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#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.

However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.

At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?

An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.

One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.

Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent.

Jeffrey Weber from Moffitt Cancer Center in Tampa presented the results of the complex phase I/II study, which included melanoma patients with either the BRAFV600 E or K mutation who had not undergone treatment of any kind. The hope was that by suppressing the MAP kinase-dependent resistance mechanisms, patients would enjoy three kinds of improvements over current treatment:

1) Improved progression-free survival (PFS), response rate, and survival

2) Prolonged duration of response

3) Decreased incidence of BRAFi-induced proliferative skin lesions

An impressive waterfall plot of tumor shrinkage for patients (n=77) with the BRAFV600K mutation drew gasps from the audience – only four patients failed to respond to the combination, while the majority had a response of 30% or better. This isn’t something you see every day in cancer research! Unlike the short lived responses we have seen with single agent therapy, the median duration of response for the BRAF naive patients with the combination was 11.3 months.  Treatment given for a median of 10.7 months and just over a third (38%) were still ongoing. With regards to efficacy, PFS was 7.4 months across all dose cohorts, which is slightly above what one might expect for single agent therapy at full dose.

There were concerns prior to this presentation whether full doses of both MEK (2mg QD) and BRAF (150mg BID) inhibitors could be given safely or whether there would be overlapping toxicities that might force dose reductions with a possible impact on efficacy. The data so far suggests that tramatenib and dabrafenib can both be given at their full dose. In the dose expansion phase of the study, the most common adverse events that caused dose reductions were fever and chills. Interestingly, though, combining MEK and BRAF inhibitors led to a lower incidence of hyperproliferative skin lesions than with dabrafenib alone.

As a result of these most encouraging findings, the randomized phase II cohort are ongoing and maturing and phase III trials with dabrafenib and tramatinib are being pursued.

Other MEK inhibitors are also in development for the treatment of cutaneous melanoma. These include MEK162, where Paulo Ascierto presented data on behalf of the Italian NCI. He envisioned a future where patients with advanced or metastatic melanoma would be treated differently according to their mutational status. He highlighted several key mutations that are druggable – aside from BRAFV600E and K, there is also c-KIT, Q61NRAS, NRAS wt and BRAF wt, where wt stands for wild type. Inevitably, the survival rates for these subsets varies, with NRAS mutants having the worse prognosis.

Whereas trametinib targets MEK1 and 2, preclinical research suggests that the MEK162 inhibitor also hits NRAS mutants (mt) in cell lines, making it an attractive option to consider in studies with patients who have either or both BRAFV600 or NRAS mutant clones.

In the open label phase II study with single agent MEK162 (45mg BID), patients (n=71) were therefore divided according to their mutational status. Prior therapies, including BRAF therapy were permitted, as were naive advanced melanoma patients.  At the time of the analysis, 28% of the NRAS and 35% of the BRAFV600 patients had responded.

In terms of efficacy and safety, the PFS curves for the two subsets were similar–3.65 months for people with the NRAS mutation, and 3.55 months for those with the BRAF mutation. Adverse events were as expected for MEK – ie diarrhea, rash, dermatitis acneiform. Blood creatinine phosphokinase was also seen to increase in both groups.  Overall, the study showed that MEK162 is the first MEK inhibitor to successfully target NRAS-mutant melanoma. Trials are ongoing and we may well see this agent in future combination studies.

At last year’s ASCO meeting, melanoma was very much to the forefront with both Zelboraf and Bristol-Myers Squibb’s anti-CTLA4 immunotherapy Yervoy (ipilimumab) presented in the plenary session. This year, a new immunotherapy emerged called BMS-936558, a fully-human IgG4 monoclonal antibody that targets the Programmed Death 1 receptor (PD-1).

Patients with stage IV melanoma have been found to have significantly higher levels of PD-1 on peripheral CD8+/CD4+ T-cells than a healthy person. And when white blood cells that have infiltrated a tumor express PD-1, it results in decreased production of cell-signaling proteins and effector function, thereby lowering immunity. PD-L 1 tumor expression may therefore correlate with adaptation to immune attack and response to therapeutic PD-1 blockade.

Dana-Farber oncologist Stephen Hodi presented the results from the study of BMS-936558. The trial included patients with advanced melanoma, as well as other tumor types,  64% of which had already been treated with other kinds of immunotherapy. The most common side effects experienced by patients taking BMS-936558 included fatigue, rash, diarrhea, and itching. About 20% of the melanoma patients experienced more serious side effects. Of note, one patient with melanoma also  had pneumonitis, an inflammation of the lung.

Results from the trial were encouraging. The overall response rate across all melanoma patients was 28%, with a median duration of response ranging from 1.9 to 24.9+ months, which is very encouraging for a new approach to treatment. On the basis of these findings, registration trials are now being explored.

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