Vemurafenib and HSP90 for BRAF positive peeps with unresectable melanoma

Folks have been looking at many meds to add to targeted therapy so that melanoma peeps (who happen to be BRAF positive....about 1/2 of us) will not develop resistance to the positive effects of those drugs.  They have been looking at HSP90 (heat shock protein 90) as well as ricolinostat (an HDAC6 inhibitor) for some time now.  Here are some prior reports:  Heat Shock Protein 

Now, there's this: 

Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma. Eroglu, Chen, Gibney, Weber, et al. Clin Cancer Res. 2018 Apr 19. 

BRAF inhibitors are clinically active in patients with advanced BRAF^V600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.

Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAF^V600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.
Objective responses were observed in 15/20 evaluable patients (75%), with 3 complete and 12 partial responses. Median progression-free and overall survival were 9.2 months (95%) and 34.6 months, respectively. The most common grade 3/4 toxicities were skin toxicities such as rash (n=4, 19%) and cutaneous squamous cell carcinomas (n=3, 14%), along with diarrhea (n=3, 14%). Pharmacodynamic analysis of patients' PBMCs showed increased day 8 HSP70 expression compared to baseline in the three cohorts with XL888 doses greater than/= to45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP-client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.

XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF^V600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF^V600-mutant melanoma.

Thanks, ratties.  We'll have to see if this moves any further along and/or if they will finally combine it with a BRAF/MEK combo which we already know does better than BRAFi alone! - c

ASCO 2016 - Inhibitors that may overcome BRAFi resistance: Heat Shock Protein 90 (HSP90) and Ricolinostat (an HDAC6 inhibitor)

In this post, Webinar for melanoma - A look forward, Weber noted "Innovative Ideas for Targeted Therapy" - Overcoming BRAF resistance by combining with: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors

Here are a couple of ASCO reports addressing some of those inhibitors:

Phase I study of vemurafenib and heat shock protein 90 (HSP90) inhibitor XL888 in metastatic BRAF V600 mutant melanoma.  ASCO 2016.  # 9544. J Clin Oncol 34, 2016.  Eroglu,Gibney, Weber, et al.

Background: BRAF inhibitors are clinically active in advanced BRAFV600 mutant melanoma patients, but resistance is common. Multiple resistance mechanisms involve HSP90 clients and preclinical data have shown abrogation of resistance using concurrent treatment with the HSP90 inhibitor XL888. Methods: The combination of vemurafenib (960 mg PO BID) with dose cohorts of XL888 (30, 45, 90 or 135 mg PO twice weekly [BIW]) was investigated in patients with advanced BRAFV600 mutant melanoma. A modified Ji dose escalation design was used. Primary endpoints were safety and determination of a recommended phase 2 dose (RP2D). Dose-limiting toxicity (DLT) was defined as treatment-related grade greater than or = to, 3 adverse event or inability to deliver 75% of planned XL888 dose in the first 8 weeks. Results: Nineteen patients (14 with M1C disease) were enrolled: cohorts 1 and 2 (n = 3 each), cohort 3 (n = 7), cohort 4 (n = 6). Two DLTs (diarrhea and pancreatitis) occurred in cohort 4, while a third patient received less than 75% of planned XL888. Therefore cohort 3 dose was determined to be RP2D: vemurafenib 960 mg BID + XL888 90 mg BIW. Most common grade 3 toxicities (in more than 1 patient) were hyperproliferative skin events (n = 5, 26%), diarrhea (n = 2, 11%), rash (n = 2) and headaches (n = 2) and one grade 4 lipase elevation. Skin toxicities were lower in cohorts 3/4. Objective responses were observed in 13 of 18 evaluable patients with 2 complete responses (CRs) and 11 partial responses (PR). Two patients with a PR who underwent surgical resection had a pathologic CR. Median PFS was 7.4 months; median overall survival was 33.1 months (5.75 – not reached). Targeted proteomics of patients’ baseline and day 8 PBMCs showed significant increases in HSP71 expression (a marker of HSP90 inhibition) in cohorts 2 through 4. Analysis of baseline and on-therapy tumor biopsies is ongoing. Conclusions: Promising clinical activity with an acceptable toxicity profile and evidence of HSP90 inhibition was observed with vemurafenib and XL888 in BRAF mutant melanoma patients. As HSP90 inhibitors also abrogate resistance to the combination of BRAF and MEK inhibitors in melanoma, clinical investigation of this approach is also planned. Clinical trial information: NCT01657591

