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Old 10-06-2014, 03:18 PM
gdpawel gdpawel is offline
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Default Combo of BRAF and MEK Inhibitors in Melanoma

For patients with advanced melanoma that is BRAF-mutation positive, the combination of a BRAF and MEK inhibitor works better than a BRAF inhibitor alone. The data come from 2 phase 3 trials presented here at the presidential session of the European Society for Medical Oncology (ESMO) Congress 2014.

Experts here say that such combinations should be the new standard of care in this patient population, which accounts for about 40% of all melanoma.

At present, the first-line treatment for these patients is a BRAF inhibitor used alone, but while these drugs can elicit dramatic responses, they do not last, and after about 5 or 6 months, patients relapse. The tumor develops resistance to the drug via the MAPK pathway, and this is blocked by a MEK inhibitor. Adding a MEK inhibitor to the BRAF inhibitor from the beginning of treatment blocks this resistance pathway and improves outcomes.

The 2 new trials are known as COMBI-v and coBRIM.

Both studies used vemurafenib (Zelboraf, Roche/Plexxikon) as the single BRAF inhibitor, but each used a different combination of BRAF and MEK inhibitor.

The coBRIM study looked at the combination of vemurafenib with an investigational MEK inhibitor cobimetinib (under development by Roche/Exelixis).

The COMBI-v study used the combination of dabrafenib (Tafinalar) and trametinib (Mekinist), both from by GlaxoSmithKline. This combination is already approved in the United States (on the basis of response rate data), but not in Europe. The European authorities said that they wanted to see phase 3 data, and these are what were presented at the ESMO meeting.

The results from both trials confirm improvement with the combination of a BRAF plus MEK inhibitor when compared with a BRAF inhibitor used alone, said Ignacio Melero, MD, PhD, professor of immunology at the Universidad de Navarra in Pamplona, Spain, who acted as a discussant for the studies.

The combinations had better response rates, progression-free survival, and overall survival than a BRAF inhibitor alone.

The combinations had similar toxicity to that seen with the BRAF inhibitor used alone, he said, but there was a notable reduction in the skin adverse events that are typically seen with BRAF inhibitors used alone, such as cutaneous squamous cell carcinoma and hyperkeratosis.

If mature data confirm the present observations, then the combination of a BRAF and MEK inhibitor is the new standard for targeted therapy of BRAF-positive melanoma, he told delegates in a packed room.

However, Dr. Melero pointed out that the improvement in progression-free survival was about 4 months, and the improvement in overall survival about 2 months (although these overall survival data are immature). He speculated about why the overall survival was not longer, and wondered if there were early events driven by bad-prognosis patients.

He also mentioned the high price of these drugs, and urged the oncology community not to accept a straight addition of costs for the 2 drugs in the combination.

Vemurafenib Plus Cobimetinib

The coBRIM study was presented at the meeting by Grant McArthur, MD, head of the cancer therapeutics program at the Peter MacCallum Cancer Centre in Melbourne, Australia. It was conducted in 495 treatment-naive patients with BRAF V600-mutation-positive unresectable locally advanced or metastatic melanoma.

The primary end point was progression-free survival, and this was increased significantly by the combination of vemurafenib with cobimetinib, with a median progression-free survival of 11.3 months, compared with 6.0 months with vemurafenib alone (hazard ratio [HR], 0.60; P = .0003).

There was also a higher response rate seen with the combination, which was "striking," Dr. Grant said. The overall response rate for the combination was 68% vs 48% with vemurafenib alone, and complete responses were seen in 10% vs 4% of patients, respectively.

Dr. Grant said that the overall survival data are immature, but the preliminary results are promising, he said. They favor the combination, suggesting that the combination reduces the risk for death by 35% compared with vemurafenib alone (HR, 0.65).

Turning to adverse events, Dr. Grant noted that there was a much lower rate of cutaneous squamous cell carcinoma with the combination (3% vs 11% with vemurafenib alone), and also of hyperkeratosis and alopecia, but both groups of patients developed photosensitivity. There was a higher rate of gastrointestinal events, such as nausea and vomiting, with the combination, but this was manageable with supportive care. In addition, adverse effects typical of MEK inhibitors, such as serous retinopathy and a decrease in ejection fraction, were seen, but no patients went on to develop cardiomyopathy, Dr. Grant said.

The combination of a BRAF and MEK inhibitor will become the new standard first-line therapy for patients with BRAF-positive advanced melanoma, he predicted.

"Before the results of this study, we knew that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumor shrinkage. However, until the performance of a scientifically rigorous randomized trial, the potential magnitude of this benefit could not be measured," Dr. McArthur commented.

Combination of Dabrafenib and Trametinib

The COMBI-v study was conducted in 705 patients with advanced BRAF-positive melanoma, and was presented at the meeting by Caroline Robert, MD, PhD, head of dermatology at the Institut Gustave-Roussy in Paris. It was stopped early due to benefit, which emerged from an interim analysis, which became the final analysis.

