Sunday, March 26, 2017

What tangled 'paths' we weave: Nilotinib for KIT mutated melanoma and Buparlisib for the PI3K pathway in melanoma brain mets

Melanoma mutations can be confusing to say the least.  This diagram helps a bit:

Here's credit and an explanation:  Melanoma Pathways....A Melanoma Molecular Disease Model

NRAS and KIT mutated patients have not had the luxury of good responses to immunotherapy and targeted therapies currently being utilized in melanoma.  But, now there's this:

Efficacy and Safety of Nilotinib in Patients With KIT-Mutated Metastatic or Inoperable Melanoma: Final Results From the Global, Single-Arm, Phase II TEAM Trial. Guo, Carcjal, Drummer,..., Hodi. Ann Oncol. 2017 Mar 6. 

The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT -mutated advanced melanoma without prior KIT inhibitor treatment.

Forty-two patients with KIT -mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT -mutated melanomas. Thirteen patients were randomized to DTIC prior to the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.

ORR was 26.2%, sufficient to reject the null hypothesis (ORR less than or = to 10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease, 10 (23.8%) had progressive disease, and 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, 4 with an L576P mutation. The median progression-free survival and overall survival were 4.2 months and 18.0 months, respectively. Three of 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.

Nilotinib activity in patients with advanced KIT -mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.  

42 patients is not a ton.  26.2% ORR...with all of those being partial responses is not fabulous...but it is definitely SOMETHING!!!  Hey, I was over the moon when ipi was approved with its 15% response rate!!!  

And ~ if you refer to the chart above will see the PI3K pathway....

Here is an initial post re the PI3K pathway in relation to brain mets by Dr. Davies:  PI3K/AKT - a pathway with potential for treating melanoma brain mets

And now there's this mousie medicine....

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo. Niessner, Schmitz, Tabatabai, et al. Clin Cancer Res. 2016 Dec 1.

Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.

Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.
These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases.

This last is certainly in its baby steps...  But, hey!  On these paths, any steps at all are a needed start!!
(However, there are many PI3K inhibitors in studies for other cancers - Buparlisib [drug noted above] and Alpelisib [for breast cancer], Duvelisib [hematologic malignancies], TGR1202 [follicular lymphoma].)

Thanks, mousies.  Hang tough, ratties!  - c

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