• Non ci sono risultati.

Il punto di vista dell’esperto

N/A
N/A
Protected

Academic year: 2022

Condividi "Il punto di vista dell’esperto"

Copied!
44
0
0

Testo completo

(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

Riferimenti

Documenti correlati

Casi di mielodeppressione, con leucopenia, trom- bocitopenia o pancitopenia, sono stati osservati so- lo raramente nell’AIG trattata con gli anti-TNF, anche se sono stati tra i

Complementary and alternative therapy can be sepa- rated into five categories: (a) alternative medical sys- tems, (b) mind-body interventions, (c) biologically- based treatments,

Table 1 (Continued ) Author , year Study location Study period Study description Testing venue Target population Interventio ns Feasibility/ acceptabilit y Economic evaluation

The only previously published work, to our knowledge, addressing MMR gene mutation frequencies in Sardinia, did not include testing for large deletions.24 The high frequency of

This emerges with particular clearness from the comparison between the statuses provided to third-country nationals legal migrants and the Union citizenship: an individual are

tieri quanto dovuto per conservare i propri capelli e Condalo poté riscuotere mol- to denaro. Solitamente, l’epikephalaion rappresentava un testatico, ma in questa

(www.moldiscovery.com). Four chromatographic lipophilicity indexes were measured. The following stationary phases were used: a) Supelcosil TM LC-ABZ alkylamide column;