New Drug Combo Might Soon Be an Option for People with Advanced Melanoma with BRAF V600 Mutation

The gist: A combination of the drugs cobimetinib and vemurafenib (aka Zelboraf) might soon become a new treatment option for U.S. patients with advanced melanoma whose tumors have a V600 mutation in the BRAF gene. The drug company Genentech submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) asking for FDA approval of the combo. In a clinical trial, Genentech researchers found that patients who take cobimetinib along with vemurafenib do better than patients who take vemurafenib alone. Both drugs are targeted therapies.

“Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the company has submitted a New Drug Application (NDA) for cobimetinib to the U.S. Food and Drug Administration (FDA) for treatment, in combination with Zelboraf® (vemurafenib), for people with BRAF V600 mutation-positive advanced melanoma. The submission is based on results of the coBRIM Phase III study, which showed people who received the MEK inhibitor cobimetinib plus Zelboraf lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.

” ‘In the past several years we have made significant progress in treating advanced melanoma, but it remains a serious and difficult to treat cancer that affects more people each year,’ said Sandra Horning, M.D., chief medical officer and head of Global Product Development. ‘We look forward to working with the FDA as they review the NDA and hope the combination of cobimetinib and Zelboraf will soon become a new option for people with BRAF mutation-positive advanced melanoma.’

“In the coBRIM study, cobimetinib and Zelboraf reduced the risk of disease worsening or death by half (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf alone. The safety profile was consistent with a previous study of the combination. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab abnormalities. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea.”


Exelixis Announces Positive Preliminary Data From an Investigator-Sponsored Phase 1 Trial of XL888 and Vemurafenib

The gist: A drug called XL888 has shown promise for people with unresectable stage III/IV BRAF V600 mutation-positive melanoma. It was tested in a clinical trial with volunteer patients. It is hoped that XL888 could help prevent resistance to the drug vemurafenib (aka Zelboraf). In the trial, a combination of XL888 and vemurafenib was safely given to patients. The patients showed good response to the treatment.

“Exelixis, Inc. (EXEL) today announced preliminary results from a phase 1 investigator-sponsored trial (IST) evaluating the safety and activity of XL888, an Exelixis-discovered small molecule oral inhibitor of Heat Shock Protein 90 (HSP90), in combination with vemurafenib in patients with unresectable stage III/IV BRAF V600 mutation-positive melanoma. Safety and efficacy results support the further investigation of 90 mg of XL888 twice weekly (BIW) and vemurafenib 960 mg twice daily (BID) in additional studies that would include a third agent.

“The trial results were presented today by Keiran Smalley, Ph.D., an investigator on the trial and an associate professor at H. Lee Moffitt Cancer Center, Tampa, Florida, in a late-breaking oral presentation session at the Society for Melanoma Research 2014 International Congress, which is taking place November 13-16, 2014, in Zurich, Switzerland. Based on these results, as well as findings from coBRIM, the phase 3 pivotal trial of cobimetinib, an Exelixis-discovered MEK inhibitor, and vemurafenib in previously untreated metastatic melanoma patients with a BRAF V600 mutation, the Moffitt Center plans to initiate a phase 1b IST of the triple combination of vemurafenib, cobimetinib, and XL888 in a similar patient population.

“ ‘The BRAF inhibitor vemurafenib is active in BRAF-mutated malignant melanoma, but development of resistance is common. Preclinical studies led by Keiran Smalley, Ph.D. suggested that most BRAF inhibitor resistance mechanisms involve proteins that are clients of HSP90, and the preclinical evaluation of XL888 showed that it is highly active in vemurafenib-resistant melanoma models,’ said Jeffrey Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute in Tampa, FL. ‘The current phase 1 data show that both drugs can be given together, and compelling initial response results suggest potential cooperative activity.’ “


Roche Drugs Shown Effective in Breast and Skin Cancers

The gist: Drug company giant Roche is mixing drugs in new combinations to provide melanoma and breast cancer patients with potential new treatments. This article outlines the company’s endeavors.

“Mixing drugs in various combinations has given Roche Holding AG (ROG) effective new treatments for skin and breast cancer strains.

“Combining Zelboraf, a melanoma drug now on the market, with experimental cobimetinib showed significant improvement over Zelboraf alone, according to data presented today at the European Society for Medical Oncology’s annual meeting in Madrid.

“Roche said yesterday that a combination of two breast cancer drugs, plus chemotherapy, could add almost 16 months to the lives of a class of patients. Roche today also reported data from an early-stage study of its MPDL3280A immune therapy treatment in bladder cancer which showed a 52 percent response rate. If successfully developed, the drug will be the first new treatment for bladder cancer in 30 years, the Basel, Switzerland-based company said.

