Pier Francesco Ferrucci
Director, Melanoma Unit
Istituto Europeo di Oncologia - Milan
Recent News and Future Perspectives
in the Treatment of Melanoma
Supernovae in Oncologia Pisa, 29-30 September 2017
NEWS FROM ADJUVANT THERAPY - Anti-PD1 Vs anti-CTLA4
- Anti-CTLA4 + anti-PD1 combination Vs anti-PD1 Ongoing - Anti-PD1 Vs Placebo EORTC Keynote 054: closed, no data yet - Anti-BRAF + anti-MEK combination Vs Placebo
- Anti-BRAF Vs Placebo Roche BRIM 8
NEWS FROM THE METASTATIC SETTING:
- 3y OS and Safety con Combinazione anti-CTLA4 e anti-PD1
- Anti-BRAF + anti-MEK +/- anti-PD1or PDL1 Ongoing - Other Combinations and Sequences Ongoing
WHICH ROLE FOR SURGERY?
News From ESMO and Beyond: Agenda 2017
Adjuvant Setting: Immunotherapy
• Clinical Protocol CA209238:
A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Nivolumab versus Ipilimumab after Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects who are at High Risk for Recurrence
CA209-067: Study Design
CA209-238: Study Design
Patients with high-risk, completely resected stage IIIB/IIIC or stage
IV melanoma
Enrollment period: March 30, 2015 to November 30, 2015
Follow-up Maximum treatment duration of
1 year NIVO 3 mg/kg IV Q2W
and
IPI placebo IV Q3W for 4 doses then Q12W from week 24
IPI 10 mg/kg IV Q3W for 4 doses then Q12W from week 24
and
NIVO placebo IV Q2W 1:1
n = 453
n = 453
Stratified by:
1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells
Study Overview
Primary endpoint
– RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death
Secondary endpoints
– OS, Safety and tolerability
– RFS by PD-L1 tumor expression – HRQoL
Current interim analysis
– Primary endpoint (RFS), safety, and HRQoL – DMFS (exploratory)
– Duration of follow-up: minimum 18 months; 360 events
DMFS = distant metastasis-free survival; HRQoL = health-related quality of life
Primary Endpoint: RFS
RFS (%)
Months
0 10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
453 399 353 332 311 291 249 71 5 0
NIVO
453 364 314 269 252 225 184 56 2 0
IPI Number of patients at risk
NIVO IPI
NIVO IPI
Events/patients 154/453 206/453
Median (95% CI) NR NR (16.6, NR)
HR (97.56% CI) 0.65 (0.51, 0.83) Log-rank P value <0.0001
66%
53%
71%
61%
PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%
NIVO IPI
Events/patients 114/275 143/286
Median (95% CI) NR 15.9 (10.4, NR)
HR (95% CI) 0.71 (0.56, 0.91)
NIVO IPI
Events/patients 31/152 57/154
Median (95% CI) NR NR
HR (95% CI) 0.50 (0.32, 0.78)
Analysis of RFS by PD-L1 Expression Level
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
275 242 204 189 171 159 129 41 3 0
NIVO
286 219 184 153 139 124 100 31 2 0
IPI
Number of patients at risk
RFS (%)
Months
152 135 130 125 122 114 105 26 2 0
NIVO
154 133 120 108 105 93 78 21 0 0
IPI
Number of patients at risk
9 64%
54%
0 10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
82%
74%
BRAF Mutant BRAF Wild type
NIVO IPI
Events/patients 63/187 84/194
Median (95% CI) NR NR (16.1, NR)
HR (95% CI) 0.72 (0.52, 1.00)
NIVO IPI
Events/patients 67/197 105/214
Median (95% CI) NR 16.6 (12.3, NR)
HR (95% CI) 0.58 (0.43, 0.79)
Analysis of RFS by BRAF Mutation Status
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
NIVO IPI
187 159 142 135 126 118 102 32 2 0
NIVO
194 155 142 118 112 100 78 26 1 0
IPI
Number of patients at risk
RFS (%)
Months 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
197 175 154 145 137 127 108 26 2 0
NIVO
214 174 140 122 111 96 80 22 1 0
IPI
Number of patients at risk NIVO IPI
72%
57%
68%
63%
Safety Summary
• There were no treatment-related deaths in the NIVO group
• There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and colitis), both >100 days after the last dose
AE, n (%)
NIVO (n = 452) IPI (n = 453)
Any grade Grade 3/4 Any grade Grade 3/4
Any AE 438 (97) 115 (25) 446 (98) 250 (55)
Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46)
Any AE leading to discontinuation 44 (10) 21 (5) 193 (43) 140 (31) Treatment-related AE leading
to discontinuation 35 (8) 16 (4) 189 (42) 136 (30)
Future Perspectives in Adjuvant Setting:
Targeted Therapy
Clinical Protocol COMBI AD
A Phase 3, Randomized, Double-blind Study of Adjuvant antiBRAF and antiMEK versus Placebo after Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects who are at High Risk for Recurrence
Rationale for Combination of BRAFi + MEKi in BRAF Mutant Tumors
Improve complete response rate
pERK
BRAF
MEK
Proliferation Survival Invasion Metastasis
BRAFi : RR 77%
MEKi RR 35%
RAS
Suppress MAP kinase dependent resistance mechanisms and improve duration of response
Decrease incidence of BRAFi-induced proliferative skin lesions
Goals of Combination:
Efficacy
At 3y: 58% vs 39%
At 3y: 86% vs 77%
Hazard Ratios for Relapse or Death,
According to Subgroup
Safety
Conclusion: Adjuvant
• New standard of care in adjuvant setting:
– Nivolumab in BRAF WT patients
– Dabrafenib + Trametinib in BRAF mutated patients
Future Perspectives in Metastatic Setting:
• Clinical Protocol 067: A Phase 3, Randomized, Double-blind Study of Nivolumab + Ipilimumab vs Nivolumab Vs Ipilimumab. NEJM 18/09/17.
