Update su terapie targeted e immunologiche nel melanoma

(1)

Update su terapie targeted e

immunologiche del melanoma

Francesco Spagnolo

IRCCS Ospedale

Policlinico San Martino

(2)

Melanoma avanzato oggi (pratica clinica)

• Espressione PD-L1 non richiesta per trattamento con anti-PD-1

• Indicazione al trattamento fino a progressione o tossicità inaccettabile

• Ritrattamento/Rechallenge non rimborsabile

• Nivolumab+ipilimumab non rimborsabile

Genomic Classification of Cutaneous Melanoma The Cancer Genome Atlas Network. Cell 2015

Biomarkers

(3)

Robert et al. NEJM 2019

(4)

Robert et al. NEJM 2019

(5)

Robert et al.

NEJM 2019

(6)

(7)

COLUMBUS PHASE 3 TRIAL: UPDATED OVERALL SURVIVAL

ASCO 2019 39%

25%

(8)

STUDY ORR (CR rate)

Median PFS coBRIM (Vemu+cobi)

Ascierto Lancet 2016 ASCO 2018

70%

(16%)

12.3 months Combi-d/Combi-v (D+T)

Robert NEJM 2019

68%

(17%)

12.0 months Columbus (Enco+bini)

Dummer ASCO 2019

75%

(16%)

14.9 months

Data reported only for combination therapy

Summary of phase 3 clinical trials

Clinical Activity

Efficacy Safety

Discontinuation rate 14%

9-15%

12%

Median OS

4-year OS

5-year OS 22.5

months

35% NA

25.9 months

37% 34%

33.6 months

39% NA

Raised LDH

M1c

46% 59%

35% 64%

29% 64%

Study Population

Anti- PD-1

17%

9%

23%

Post-

PD Tx

(9)

Most Frequent adverse events - Summary

Drug Adverse Event

Dabrafenib+Trametinib (Combi-d)

Fever

(51%) Fatigue

(35%) Headache

(30%) Nausea

(30%) Chills (30%) Vemurafenib+Cobimetinib

(CoBrim)

Diarrhea

(56%) Nausea

(40%) Rash

(38%) Photosensitivity

(28%) Vomiting (21%) Encorafenib+Binimetinib

(Columbus)

Nausea

(42%) Diarrhea

(37%) Vomiting

(30%) Arthralgia (26%)

increased CPK (23%)

• Some toxicities are common to all BRAF+MEK inhibitors combos

• Photosensitivity and diarrhea are common with vemurafenib+cobimetinib but rare with dabrafenib+trametinib, while fever and chills are common with dabrafenib+trametinib

The type and severity of these toxicities vary considerably

and may influence choice of drug

(10)

Robert et al.

Lancet Oncol 2019

5 y OS: 39%

4 y PFS: 23%

(11)

Robert et al. Lancet Oncol 2019

(12)

Hodi et al. Lancet Oncology 2018

(13)

53%

46%

30%

58%

51%

34%

37%

31%

9%

39%

32%

10%

Hodi et al. Lancet Oncology 2018

(14)

Lebbè et al. JCO 2019

(15)

Lebbè et al. JCO 2019

(16)

CheckMate-067

Higher survival plateau

Targeted therapy Higher early benefit

53%

46%

30%

Hodi et al. Lancet Oncology 2018 58%

51%

34%

(17)

Ascierto et al. Nature Medicine 2019

(18)

• More patients had grade 3-4 treatment-related AE

• ORR was similar in the two arms, but more CR were

observed in the experimental arm

• The duration of response was longer

• PFS did not reach statistical significance due to the small sample size (i.e. study was underpowered)

• In terms of PFS, triplet combination did better

compared to targeted therapy alone in patients with poor prognostic features

• At a median follow-up of 9.6 months, no significant

differences in OS were noted

WHAT WE HAVE LEARNT FROM KEYNOTE-022 TRIAL

Ascierto et al. Nature Medicine 2019

(19)

ONGOING PHASE III TRIALS WITH

«TRIPLETS»

IN BRAF- MUTANT PATIENTS

COMBI-I

TRILOGY

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Sequential Combo Immuno and Target Therapy Study (SECOMBIT)

EORTC-1612-MG: Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With

Encorafenib and Binimetinib (EBIN)

Patients with BRAF-

Mutant Melanoma

n=270

Primary endpoint:

OS

Primary endpoint:

PFS

Randomization

Nivolumab + low- dose ipilimumab q3w for 4 injections

Nivolumab 480 mg q4w for 2 years or until PD

Encorafenib 450

mg QD +

binimetinib 45 mg BID for 12 weeks

Nivolumab + low- dose ipilimumab q3w for 4 injections

1 week

Nivolumab 480 mg q4w for 2 years or until PD

EVALUATION OF TARGETED THERAPY IN

SEQUENCES WITH

IMMUNOTHERAPY

(21)

Targeted therapy plus immunotherapy in patients with brain metastases

TRICOTEL Trial: Study design

(22)

