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].”


Cobimetinib and Vemurafenib Combination Treatment Is Highly Active in BRAF+ Melanoma

“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced follow-up data from two studies of the investigational MEK inhibitor cobimetinib in combination with Zelboraf® (vemurafenib). Updated data from the pivotal coBRIM Phase III study showed the combination helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of one year (12.3 months) without their disease worsening or death (progression-free survival; PFS) compared to 7.2 months with Zelboraf alone (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.46-0.72).1

“ ‘The combination of cobimetinib and Zelboraf extended the time people lived without their disease getting worse to a year,’ said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. ‘These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow.’ “


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.”


More on the Use of Nivolumab and Ipilimumab in Melanoma

“As single agents, immune checkpoints blockers nivolumab (Opdivo) and ipilimumab (Yervoy) both have demonstrated improvements in overall survival for patients with metastatic melanoma. However, when taken together, these agents have demonstrated even more impressive findings.

“Earlier reported findings from a phase I dose-escalation study demonstrated that the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab demonstrated encouraging antitumor activity. Additionally, an ongoing phase III clinical trial is assessing nivolumab or ipilimumab plus nivolumab versus ipilimumab alone in previously untreated patients with advanced melanoma (CheckMate-067; NCT01844505).

“At the 2015 AACR Annual Meeting, F. Stephen Hodi, MD, presented findings from the phase II CheckMate-069 trial, further validating the efficacy seen with the combination in earlier studies and providing hints at what could be expected in the phase III trial. In this analysis, nivolumab plus ipilimumab delayed disease progression by 60% compared with 11% in patients who were given ipilimumab alone (HR = 0.40; 95% CI, 0.23-0.68; P .001). With the combination, the ORR was 61% in BRAF wild-type (WT) patients and 52% in BRAF-positive patients.

“Included in the phase II CheckMate-069 study were 142 treatment-naïve patients with advanced melanoma with a median patient age of 65 years. Patients were randomized to receive ipilimumab at 3 mg/kg with either nivolumab at 1 mg/kg (n = 95) or placebo (n = 47) every 3 weeks for four doses. This was followed by nivolumab or placebo every 2 weeks until progression or unacceptable toxicity.”


NRAS & BRAF Mutational Status May Help Guide Therapy in Melanoma Patients

“A new study is suggesting that it may be important to look at mutational status when determining adjuvant treatments for melanoma patients. Researchers at the University of North Carolina (UNC) School of Medicine are now reporting that NRAS and BRAF mutations in melanoma patients should be identified early, and may need to be taken into consideration when establishing treatment paradigms.

“The results of this study were published online in the April 9, 2015 issue of JAMA Oncology.

“Researchers looked at data from the Genes, Environment, and Melanoma (GEM) Study, which included 912 patients with a median follow-up of 7.6 years. They examined tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status.  They found 13% of the patients had tumors with NRAS mutations, 30% had BRAF mutations, and 57% had neither.

“There was no statistically significant difference in the 5-year survival rates for patients with NRAS or BRAF-mutated melanoma tumors compared with survival in those patients with tumors lacking mutations. However, there were lower 5-year survival rates for patients with higher-risk tumors with mutations. The study suggested the 5-year survival rate was 73% for patients with high-risk NRAS-mutated tumors, 71% for patients with high-risk tumors with BRAF mutations, and 82% for patients with high-risk cancer and lacking either mutation.”


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.”


Nivolumab Works in Melanoma Patients for Whom Previous Treatments Did Not

“More patients with advanced melanoma who had progressed on ipilimumab with or without a BRAF inhibitor were able to achieve an objective response when treated with the PD-1 immune checkpoint inhibitor nivolumab than with alternative chemotherapy options, according to the interim analysis results of the CheckMate 037 trial published recently in Lancet Oncology.

“In fact, the rate of objective response was about threefold greater with nivolumab compared with investigator’s choice of chemotherapy; however, no difference in progression-free survival in the intention-to-treat population was noted.

“These results were the basis of the December 2014 US Food and Drug Administration accelerated approval of nivolumab for this patient population.

“ ‘Findings from our study show that nivolumab leads to clinically meaningful improvements in the proportion of patients achieving an objective response and provide a manageable safety profile when compared with chemotherapy,’ wrote Jeffrey S. Weber, MD, of Moffitt Cancer Center, Tampa, Florida, and colleagues. ‘Nivolumab can now be considered as a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAF V600–mutated.’ ”


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.”