ESMO 2014 Press Release: New Data on Combination Treatments for Melanoma

The gist: Researchers tested a new melanoma treatment in a clinical trial—a research study with volunteer patients. The treatment combines the targeted drugs vemurafenib and cobimetinib. All of the patients who participated in the trial had melanoma tumors with mutations in the BRAF gene, as detected by molecular testing. The combination treatment proved more beneficial for these patients than vemurafenib alone.

“Combination therapy with both BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib achieves greater progression-free survival and response rates than vemurafenib plus placebo in BRAF-mutation positive melanoma, according to phase III data presented at the ESMO 2014 Congress in Madrid, Spain.

“ ‘Before the results of this study, we knew that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumour shrinkage; however until the performance of a scientifically rigorous randomised trial the potential magnitude of this benefit could not be measured,’ says lead author Dr Grant McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia.

“The ongoing CoBRIM study enrolled 495 treatment-naive patients with BRAFV600-mutation-positive unresectable locally advanced or metastatic melanoma. Patients were randomised to received a 28-day treatment cycle of vemurafenib (960 mg, twice daily), and either cobimetinib or placebo (60 mg daily from days 1-21), with a primary end-point of progression-free survival.

“Patients in the combination arm of the study showed a significantly improved median progression-free survival of 9.9 months, compared to 6.2 months in the placebo arm, and a 49% reduction in the risk of progression. Researchers observed a response rate of 68% in the combination arm and 45% in the control arm, including a complete response in 10% of patients treated with combination therapy compared to 4% of patients treated with vemurafenib alone.”


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]).”


Combined MEK, BRAF Inhibitors Promising in Melanoma

The gist: Researchers have conducted a clinical trial with volunteer patients to test a new melanoma treatment that combines the drugs cobimetinib and vemurafenib. The participants all had melanoma tumors with BRAFV600 mutations. People with BRAFV600 mutations often become resistant to treatment if they take a “BRAF inhibitor” like vemurafenib. The hope is that drugs like cobimetinib can be given alongside vemurafenib to circumvent resistance. The researchers found that the combination treatment was safe for these patients, and there was some promising evidence that the treatment was effective, but more follow-up will be needed.

“Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.

“Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.

“According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, ‘which frequently reactivates the MAPK pathway through MEK.’ Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.”


GSK's Melanoma Study Stopped Early on Survival Boost

The gist: In the U.S. and Australia, oncologists are allowed to prescribe a treatment that combines the drugs Mekinist (trametinib) and Tafinlar (dabrafenib) for people with unresectable or metastatic melanoma whose tumors have a V600E or V600K mutation in the BRAF gene. European regulators would like to see more data on the benefits and risks of the treatment before approving it for European patients. The company that produces the treatment was conducting a clinical trial with volunteer patients to capture that data, but has now decided to halt the trial, which was comparing the combo treatment to the drug Zelboraf (vemurafenib). The trial found that the combo treatment has such a significant improvement on patient survival that the patients who had been taking vemurafenib for comparison should be allowed to switch to the combo treatment, and the trial ended early.

“GlaxoSmithKline has stopped a Phase III study of its combination therapy for advanced cutaneous melanoma ahead of schedule after it showed a significant survival benefit.

“The UK drug giant said an Independent Data Monitoring Committee (IDMC) has made the recommendation as it emerged patients with metastatic melanoma – carrying a BRAFV600 mutation – who took a combo of Mekinist (trametinib) and Tafinlar (dabrafenib) demonstrated an overall survival benefit compared to those taking vemarufenib.

“Safety signals were also good, remaining consistent with that for the MEK inhibitor and BRAF inhibitor observed to date, the firm said.”


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.


Combining Targeted Therapy with Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

Editor’s note: Targeted therapies that fight tumors with specific genetic mutations opened up a new era in cancer treatment, but many patients become resistant to these treatments, and their cancer grows back. A new type of treatment called immunotherapy boosts a patient’s own immune system to fight cancer. Researchers are hopeful that combining targeted drugs with immunotherapy drugs could be highly effective. This article discusses the idea of combining immunotherapy with targeted drugs developed to treat melanomas with mutations in the GRAF gene. It is a scientific article, but may interest some patients and caregivers dealing with BRAF-mutant melanoma.

“Hu–Lieskovan S, et al. – In this review,the authors present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

  • “Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer.
  • “Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high.
  • “Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma.
  • “These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration.
  • “Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.
  • “However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.”

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…