– 3 y OS
– BRAF mutated Vs WT OS – toxicities
• SZNOL et al: A Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients with Advanced Melanoma. JCO, 15/09/17
– pubblicazione + dati pooled analysis x toxicities
CA209-067: Study Design
18 Study design:
Randomized, double-blind, phase III study to compare NIVO alone or NIVO + IPI to IPI alone
Unresectable or Metatastic Melanoma
• Previously untreated
• Tissue available for PD-L1 testing
Treat until progression**
or unacceptable
toxicity NIVO 3 mg/kg Q2W +
IPI-matched placebo
NIVO 1 mg/kg + IPI 3 mg/kg Q3W for
4 doses then NIVO 3 mg/kg Q2W + NIVO-
matched placebo
IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo
Randomize 1:1:1
Stratify by:
• PD-L1 status*
• BRAF status
• AJCC M stage
*Verfied PD-L1 assay using 5% cutoff, was used for the stratification of patients;
validated PD-L1 assay was used for the results of the study.
**Patients could have been treated beyond progression under protocol-defined circumstances.
Results
Rapid and durable changes in target lesions
+ 1 mese + 2 mesi
+ 12 mesi + 5 mesi
Tempo 0
+ 8 mesi
Safety Summary
Patients Reporting Event, %
NIVO (N=313) NIVO + IPI (N=313) IPI (N=311) Any
Grade Grade 3–4
Any Grade
Grade 3–
4
Any Grade
Grade 3–
4 Treatment-related adverse
event (AE) 82.1 16.3 95.5 55.0 86.2 27.3
Treatment-related AE leading to
discontinuation 7.7 5.1 36.4 29.4 14.8 13.2
Diarrhea 1.9 1.3 8.3 6.7 4.5 4.2
Colitis 0.6 0.6 8.3 6.4 7.7 7.4
Treatment-related death* 0.3 0 0.3
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest)
24
This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeksand then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management.
Among 448 patients, median duration of follow-up was 13.2 months.
Phase Ib open-label dose-escalation study CA209-004 cohort 8; Phase II randomized study CheckMate 069; Phase III randomized study CheckMate 067.
Median times to onset for all-grade treatment-related select adverse events were as follows: 2.0 weeks for skin, 5.0 weeks for GI, 6.1 weeks for hepatic, 7.4 weeks for endocrine, 10.6 weeks for pulmonary, and 10.2 weeks for renal systems.
Time to onset of G3/4 treatment-related AEs
Resolution is shown over time in patients whose AEs had not yet resolved. Median times to resolution for all-grade AEs were as follows: 10.9 weeks for skin, 3.0 weeks for GI, 4.6 weeks for hepatic, 42.7weeks for endocrine, 6.1 weeks for pulmonary, and 1.9 weeks for renal systems. IM, immune-modulating agent; NA, not available.
Time to resolution of G3/4 treatment-related
AEs
• An international, multicenter, randomized, phase 3 trial to evaluate the usefulness of completion lymph-node dissection in patients with melanoma and sentinel-node metastases (MLSTII)
• Patients: 931 observation Vs 824 Complete Lymphnodal Dissection
News From the Literature: Surgical Approach
Results
• The mean 3-year rate of mel-specific survival was similar in the dissection group and the observation group (86±1.3%
and 86±1.2%, respectively) at a median follow-up of 43 months.
• The rate of DFS was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P = 0.05) at 3 years, mainly related to local recurrence these results must be interpreted with caution.
• Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.
• Breslow thickness was a significant prognostic factor in both groups, and the pathologic status of nonsentinel nodes was a significant prognostic factor in the dissection group. The number of involved sentinel nodes was not a significant prognostic factor.
Results
Conclusion
Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma- specific survival among patients with melanoma and sentinel-node metastases:
• CLND or not? BLS or not?
• EORTC Melanoma Group fall meeting focused on
reaching an international consensus
What may the Future Hold?
Combination
Chemotherapy Radiotherapy Targeted agents Other I-O therapies
Immune checkpoints
inhibitors
Novel targets Earlier
in disease Adjuvant Neoadjuvant
Optimization
Biomarkers Schedule/regimen Outcomes assessment
Sequence
Chemotherapy Radiotherapy Targeted agents Other I-O therapies
