What is the optimal dosing regimen for BRAF inhibitors?

1. 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?

2. 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?

3. 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

4. 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?

5. 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

6. 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?

7. 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

8. 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

9. 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

10. 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?

11. 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

12. Skin toxicity from vemurafenib soon after ipilimumab Harding et al, N Engl J Med 2012; 366: 866–8

13. 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

14. 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