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
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
……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
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
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
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
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