Overview of recent adjuvant trials

Study

Patients

N

Stage

Primary Endpoint

Treatment Experimental

arm

Control Duration

CA184-029/

EORTC 18071

1211 IIIA (>1 mm)/IIIB/IIIC

RFS Ipilimumab Placebo 3 years

COMBI-AD 852 IIIA (>1 mm)/IIIB/IIIC

RFS Dabrafenib + trametinib

Placebo 1 year

CA209-238 800 IIIB/IIIC/

resected IV

RFS Nivolumab Ipilimumab 1 year

KEYNOTE-054 900 IIIA (>1 mm)/IIIB/IIIC

RFS Pembrolizumab Placebo 1 year

Approved by the FDA in 2017 and EMA in 2018

Approved by EMA

in 2018 and the

FDA in 2019

Approved by the

FDA in 2015

(23)

Primary endpoint: RFS

(24)

Slide 7

Presented By Jeffrey Weber at 2018 ASCO Annual Meeting

HR: 0.66

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Subgroup Analysis of RFS: 5% PD-L1 Expression Level

(26)

Subgroup Analysis of RFS: BRAF Mutation Status

(27)

Subgroup Analysis of RFS: Disease Stage III and IV

(28)

Keynote 054: Pembrolizumab vs Placebo

(29)

Eggermont et al. NEJM 2018

75.4%

61.0%

71.4%

53.2%

RFS

HR: 0.57

(30)

Eggermont et al. NEJM 2018

DMFS

HR: 0.53

(31)

Checkmate-915

Primary Endpoint: DFS

Emendamento per sample size fino a 2000 pazienti

(32)

(33)

Primary end point: relapse-free survival

Haushild et al. JCO 2019

HR, 0.49 (95% CI, 0.40 to 0.59)

(34)

Stage IIIA Stage IIIB

Stage IIIC Stage IIID

Haushild et al. JCO 2019

Relapse-free survival by stage (8

^th

ed.)

(35)

Secondary end point: overall survival

Long et al. NEJM 2017

86%

77%

91%

83%

97%

94%

Δ=3%

Δ=8%

Δ=9%

(36)

Adjuvant setting: summary

Study Treatment Stage HR for RFS HR for

OS Interferon

meta-analysis

Interferon different regimens

IIB -> IIIC 0.82

vs placebo

0.89 CheckMate- 029

Ipilimumab Placebo

IIIA (>1

mm)/IIIB/IIIC

0.76 vs placebo

0.72 CheckMate- 238

Nivolumab

Ipilimumab IIIB/IIIC/resected IV 0.65

vs ipilimumab

Not

available Keynote-054 Pembrolizumab

Placebo

IIIA (>1 mm)/

IIIB/IIIC

0.57 vs placebo

Not

available

Combi-AD Dabrafenib+trameti nib

Placebo

IIIA (>1 mm)/

IIIB/IIIC

0.49 vs placebo

0.57

(37)

Eggermon et al. Nature Reviews Clinical Oncology 2018

Kaplan–Meier

curves of estimated RFS in key trials of adjuvant therapies

for melanoma

(38)

Melanoma adjuvant setting

Stage IIB/C

Ulcerated primary

Non- ulcerated

primary

Interferon

Observation

(39)

Efficacy of interferon by ulceration

Ives et al. European Journal of Cancer 2017

HR: 1.02 (CI 0.87- 1.20)

HR: 0.77

(CI 0.64-

0.92)

(40)

(41)

Melanoma adjuvant treatment

Stage IIB/C

Ulcerated primary

Non- ulcerated

primary

Interferon

Observation

Stage III

BRAF V600 BRAF wild- type

BRAF+MEKi

Anti-PD-1

(42)

Long-lasting

Eggermont ESMO 2018

(43)

Verver et al. EJC 2018 Van Akkoi et al. Ann Surg 2008

Low burden stage III disease

(44)

Melanoma adjuvant treatment

Resected Stage IV

Anti-PD-1

Stage IIB/C

Ulcerated primary

Non- ulcerated

primary

Interferon

Observation

Stage III

BRAF V600 BRAF wild- type

BRAF+MEKi

Anti-PD-1

(45)

Why shall we go for neoadjuvant therapy?

1) Therapy efficacy can de determined within the individual patient for possible additional adjuvant therapy

2) Reduce tumor burden before surgery

3) Utilize pathological response data as surrogate outcome markers for relapse free and overall survival

4) In the case of T cell checkpoint blockade neoadjuvant therapy could induce stronger and broader tumor-specific T cell

response

(46)

(47)

Amaria et al. Lancet Oncology 2018

Relapse-free survival

Distant metastasis-free

survival

(48)

OpACIN-neo trial

Pathological response

• Arm A: 80% with 47% of pCR

• Arm B: 77% with 57% of pCR

• Arm C: 65% with 23% of pCR

Toxicity (Grade 3-4)

• Arm A: 40%

• Arm B: 20%

• Arm C: 50%

Rozeman et al. Lancet Oncology 2019

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