1. 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?

2. 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?

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. 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?

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. 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?

7. 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 061224183036 Months PFS (%) 60 40 20 80 lpilimumab then BRAF inhibitor (n=48) BRAF inhibitor then ipilimumab (n=45) 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)

8. 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 Disease34 Stable Disease2 Partial Response0 Complete Response0 Progression on ipilimumab No4 Yes36 Number of ipilimumab doses received < 420 > 420 Response to ipilimumab is limited following BRAFi and only half of patients can even receive all 4 doses

9. Combining / sequencing immune and targeted therapy for melanoma? Adapted from Ribas et al, Clin Cancer Res 2012; 18: 336–341 Years ImmunotherapyTargeted therapy Percent alive 12301230 Years Combination? Percent alive 1230 Years Hodi et al, N Engl J Med 2010;363:711–723 Chapman et al, N Engl J Med 2011;364:2507–2516.

10. 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?

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 Patient numberAge Stage of metastasis Ipilimumab dose Number of doses of ipilimumab Immune-related adverse event with ipilimumab Number of days from last dose of ipilimumab to start of vemurafenibRash Number of days to onset of rash 163M1c34Yes20Grade 36 225M1c34No24Grade 38 372M1c36No28Grade 38 444M1c31Yes36No 561M1c34No51Grade 1Not reported 651M1c101Yes76No 746M1c34Yes83Grade 12 831M1c34No117Grade 115 939M1c311No147Grade 113 1049M1c101Yes168No 1150M1c103Yes247Grade 37 1259M1a104Yes294Grade 128 1365M1b105Yes955No

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