In vitro and in vivo anti-melanoma activity of ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties.  ASCO 2016.  # e21075.  J Clin Oncol 34, 2016.  Cheng. Laino, Wang, Weber, et al.

Background: Previously, we have shown that pan-HDAC inhibitors induce apoptosis and changes in the immunogenicity of melanoma cells. Further studies identified HDAC6 playing a central role in regulating melanoma immunogenicity. Genetic knockdown (KD) of HDAC6 in murine and human melanoma cells increased the expression of MHCI and costimulatory molecules as well as melanoma associated antigens. In vivo studies demonstrated that the growth of melanoma cells lacking HDAC6 was significantly delayed as compared to wild-type cells. Methods: C57BL/6 mice were given melanoma cells sc. When mice developed a palpable mass they were treated with vehicle control, ricolinostat alone, or in combination with anti PD-1 or anti CTLA-4 antibodies. To assess the effects of ricolinostat upon T cells, murine T-cells were activated with anti-CD3/CD28 dynabeads in the presence -or not- of 1 uM ricolinostat for 24 hour. Then, cells were adoptively transferred into B16 bearing mice. T-cell subpopulations from the lymph nodes were analyzed ex vivo.Results: First, invivo treatment of melanoma bearing mice with ricolinostat resulted in a dose-dependent inhibition of tumor growth (p < 0.05). No toxicities were observed at the doses studied. Second, the antitumor effect exerted by ricolinostat was not observed when melanoma bearing SCID mice were treated with this compound, indicating that an intact adaptive immune system is required for the observed antitumor activity. In lieu of these previously unknown immunomodulatory properties of ricolinostat, we next assessed the effects of this compound upon T-cells in vivo. We show here that treatment of murine T-cells with ricolinostat resulted in a significant increase in central memory T-cells endowed with a strong anti-melanoma activity in vivo as compared to control-treated T-cells (p < 0.05). Finally, the addition of ricolinostat treatment to either anti-CTLA-4 or anti-PD-1 treatment was associated with an enhanced inhibition of melanoma tumor growth. Conclusions: Our results have identified HDAC6 as a novel target for melanoma immunotherapy and point to ricolinostat as an attractive agent to add to the immuno-oncology armamentarium.

Ratties....keeping it going! - c

BRAF/MEK combined with immunotherapy!!!

I thought this was a very informative article regarding BRAF inhibitors, MEK inhibitors...what we've learned and where research is looking with those drugs.

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.  Eroglue and Ribas.  Ther Adv Med Onc. Jan 2016.

 Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents.

The article goes on to report:  "About one half of melanoma patients carry the BRAF V600E mutation.  BRAF inhibitors illicit 48-59% response rates in those patients. However, duration of response is limited in most patients with a median PFS of 5-7 months “although a minority can last for over 5 years”.  BRAF inhibitors combined with MEK inhibitors improved things further with decreased side effects and increased PFS, amounting to 11-12 months depending on the combo.  It also reviews the importance of intermittent dosing as opposed to continuous therapy with BRAFi in order to delay resistance.  Other drugs combined with BRAF/MEK , like heat shock protein 90 (HSP90) inhibitors, like XL88 can overcome resistance.  There are also plans for additional studies using a triple therapy approach.

