Tuesday, June 13, 2017

ASCO 2017: Hope for NRAS melanoma

Melanoma is a complicated disease entity to say the least.  Tumors, that are now all lumped together as 'melanoma' demonstrate many different mutations and develop via a variety of pathways.  About half of us are BRAF positive.  Aboust 20% of us have the NRAS mutation.  Then there's all sorts of other delineations!  This post:  What tangled paths we weave...
Which contains this diagram:
Probably makes the pathway as clear as anything else!!

Thus far, targeted therapy (using a combination of a BRAF inhibitor with a MEK inhibitor) has been found to be most effective for only those with a V600 BRAF mutated melanoma.  However, this post in 2016 addresses how nelfinavir (also called Viracept, an HIV protease ihibitor) can be used to decrease resistance to those meds in both BRAF and NRAS mutant melaonma:  Stopping resistance to targeted therapy- nelfinavir- for BRAF and NRAS mutant melanoma

Here an older cardiac drug was paired with a MEK inhibitor: Digoxin and trametinib for BRAF wild type melanoma

Recently I posted this study in which binimetinib (a MEK inhibitor) was paired with encorafenib (a BRAF inhibitor):   Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS
Within it was noted that, "In March, Array withdrew its FDA new drug application for single-agent binimetinib as a treatment for patients with NRAS-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting."

However, from ASCO  2017...this study pairs binimetinib with ribociclib (also named Kisquali [What the f@%K?????] a  CDK 4/6 inhibitor, approved this year for use in HR+/HER 2 breast cancer):  

Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D).

2017 ASCO. J Clin Oncol 35, 2017. Schuler, Ascierto....Postow....Sosman....Daud...et al.

Background: Simultaneous inhibition of MEK and CDK4/6 may suppress MAPK pathway activation and cell-cycle checkpoint dysregulation in NRAS-mutant melanoma, resulting in enhanced antitumor activity. Phase 1b data are reported. Methods: The phase 1b primary objective was to determine maximum tolerated dose (MTD)/RP2D. A 28-d cycle of oral ribociclib (RIBO) once daily (QD) for 21 d + oral binimetinib (BINI) twice daily (BID) for 28 d, and a 21-d cycle of RIBO QD + BINI BID, both for 14 d per cycle, were evaluated. Secondary objectives were to evaluate efficacy, safety and pharmacodynamics. Results: Based on dose escalation, MTD was 600mg RIBO/45mg BINI for the 21-d and 200/45 for the 28-d regimens. Due to promising activity, the 28-d cycle was selected as RP2D (unconfirmed partial response [PR] with limited follow-up occurred in 35% of pts).  As of Jan 2017, the RP2D was received by 16 pts in phase 1b (ECOG PS 0/1/2, 63%/31%/6%; elevated lactate dehydrogenase, 44%; stage IVM1c disease, 50%; prior ipilimumab [ipi], 44%; prior anti–programmed death [PD]-1/PD-L1, 31%). Median (range) exposure was 4 (0–13) mo. Common adverse events (AEs) were increased blood creatine phosphokinase, elevated AST, peripheral edema, acneiform dermatitis, diarrhea and fatigue. Common grade 3/4 AEs were elevated AST and ALT (19%/6%), nausea (19%/0%), rash (19%/0%), vomiting (6%/6%) and neutropenia (12%/0%). Confirmed PR (cPR) occurred in 4 pts (25%; time to response, 48–168 d), stable disease in 7 pts (44%), disease progression in 3 pts (19%); 2 pts (12%) were not evaluable. Among cPR pts, 3 had prior ipi and/or anti–PD-1/PD-L1. Median progression-free survival (mPFS) was 6.7 mo. Sequence analysis of synchronous non-RAS genetic alterations will be presented. Conclusions: Combined RIBO/BINI at the selected RP2D had a manageable safety profile and favorable efficacy (based on mPFS) for NRAS-mutant melanoma in phase 1b. Based on these promising data, the phase 2 expansion is underway to assess antitumor activity at the RP2D. Clinical trial information: NCT01781572

So both are oral meds...given in a 28-day cycle as noted above, to 16 patients - 44% of whom had increased LDH, 44% had been previously given ipi, 31% had been previously treated with anti-PD-1 or anti-PD-L1.  Meds were given for an average of 4 months.  There was a confirmed partial response in 4 patients, stable disease in 7, disease progression in 3 and 2 were not evaluated.  For what it's worth...

When looking at immunotherapy in NRAS patients, I posted this in 2015:  Good news for NRAS positive folks, especially in regard to anti-PD1!!!! Now there is this:

NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.
2017 ASCO. J Clin Oncol 35, 2017. Kirchberger, Ugurel, Mangana, et al.

Background: About 20% of metastatic melanomas harbor NRAS mutations which constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. The response of patients with NRAS-mutated melanoma to checkpoint inhibitor therapy is so far unknown. A previous study suggested a higher response rate of NRAS-mutated melanoma to anti-PD-1/anti-PD-L1 with an objective response in 7 out of 11 (64%) patients compared to 35% and 21% in BRAF wildtype or BRAF V600-mutated melanoma, respectively. Methods: In total, 224 patients with NRAS-mutated melanoma were analyzed. Of these, 180 patients received ipilimumab, 98 anti-PD1 monotherapy, and one patient combined ipilimumab and anti-PD1 therapy. We evaluated overall response rate (ORR), disease control rate, progression-free survival (PFS) and overall survival to checkpoint inhibitor therapy in these patients. Results: In this patient cohort with NRAS-mutated melanoma, 27% had brain metastases, 62% an elevated LDH and 22% an ECOG greater than/ = to 1. ORR was 15% for treatment with ipilimumab and 34% for anti-PD1 therapy. Disease control rates were 27% for ipilimumab and 52% for anti-PD1 therapy. PFS was 4.5 months for ipilimumab and 11.4 months for anti-PD1 therapy. Overall survival of all patients was 29 months. Conclusions: The efficacy data of ipilimumab or anti-PD1 therapy in NRAS-mutated melanoma patients were similar to the known response rates of NRAS wildtype melanoma patients.

In this study, 224 NRAS mutated melanoma patients were studied. 180 were treated with ipi, 98 with anti-PD-1 and 1 was given the ipi/nivo combo.  The overall response rate was 15% for those treated with ipi and 34% for those treated with anti-Pd-1....which is in keeping with response rates for those drugs generally.

Good to know. - c

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