA 209-038

BRAF mutated pts: about 40%

(7)

SUBGROUP ANALYSES

COMBI-AD CA 209-038

(8)

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

(9)

Only IIIB/IIIC patients

(10)

Checkmate-238

Nivolumab vs Ipilimumab

(11)

……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….??

(12)

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….

(13)

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??

(14)

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

(15)

17

CheckMate 067 (ESMO2017)

(16)

CheckMate 067 (ESMO2017)

(17)

CA 209-067

BRAF mutated pts: 31-32%

(18)

CA 209-067

(19)

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

(20)

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?

(21)

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

Teng MWL, Cancer Research 2015

~40% ~40%

~20% ~1%

(22)

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 cells

1

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

2,3

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.

(23)

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 TRAE

b

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 TRAE

b

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)

Myocarditis

c

2 (0.7) 0

Pyrexia 2 (0.7) 0

Any TRAE leading to

discontinuation

b

11 (4.1) 8 (3.0)

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

t

(24)

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 percent c han ge in sum of target lesion d iameters from b aseline

a,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

(25)

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

ECHO-202/KEYNOTE-037

(26)
(27)

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

(28)

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

(29)
(30)

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

(31)

(1% due to tox)

(32)
(33)
(34)

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

(35)

TARGETED THERAPIES AND IMMUNOTHERAPIES HOW TO USE THESE AGENTS TOGETHER?

SEQUENCES???

 after progression?

 at predefinite time?

CONCURRENT COMBINATIONS???

METASTATIC MELANOMA

BRAF MUTATED DISEASE

(36)

BRAF inhibitors and immune system

(37)
(38)
(39)
(40)
(41)

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].

(42)

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

(43)

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: Truth is different than perception Perceptions...

• 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

(44)

Grazie

Melanoma treatment

Figure

Updating...

References

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