What is the optimal dosing regimen for braf inhibitors
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What is the optimal dosing regimen for BRAF inhibitors? PowerPoint PPT Presentation


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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 ?

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What is the optimal dosing regimen for BRAF inhibitors?

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What is the optimal dosing regimen for braf inhibitors

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 inhibitors1

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?


Braf inhibitors beyond progression

BRAF inhibitors beyond progression?

BRIM2, BRIM3, BREAK3 and BRAF + MEK trials all allowed treatment beyond the endpoint of progression

In 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


What is the optimal dosing regimen for braf inhibitors2

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?


Rationale for discontinuous dosing of 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


What is the optimal dosing regimen for braf inhibitors3

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?


Brafi followed by ipi or ipi followed by brafi overall s urvival

BRAFifollowed by Ipi or Ipifollowed by BRAFi: Overall survival

PFS (%)

Median OS

BRAF 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)

100

80

60

lpilimumab then BRAF inhibitor (n=48)

40

20

BRAF inhibitor then ipilimumab (n=45)

0

Months

0

6

12

18

24

30

36

Ascierto et al, ASCO 2013; 9035

Median follow-up of 11 months (range: 1–34)

Median OS in patient subgroups unbalanced at baseline (ipi-BRAFivsBRAFi-ipi)

  • Elevated LDH: 14 months (95% CI: 13.4–14.6) vs7.5 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


If brafi creates an immune milieu then why are ipi responses poor after failing vemu

If BRAFi creates an “immune” milieu, then why are IPI responses poor after failing Vemu?

Response to ipilimumab is limited following BRAFi and only half of patients can even receive all 4 doses

Ackerman et al, SITC 2012: 24


Combining sequencing immune and targeted therapy for melanoma

Immunotherapy

Targeted therapy

Combination?

Percent alive

Percent alive

Percent alive

0

1

2

3

0

1

2

3

0

1

2

3

Years

Years

Years

Combining / sequencing immune and targeted therapy for melanoma?

Chapman et al, N Engl J Med 2011;364:2507–2516.

Hodi et al, N Engl J Med2010;363:711–723

Adapted from Ribas et al, Clin Cancer Res 2012; 18: 336–341


What is the optimal dosing regimen for braf inhibitors4

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?


Timing of brafi with xrt and ipilimumab

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

Skin toxicity from vemurafenib soon after ipilimumab

Harding et al, N Engl J Med 2012; 366: 866–8


Simultaneous ipilimumab vemurafenib

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

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


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