NCT01657591:  (Active, not recruiting) - Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

NCT01902173:  (stopped for assessment) - Akt Inhibitor GSK2141795, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer

NCT02110355:  (recruiting) - A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma

BRAF/MEK has provided response rates of up to 70% in trials but with limited durability of that response, researchers are looking at combining those drugs with checkpoint inhibitors like ipi, anti-PD1, or anti-PD-L1.  When dabrafenib, trametinib and ipi were combined patients experienced colitis with perforation.  So that arm was stopped, though the ipi and dabrafenib arm is ongoing.  Another trial is currently looking at dabrafenib, trametinib and anti-PD-L1 (MEDI4736).  So far, the ratties are demonstrating a 69% ORR and 16 of 18 patients have an ongoing response."

NCT02130466 is ongoing and recruiting:  A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

 Here's a link to the whole paper:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/ 

Hope that helps, for what it's worth - c

Available melanoma trials at Moffitt, in Tampa, Florida

While interested folks will be much better served by checking out national sites for cancer trials and the Moffitt web site....here is a partial listing of melanoma trials currently ongoing at Moffitt.  I do not profess to know which are currently recruiting.  If you are interested...CALL!!!!! EMAIL!!!  1-888-MOFFITT (1-888-663-3488) cutonc@moffitt.org

Phase 1 trial with multiple peptides and escalating doses of anti-PD1 (BMS-936558) for patients with Stage III/IV resected melanoma (my trial) and the sister arm that is for Stage III/IV unresectable melanoma.

Variations of the above trial...some with vaccines, some without, some specifically for patients who have failed ipi.

Pilot study (? phase 1) of Oncovir Poly IC:LC and peptides +/- CP870,893 at one of 5 dose levels for Stage III/IV resected.

Phase 1 study of MK 3475 (Merck's anti-PD1 product) for unresectable Stage III/IV with measurable disease.  Reportedly in open recruitment.

Phase III, Resected, Randomized trial of ipi vs interferon...to include 1,500 patients.  (Poor little ratties!!!!!!)

A randomized Phase 2 study of Yervoy (ipi) with Sylatron (peg interferon) for patients with unresectable Stage III/IV melanoma.

Ipi 3 mg/kg vs ipi 10 mg/kg for Stage III/IV unresectable.

Trial with a RAF kinase inhibitor for Braf + patients with measurable disease.

TIL

Biochem with combination of:  BRAF inhibitor + cyclophosphamide + high dose IL2 + fludarabine

A trial that combines HSP 90 (heat shock protein 90...a chaperon protein that promotes stability in other proteins) and BRAF inhibitor for Stage III/IV unresectable patients.  (Background:  this is to see if the duration of response to BRAF inhibitors can be extended with this combo.)

Hope this helps.  Errors may abound...but please, call!  Check out any options that might be available to you!  c

HDAC (Histone deacetylase) inhibitors for melanoma

HDAC inhibitors have been mentioned by melanoma experts previously as something that might aid melanoma patients in overcoming BRAFi resistance:  ASCO 2016 - Inhibitors that may overcome BRAFi resistance: Heat Shock Protein 90 (HSP90) and Ricolinostat (an HDAC6 inhibitor)

Now there is this:

Inhibition of histone deacetylases in melanoma-a perspective from bench to bedside.  Hornig, Heppt, Graf, et al.  Exp Dermatol. 2016 Nov 25.

Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective. The molecular functions of HDACs can be classified into histone and non-histone effects with diverse implications in proliferation, cell cycle progression and apoptosis. HDAC inhibition results in G1 cell cycle arrest, induces apoptosis and increases the immunogenicity of melanoma cells. Some studies proposed that HDAC inhibition may overcome the resistance of melanoma cells to BRAF inhibition. Several inhibitors such as vorinostat, entinostat and valproic acid have recently been tested in phase I and early phase II trials, yet most agents show limited efficacy and tolerability as single agents. The most frequent adverse events of HDAC inhibition comprise haematological toxicity, fatigue, nausea and laboratory abnormalities. Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition.

As noted here, studies of HDACs are proving helpful in multiple myeloma patients when combined with other drugs.  However, thus far, beneficial results for melanoma patients has been minimal.  Keeping my fingers crossed, though!!! - c