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 cells
1• LAG-3 and PD-1 receptors are overexpressed and/or co- expressed on tumor-infiltrating lymphocytes in melanoma
2,3Nivolumab 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 TRAE
b137 (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
b18 (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
c2 (0.7) 0
Pyrexia 2 (0.7) 0
Any TRAE leading to
discontinuation
b11 (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 percent c han ge in sum of target lesion d iameters from b aseline
a,baSix 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].