Novartis Presents New Data at ASCO for Zykadia® and Combination of Tafinlar® and Mekinist® in Certain NSCLC Patients with Unmet Needs

“Novartis today announced new data from two Phase II studies of Zykadia® (ceritinib), as well as one Phase II study of Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) in certain patients with non-small cell lung cancer (NSCLC). Data from these studies were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“The results of the Zykadia studies – ASCEND-2 and ASCEND-3 – reinforce the efficacy of the medicine in patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC who had received previous treatment with an ALK inhibitor and in those receiving an ALK-targeted therapy for the first time. Overall response rates (ORR) seen in these trials were 38.6% and 63.7%, respectively, based upon investigator assessment. Comparable ORR results were observed in patients with ALK+ NSCLC who entered the studies with brain metastases (33% and 58%, respectively)[1],[2].

“Separately, the study of dabrafenib in combination with trametinib in patients with metastatic BRAF V600E-mutation positive NSCLC who had failed at least one round of chemotherapy demonstrated an ORR of 63% in this population[3].”


AstraZeneca-Novartis Three-Drug Melanoma Treatment Found Safe

“A first-of-its-kind combination of three drugs to treat a deadly form of skin cancer can be taken safely, passing the first hurdle to regulatory approval for a potentially long-lasting treatment.

“The treatment was tested in an early-stage trial that was a collaboration between AstraZeneca Plc and Novartis AG. Researchers combined two drugs, dabrafenib and trametinib — a so-called doublet therapy that has been proven effective in targeting melanomas with mutations in the BRAF gene — with an immune system-based treatment that may prevent the disease from relapsing.

“Dabrafenib, sold as Tafinlar, and trametinib, sold as Mekinist, were developed by GlaxoSmithKline Plc and acquired by Novartis in March. The immune therapy drug, MEDI4736, is being developed by AstraZeneca.

“Melanoma is a rare but deadly form of skin cancer for which a number of drugs have been approved in recent years. Among them are BRAF inhibitors like dabrafenib, which target mutations found in about half of all melanoma patients, as well as immune therapies like Bristol-Myers Squibb Co.’s Yervoy, which unleash the body’s own immune system. Because the immune system can be trained, those therapies may be more durable than other forms of treatment.”


Dabrafenib plus Trametinib Improves Health-Related Quality of Life in Metastatic Melanoma

“The addition of trametinib to dabrafenib improved health-related quality of life and reduced pain in patients with BRAF V600-mutated metastatic melanoma, according to results of a randomized phase 3 study.

“The combination of dabrafenib (Tafinlar, GlaxoSmithKline) and trametinib (Mekinist, GlaxoSmithKline) received accelerated approval from the FDA in 2014 based on the results of a phase 1/2 study that compared the combination with dabrafenib monotherapy. Results from a phase 3 trial later demonstrated significantly improved PFS and objective rate response with the combination vs. dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.

“In the current analysis, Dirk Schadendorf, MD, of the department of dermatology at the University Hospital Essen in Germany, and colleagues sought to evaluate the effect of the combination on health-related quality of life among patients treated in the phase 3 study.”


Drugs That Work in Melanomas with BRAF Mutation Also Work in Lung Cancers with Same Mutation

“A subset of lung cancer patients can derive important clinical benefits from drugs that are more commonly used to treat melanoma, the authors of a new academic clinical trial in Europe have reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

“Dr. Oliver Gautschi, a medical oncologist from Lucern Cantonal Hospital in Switzerland, presented the results of the retrospective EURAF cohort study, which included lung cancer patients whose tumours carried specific mutations in the BRAF gene. The study was conducted by a network of European oncologists, without company involvement.

“BRAF mutations are commonly seen in melanoma patients, and are found in about 2% of lung adenocarcinomas, Gautschi explains. Several inhibitors of the B-Raf protein, including vemurafenib and dabrafenib, have been developed for use in melanoma patients, however there is currently no approved drug for BRAF-mutant lung cancer.

“As a result, experience with B-Raf inhibitors in lung cancer remains limited. ‘In the current study, we wanted to find out how many patients in Europe received B-Raf inhibitors outside of a clinical trial, and what their outcomes were,’ Gautschi says.

