ASCO 2015: New BRAF inhibitor combo's for melanoma

Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.  J Clin Oncol 33, 2015.  Ribas, Butler, Lawrence, Robert, et al.

Inhibition of the MAPK pathway with dabrafenib (D) and trametinib (T) is efficacious in BRAF-mutant melanoma.  MEK inhibitors have also shown activity in BRAF WT melanoma, particularly in NRAS-mutant tumors.  However, most patients develop resistance.  MEDI4736 (M), is a human IgG1 mAB that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown clinical activity with durable responses and an acceptable safety profile in multiple tumor types.  Combine therapy with these agents may lead to enhanced durable tumor responses.  Phase 1 study:  MEDI4736 was given at 3 or 10 mg/kg IV q2w in combination with dabrafenib 150mg twice daily and trametinib 2 mg daily, OR trametinib alone in patients with stage IIIc/IV melanoma.  Patients were divided into various cohorts based on BRAF status and dosing combo.  Prior BRAF/MEK inhibitor use was prohibited.  Prior immmunotherapy (including anti-PD1 and anti-PD-L1) was allowed.  RESULTS:  As of 12/5/2014, 50 patients were treated.  After review, MEDI 4736 at 10mg/kg q 2 wks was chosen for expansion.  Most frequent AE's were fever (63%) and fatigue (54%), along with diarrhea and rash in cohort B, and vomiting in cohort C.  2 patients stopped treatment due to toxicity - 1 with Grade 3 thrombocytopenia, and 1 with reversible choroidal effusion.  
Cohort A1 - (3mg/kg M + D + T):
n = 6, Any AE = 100%, Grade 3 AE = 17%, Complete response = 6.
Cohort A2 - (10mg/kg M + D + T):
n = 18, Any AE = 94%, Grade 3 AE = 39%, Complete response = 10.  Partial response = 15
Cohort B - (10mg/kg M + T)
n = 20, Any AE = 90%, Grade 3 AE = 40%, Complete response = 3. Partial response = 14.
Cohort C - (sequential T + 10mg/kg M)
n = 6, Any AE = 100%, Grade 3 AE = 17%, Complete response = 3. Partial response = 6.

Phase 1 trial of the CDK 4/6 inhibitor, P1446A-05 (voruciclib) in combination with the BRAF inhibitor vermurafenib in advanced, BRAF-mutant melanoma.  J Clin Ocol 33, 2015.  Diab, Martin, Simpson, Daud, et al.

P1446A-05 is a potent, selective CDK 4/6 inhibitor with activity in multiple BRAF-mutant and wild type cell lines.  BRAF inhibitors have been transformative in the therapy of BRAF-mutant melanoma.  However, resistance does develop frequently, often in only a few months.  The addition of a CDK 4/6 inhibitor to BRAFi is supported by extensive preclinical data.  Phase 1 trial.  4 cohorts.  Plan = Vermurafenib from 720mg po bid to 960mg po bid and P1446A-05 from 150mg up to 350mg po q d.  Each cohort to have 3-6 patients.  Eligible patients could be BRAFi naive or resistant.  RESULTS:  9 patients so far. (3 BRAFi naive and 6 refractory).  AE's = fatigue, headache, and constipation.  No DLTs.  Responses were seen in 3/3 BRAFi naive patients - 1 complete and 2 partial.  Combination recommended for further testing = Vermurafenib 960mg po bid with P1446A-05 150mg po qd.

A phase Ib/II study of BRAF inhibitor encorafenib (ENCO) plus MEK inhibitor binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment.  J Clin Ocol 33, 2015.  Sullivan, Weber, Patel, et al.

MEKi addition to BRAFi therapy has been reported to increased response rate and duration of response.  ENCO and BINI have each shown promising single-agent activity in BRAFV600 mutant melanoma.  BRAF positive, BRAFi naive patients were enrolled. 9 patients were given ENCO at 400 or 450 mg daily.  39 patients were given ENCO at 600mg daily.  All were given BINI.  At ENCO 600 AE's = nausea (54%), diarrhea (44%), fatigue and arthralgia (both at 33%), vomiting, fever, and increased AST (31% each).  At 400/450 ENCO dose, AE's = nausea/fatigue (44% each), diarrhea, vomiting, and increased AST (33% each), arthralgia and fever (11% each).  Grade 3/4 AE's in 600 group were 64%, most often = increased ALT, lipase, AST, and creatine phosphokinase.  At 400/450 dose, grade 3/4 AE's occurred in 67% of patients and was increased lipase most often.  Photosensitivity and fever were rare.  Response rate for patients treated at ENCO 400/450 was 78% (1 complete and 6 partial).  At ENCO 600 response rate was 72% (3 complete and 25 partial).  

And....this trial is starting:

Neoadjuvant BRAF (dabrafenib) and MEK (trametinib) inhibition for high-risk stage III and IV melanoma.  J Clin Oncol 33, 2015.  Wargo, Amaria, Ross, et al.

2 currently recruiting phase II trials - at MD Anderson and Melanoma Institute Australia - of neoadjuvant combined BRAFi (dabrafenib, 150mg po bid) and MEKi (trametinib 2mg po q day) for high risk resectable metastatic melanoma.  Both trials incorporate serial biopsies during the course of treatment for research on biomarkers.  At MD Anderson patients are randomized in a 2:1 fashion to neoadjuvant BRAF/MEK X 8 wks with adjuvant BRAF/MEK X 44 wks vs surgery alone with standard of care for disease per study doc.  (target accrual = 48 patients). 

Here's the MD Anderson trial link  Here's the Clinicaltrials.gov description of the groups:

Experimental Group A: Surgery + Standard of Care.  Surgery alone within 4 weeks after enrolling in study. Participant then treated with standard care for the disease after surgery per study doctor.

Experimental Group B: Dabrafenib + Trametinib + Surgery. Starting Dose of Dabrafenib: 150 mg by mouth twice a day. Starting Dose of Trametinib: 2 mg by mouth once daily. At Week 8 after starting Dabrafenib and Trametinib, participant has MRI and/or CT scans of brain to check status of disease. Participant also has CT scans of the chest, abdomen, and pelvis. If scans show disease has not spread or grown, surgery is scheduled. Participant continues taking study drugs until day of surgery. Study drugs continued after surgical recovery for up to an additional 44 weeks.

Don't forget this BRAFi info from earlier this year:  BRAFi, better when combined with or after immunotherapy or surgery!

Lots of new drugs and new combo's.  Time will tell.  Sosman has been doing good things for a while with the CD4/6 inhibitor LEE011 combined with a MEK inhibitor.  Hopefully, that will hold up.  BRAFi with surgery was shown promise as well.  You gotta love Phase 2 trials...where somebody ends up with little or nothing!  I can only hope that some of these drugs or combo's will quickly prove worth it, so that "something" can be available and effective for everybody!! - c