should braf inhibitors be continued ‘beyond progression’? is there a rationale for discontinuous...
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• Should BRAF inhibitors be continued ‘beyond progression’?
• Is there a rationale for discontinuous dosing of BRAF inhibitors?
• Is there a rationale for alternation of BRAF inhibition and ipilimumab?
• What interval should there be between BRAF inhibitors and other therapy for melanoma?
What is the optimal dosing regimen for
BRAF inhibitors?
• Should BRAF inhibitors be continued ‘beyond progression’?
• Is there a rationale for discontinuous dosing of BRAF inhibitors?
• Is there a rationale for alternation of BRAF inhibition and ipilimumab?
• What interval should there be between BRAF inhibitors and other therapy for melanoma?
What is the optimal dosing regimen for
BRAF inhibitors?
BRAF inhibitors beyond progression?
BRIM2, BRIM3, BREAK3 and BRAF + MEK trials all allowed treatment beyond the endpoint of progressionIn a patient that has been treated with prior immunotherapy, I would treat beyond progression given that clear benefit has been observed with long remissions after surgical resection with continued BRAFi
• Should BRAF inhibitors be continued ‘beyond progression’?
• Is there a rationale for discontinuous dosing of BRAF inhibitors?
• Is there a rationale for alternation of BRAF inhibition and ipilimumab?
• What interval should there be between BRAF inhibitors and other therapy for melanoma?
What is the optimal dosing regimen for
BRAF inhibitors?
Rationale for discontinuous dosing of BRAF inhibitors
Pre-clinical rationale: Murine data support the idea in vitro and in
vivo to decrease generation of BRAF inhibitor resistance
Clinical rationale: Occasional patients have had late
regression of disease after stopping BRAF inhibitors (rare)
Decreased selection pressure for resistance
Plan: to be tested in a randomized study, but not recommended at this time
• Should BRAF inhibitors be continued ‘beyond progression’?
• Is there a rationale for discontinuous dosing of BRAF inhibitors?
• Is there a rationale for alternation of BRAF inhibition and ipilimumab?
• What interval should there be between BRAF inhibitors and other therapy for melanoma?
What is the optimal dosing regimen for
BRAF inhibitors?
BRAFi followed by Ipi or Ipi followed by BRAFi:
Overall survival
Ascierto et al, ASCO 2013; 9035
Median follow-up of 11 months (range: 1–34)
Median OS in patient subgroups unbalanced at baseline (ipi-BRAFi vs BRAFi-ipi) Elevated LDH:
14 months (95% CI: 13.4–14.6) vs 7.5 months (95% CI 3.6–11.4) respectively
Brain metastasis: 12.3 months (95% CI: 7.9–16.7) vs 7.5 months (95% CI 5.6–9.4) respectively
0
100
0 612
24
18
30
36
Months
PFS (%)
604020
80
lpilimumab then BRAF inhibitor (n=48)
BRAF inhibitor then ipilimumab (n=45)
Median OSBRAF inhibitor then ipilimumab: 9.9 months (95% CI: 5.8–14.0)lpilimumab then BRAF inhibitor: 14.5 months (95% CI: 11.1–17.9)
If BRAFi creates an “immune” milieu, then why are IPI responses poor after
failing Vemu?
Ackerman et al, SITC 2012: 24
Number of patients(n=40)
Response to ipilimumab (36 evaluable)
Progressive Disease 34
Stable Disease 2
Partial Response 0
Complete Response 0
Progression on ipilimumab
No 4
Yes 36
Number of ipilimumab doses received
< 4 20
> 4 20
Response to ipilimumab is limited following BRAFi and only half of patients can even receive all 4 doses
Combining / sequencing immune and targeted therapy for melanoma?
Adapted from Ribas et al, Clin Cancer Res 2012; 18: 336–341
Years
Immunotherapy Targeted therapy
Perc
en
t alive
Perc
en
t alive
1 2 30 1 2 30Years
Combination?
Perc
en
t alive
1 2 30Years
Hodi et al, N Engl J Med 2010;363:711–723
Chapman et al, N Engl J Med 2011;364:2507–2516.
• Should BRAF inhibitors be continued ‘beyond progression’?
• Is there a rationale for discontinuous dosing of BRAF inhibitors?
• Is there a rationale for alternation of BRAF inhibition and ipilimumab?
• What interval should there be between BRAF inhibitors and other therapy for melanoma?
What is the optimal dosing regimen for
BRAF inhibitors?
Timing of BRAFi with XRT and ipilimumab
Many investigators will stop BRAF inhibitors 24 hours before surgery or radiation and only continue 48 hours later
At Melanoma Institute of Australia, BRAF inhibitors are continued through whole brain or stereotactic radiosurgery
Serious concerns have arisen about administering ipilimumab and vemurafenib in close proximity
Skin toxicity from vemurafenib soon after ipilimumab
Harding et al, N Engl J Med 2012; 366: 866–8
Patient
number Age
Stage of metastas
isIpilimumab
dose
Number of doses
of ipilimum
ab
Immune-related
adverse event with
ipilimumab
Number of days from last
dose of ipilimumab to
start of vemurafenib Rash
Number of days to onset of
rash
1 63 M1c 3 4 Yes 20 Grade 3
6
2 25 M1c 3 4 No 24 Grade 3
8
3 72 M1c 3 6 No 28 Grade 3
8
4 44 M1c 3 1 Yes 36 No
5 61 M1c 3 4 No 51 Grade 1
Not reported
6 51 M1c 10 1 Yes 76 No
7 46 M1c 3 4 Yes 83 Grade 1
2
8 31 M1c 3 4 No 117 Grade 1
15
9 39 M1c 3 11 No 147 Grade 1
13
10 49 M1c 10 1 Yes 168 No
11 50 M1c 10 3 Yes 247 Grade 3
7
12 59 M1a 10 4 Yes 294 Grade 1
28
13 65 M1b 10 5 Yes 955 No
Simultaneous ipilimumab + vemurafenib
Ribas et al, N Engl J Med 2013; 368: 1365–6
12 patients treated in two cohorts All BRAF mutated patients
One month lead-in of vemurafenib, then 4 doses of ipilimumab at 3 mg/kg standard dose In first 6 patients at full doses of
vemurafenib and ipilimumab:4/6 DLTs of hepatotoxicity
In second 6 patients at reduced doses of vemurafenib: 3/6 DLTs of hepatotoxicity
These data suggest that at therapeutic doses of the 2 agents, toxicity would preclude adequate dosing
Safe interval between BRAFi and ipilimumab?
BRAFi→ipi Data suggest that a 6–8 week
interval may be needed Ipi→BRAFi It may be more difficult to
administer IPI then a BRAF inhibitor Skin toxicity
Ipi+BRAFi Simultaneous administration
associated with hepatotoxicity