The primary end point of this trial was overall survival, which was significantly improved by the combination of dabrafenib and trametinib. The median overall survival for the combination has not yet been reached vs 17. 2 months for vemurafenib alone (HR, 0.69; P = .005). At the time of the analysis (median follow-up was 10 to 11 months), 28% of the patients on the combination had died vs 35% on vemurafenib alone.

Significant improvements were also seen in secondary end points. The median progression-free survival with the combination was 11.4 months vs 7.3 months with vemurafenib alone (HR, 0.56; P < .001). Overall response rate with the combination was 64% vs 51% with vemurafenib alone, and complete responses were seen in 13% vs 8% of patients, respectively. The duration of response was 13.8 months with the combination vs 7.8 months with vemurafenib alone.

These results further corroborate the early preclinical data that suggested that a more complete blockade of the MAP kinase pathway with both a BRAF and a MEK inhibitor delays the emergence of resistance, translating into longer survival for the patients, Dr. Robert concluded.

She also emphasized the fact that there was a much lower rate of cutaneous squamous cell carcinoma and hyperproliferation seen with the combination, and that photosensitivity was seen only with vemurafenib alone, and not with the combination. The main adverse events seen with the combination that were not seen with vemurafenib alone were pyrexia and a decrease in ejection fraction, she added.

"Convincing Evidence" for Combinations

Commenting on the results from the 2 new studies, Reinhard Dummer, MD, from the University of Zurich Hospital and ESMO faculty coordinator for melanoma, said: "While monotherapy with a BRAF inhibitor is currently considered as a standard of care for patients with BRAF-mutated advanced melanoma, the data from these 2 trials, along with trial data presented earlier this year, provide convincing evidence that combination therapy with either dabrafenib and trametinib or vemurafenib and cobimetinib will be the standard systemic therapy for this patient population."

The data show that the combinations provide more efficacy in terms of response rate and progression-free survival, and there is also now an overall survival benefit documented for the trametinib and dabrafenib combination, he said.

At the same time, there is a similar to lower load of adverse reactions, Dr. Dummer noted. "Of special relevance is the lower risk for new cutaneous malignancies, which might be a surrogate for other secondary malignancies associated with the use of monotherapy BRAF inhibitors," he said.

The COMBI-v study was funded by GlaxoSmithKline. The coBRIM study was funded by Roche/Exelixis.

European Society for Medical Oncology (ESMO) Congress 2014: Abstracts 5LBA_PR and 4LBA_PR. Presented September 29, 2014.

Citation: New Standard in Melanoma: Combo of BRAF and MEK Inhibitors. Medscape. Sep 30, 2014.
Gregory D. Pawelski
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Old 10-06-2014, 03:20 PM
gdpawel gdpawel is offline
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Default The Future of Functional Profiling Platform and Targeted Agents

In a presentation at the 2010 ASCO Annual Trade Show, Dr. Robert Nagourney showed clinical response rates were doubled by using the Phenotype Analysis of Programmed Cell Death (functional profiling) platform with standard FDA approved chemotherapeutic agents in NSCLC patients.

If he can achieve these types of results by simply reconfiguring existing drugs, it suggests that the functional profiling platform could provide even better results as they introduce larger numbers of active, targeted agents.

One such agent, PF-1066 provided an overall response rate of 64 percent when patients were selected for the EML4-ALK fusion oncogene. With this type of approach, the selection of candidates for therapy predicated upon the biology of the patient, is precisely the premise underlying all of phenotype analysis.

While the PF-1066 data was strongly positive, it represented a very select population of lung cancer patients who carry a specific gene profile. Of all NSCLC patients, only 3-4 percent carry this gene.

While recognizing targets like EGFR and ALK continue to improve responses, the functional profiling platform is capable of identifying patients for response even when the specific underlying genetic mechanism may be less well characterized.

The capacity of the functional profiling platform to measure global cellular response enables his lab to select candidates for whom no known genetic predisposition exists.

At an experimental and molecular therapeutics session at the AACR 102nd annual meeting in 2011, Dr. Robert Nagourney may a presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, he saw a good signal for both compounds utilizing the Phenotype Analysis of Programmed Cell Death (functional profiling) platform. Second, he saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with their expectation.

After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that he blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This is interesting, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway.

Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in his report was, perhaps, its most important. Specifically, that his lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest.

When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the functional profiling platform to identify important leads much faster than the clinical trial process.
Gregory D. Pawelski
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Old 10-06-2014, 03:23 PM
gdpawel gdpawel is offline
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Default Good Combinations of Targeted Drugs

According to an article in the Journal of the National Cancer Institute, it is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects.

Intelligent combinations are a principle focus of functional cytometric profiling. In fact, the application of synergy analyses may represent one of the most important applications of the platform, enabling clinicians to explore both anticipated and unanticipated favorable interactions.

Equally important may be the platform's capacity to study drug antagonism wherein two effective drugs counteract each others' benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs because they can, and then see what happens.

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicted on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

Functional cytometric profiling assay labs have always tested new drugs in combination with each other, simultaneously measuring direct anti-tumor activity and anti-vascular activity. These analyses are revolutionizing the way the platform applies newer classes of drugs and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations.
Gregory D. Pawelski
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