“The EURAF study gathered information on 35 lung cancer patients who had been identified as carrying BRAF mutations, who were treated with B-Raf inhibitors between 2012 and 2014.”


Triple Combo: Two Targeted Drugs Plus Immunotherapy Show Promise in BRAF-Mutant Melanoma

“Results of a new study by UCLA researchers has found that a groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combos alone, and with increased immune response and fewer side effects.

“An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

“In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients’ own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance.

“This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.”


Advanced Melanoma Therapy Should Continue beyond Disease Progression

“Continued use of vemurafenib, even after disease progression, can improve survival outcomes for patients with BRAF V600-mutated advanced melanoma.

“More than half of diagnosed melanomas harbor BRAF V600 mutations, and the introduction of targeted agents such as vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib (Tafinlar, GlaxoSmithKline) triggered a paradigm shift in the treatment of BRAF-mutated melanoma.

“However, standard treatment practice is to discontinue use of these targeted agents upon disease progression, not unlike classic regimens such as cytotoxic chemotherapy.

“Because BRAF-mutated melanoma progresses rapidly after treatment, John Haanen, PhD, of the division of immunology at Netherlands Cancer Institute, and colleagues conducted a single-institution retrospective study to determine whether continued use of vemurafenib after disease progression could extend OS in patients with BRAF V600-mutated advanced melanoma.


Good Results for Tafinlar in BRAF V600E Metastatic Melanoma

The gist: An ongoing clinical trial has shown good results for certain metastatic melanoma patients treated with the drug dabrafenib (Tafinlar). Patients in the trial have tumors with “BRAF V600E” mutations. The researchers report that 45% of patients treated with Tafinlar are still alive at two years.

“GSK today announced updated results for Tafinlar® (dabrafenib) from a planned analysis of the phase III BREAK-3 study in 250 patients with BRAF V600E mutant metastatic melanoma. These results, which include new survival data, showed 45 per cent of patients treated with dabrafenib were still alive at two years.1 The data were presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.

“Analysis of the study’s primary endpoint, progression free survival (PFS), was reported in 2012.2 Today’s results relate to a secondary endpoint from this study, with a final analysis of the overall survival (OS) endpoint expected in 2016.

“45 per cent of patients treated with dabrafenib only, were alive at two years compared to 32 per cent of patients who began treatment with dacarbazine (DTIC).  59 per cent of patients on DTIC treatment whose disease progressed subsequently received dabrafenib treatment and are included in the DTIC control arm results. While allowing this treatment cross over means patients in the control arm get the potential benefit of an active experimental drug, this can impact the comparative study findings as patients who received both medicines are included in the DTIC arm results. At the planned two-year follow up, the study showed a median OS of 20.0 months for the dabrafenib arm (95% CI 16.8-24.4) compared to 15.6 months for the DTIC arm (95% CI 12.7-21.2) [hazard ratio (HR) 0.77 (95% CI 0.52-1.13) – not statistically significant].

“ ‘We are encouraged by the 45 per cent survival rate with dabrafenib at two years,’ said Dr. Paolo Paoletti, President of Oncology, GSK. ‘Treatments for melanoma have come a long way in recent years and we’re now seeing the benefits precision medicines can bring to the right patients.’ ”


Dabrafenib–Trametinib Combination Extended Survival in Metastatic Melanoma

The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors have mutations called BRAF V600E or BRAF V600K. This treatment combines the drugs dabrafenib and trametinib. In the trial, some patients were treated with the combination, and some were treated with only the drug vemurafenib (aka Zelboraf). People who took dabrafenib and trametinib lived several months longer than people who took vemurafenib. None of the patients had taken any previous treatments for their melanoma.

“The combination of dabrafenib and trametinib significantly extended OS compared with vemurafenib monotherapy in patients with treatment-naive metastatic melanoma who harbored BRAF V600E or V600K mutations, according to results of a randomized, open-label phase 3 study.

“The regimens demonstrated comparable toxicity profiles, researchers wrote.

“ ‘Together with the previously reported phase 2 and 3 trials of dabrafenib plus trametinib as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,’ Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave-Roussy in Paris, and colleagues wrote.”


Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma


Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…