Update su terapie targeted e immunologiche del melanoma

Update su terapie targeted e

immunologiche del melanoma

Francesco Spagnolo

IRCCS Ospedale Policlinico San Martino

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

Robert et al. NEJM 2019

COLUMBUS PHASE 3 TRIAL: UPDATED OVERALL SURVIVAL

ASCO 2019

39%

25%

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

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%)

CPK increased

(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

Robert et al. Lancet Oncol

2019

5 y OS: 39%

4 y PFS: 23%

Robert et al. Lancet Oncol 2019

Hodi et al. Lancet Oncology 2018

53%

46%

30%

58%

51%

34%

37%

31%

9%

39%

32%

10%


Lebbè et al. JCO 2019

CheckMate-067 Higher survival plateau

Targeted therapy Higher early benefit

53%

46%

30%


58%

51%

34%

Ascierto et al. Nature Medicine 2019

• 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

ONGOING PHASE III

TRIALS WITH «TRIPLETS»

IN BRAF-MUTANT PATIENTS

COMBI-I

TRILOGY

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

Targeted therapy plus immunotherapy in patients with brain metastases

TRICOTEL Trial: Study design

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

Primary endpoint: RFS

Presented By Jeffrey Weber at 2018 ASCO Annual Meeting

HR: 0.66

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


Subgroup Analysis of RFS: BRAF Mutation Status


Subgroup Analysis of RFS: Disease Stage III and IV


Keynote 054: Pembrolizumab vs Placebo

Eggermont et al. NEJM 2018

75.4%

61.0%

71.4%

53.2%

RFS HR: 0.57

Eggermont et al. NEJM 2018

DMFS HR: 0.53

Checkmate-915

Primary Endpoint: DFS Emendamento per sample size fino a 2000 pazienti

Primary end point: relapse-free survival

Haushild et al. JCO 2019

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

Stage IIIA Stage IIIB

Stage IIIC Stage IIID

Haushild et al. JCO 2019 Relapse-free survival by stage (8th ed.)

Secondary end point: overall survival

Long et al. NEJM 2017

86%

77%

91%

83%

97%

94%

Δ=3% Δ=8%

Δ=9%

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+trametinib Placebo

IIIA (>1 mm)/ IIIB/IIIC

0.49 vs placebo

0.57

Eggermon et al. Nature Reviews Clinical Oncology 2018

Kaplan–Meier curves of estimated RFS in key trials of adjuvant therapies

for melanoma

Melanoma adjuvant setting

Stage IIB/C

Ulcerated primary

Non-ulcerated primary

Interferon Observation

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)

Melanoma adjuvant treatment

Stage IIB/C

Ulcerated primary



Stage III

BRAF V600 BRAF wild-

type

BRAF+MEKi Anti-PD-1

Long-lasting Eggermont ESMO 2018

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

Low burden stage III disease

Melanoma adjuvant treatment

Resected Stage IV

Anti-PD-1

Stage IIB/C

Ulcerated primary



Stage III

BRAF V600 BRAF wild-

type

BRAF+MEKi Anti-PD-1

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

Amaria et al. Lancet Oncology 2018

Relapse-free survival

Distant metastasis-free survival

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

• IPI+NIVO: ORR 73%, pCR 45%, toxicity 73% grade 3 trAEs)

• NIVO: ORR 25%, pCR 25%, toxicity 8% grade 3 trAEs.

Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma

Amaria et al. Nat Med 2019

Update su terapie targeted e immunologiche del melanoma

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