“ ‘This is a good meeting for Roche,’ said Asthika Goonewardene, an analyst with Bloomberg Intelligence. ‘They’re firing in three different areas.'”


Successful Vemurafenib Treatment of Progressive BRAF V600E–Mutated Anaplastic Pleomorphic Xanthoastrocytoma

Editor’s note: Oncologists sometimes suggest a treatment based on specific mutations found in a patient’s tumor. People with metastatic melanoma whose tumors have mutations in the BRAF gene are often treated with the targeted drug vemurafenib (brand name Zelboraf). But BRAF mutations can also be found in other types of cancer. This story tells how a patient with a brain tumor that had a BRAF mutation was successfully treated with vemurafenib.

“The BRAF inhibitor vemurafenib (Zelboraf) is approved for treatment of BRAF-mutated metastatic melanoma. There are reports indicating that vemurafenib may be active in the treatment of intracranial neoplasms with BRAF mutations. As reported in the Journal of Clinical Oncology, Lee et al from Brigham and Women’s Cancer Center successfully treated a BRAF V600E–mutated glioma with vemurafenib monotherapy.

“The patient was a 41-year-old man with WHO grade 2 anaplastic pleomorphic xanthoastrocytoma with a BRAF V600E mutation who developed radiographic progression despite surgery, radiation, and treatment with temozolomide. The patient was initially observed with serial imaging for approximately 2 years until magnetic resonance imaging (MRI) showed increased surrounding enhancement. Treatment with temozolomide was followed by radiographic progression after two cycles.”


Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”


Cancer Drugs Yervoy, Xtandi Get NICE Thumbs Up

“Cost regulators for the National Health Service in England and Wales have this morning issued guidance recommending the use of Bristol-Myers Squibb’s Yervoy (ipilimumab) for skin cancer and Astellas’ Xtandi (enzalutamide) for prostate cancer.

“First-line use of Yervoy will be funded in patients with advanced malignant melanoma when the full tumour cannot be removed or the cancer has spread to other parts of the body.

“The drug costs £3,750 per 10-ml vial or £15,000 per 40-ml vial, but B-MS has also agreed a patient access scheme with the Department of Health, in which it will be sold to the NHS at a discounted price.

“NICE analysis concluded that the most plausible cost per Quality Adjusted Life Year (QALY) was £47,900 for Yervoy compared with the chemotherapy dacarbazine and £28,600 per QALY compared with Roche’s Zelboraf (vemuraf [sic]).”


UPDATE 1-Roche Skin Cancer Drug Meets Main Goal in Combination Study

“An experimental drug from Roche helped people with an advanced form of skin cancer live longer without their disease worsening when used in combination with another treatment, the Swiss drugmaker said on Monday.

“Pharmaceutical companies are looking to combination therapy to yield better results and drug cocktails are expected to be crucial as oncologists seek to block cancer on multiple fronts.

“Cobimetinib, which is being developed in collaboration with Exelixis Inc, is designed to be used with another Roche drug called Zelboraf for patients with tumors that have a mutation in a gene known as BRAF that allows melanoma cells to grow.”

Editor’s note: Cobimetinib is meant to be used in combination with the targeted therapy Zelboraf (vemurafenib) to treat people with melanoma whose tumors have a mutation in the BRAF gene. Oncologists can use a method called molecular testing to figure out whether a patient has a BRAF mutation.


ASCO 2014: Highlights for People Dealing with Melanoma


Every year, new cancer treatment insights are shared at the American Society of Clinical Oncology (ASCO) Annual Meeting. Here are some of the most notable recent developments in melanoma treatment, gleaned from researchers’ presentations at ASCO last month: Continue reading…


Ipilimumab Yielded no Major Benefit in Prostate Cancer Bone Metastases

“Ipilimumab failed to significantly extend OS compared with placebo for treatment of bone metastases in patients with castration-resistant prostate cancer, according to results of a randomized, double blind, phase 3 trial.

“However, researchers indicated they observed signs of activity with ipilimumab that warrant further investigation.”

Editor’s note: Yesterday we published a hopeful story about the possibility that immunotherapy drugs like ipilimumab may soon be approved for treating some men with prostate cancer. But this particular study found disappointing results for the treatment; it did not significantly improve survival time when used to treat bone metastases in patients with castration-resistant prostate cancer. Nonetheless, ipilimumab may still be found to help some prostate cancer patients.