Anti–PD-1 Antibody Pembrolizumab Shows Activity and Good Tolerability in Ipilimumab-Refractory Advanced Melanoma

The gist: Some people with melanoma who do not respond to treatment with ipilimumab (Yervoy) might benefit from immunotherapy drugs, which activate a patient’s own immune system to fight cancer. Researchers are testing an “anti-PD-1” immunotherapy drug called pembrolizumab in a clinical trial with volunteer patients. The results suggest that pembrolizumab might be a good treatment for advanced melanoma patients who have few other options. Learn more about immunotherapy treatments for melanoma at our Need to Know blog.

“As reported in The Lancet by Robert et al, the anti–programmed death receptor-1 (PD-1) antibody pembrolizumab produced responses and was well tolerated at two dose levels in an expansion cohort of a phase I trial in patients with ipilimumab (Yervoy)-refractory advanced melanoma.

“In this open-label multicenter trial, 173 adult patients with advanced melanoma progressing after at least two ipilimumab doses were randomly assigned to receive intravenous pembrolizumab at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was overall response rate on independent central review…

“The investigators concluded, ‘The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.’ ”

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.”

Two Mutations Linked to Success of Adoptive T-Cell Therapy in Melanoma

“Two novel mutations, KIF2C and POLA2, appeared to be linked to complete cancer regression in two patients with metastatic melanoma who underwent adoptive T-cell immunotherapy, according to study results.

“ ‘This study provides the technical solution to identify mutated tumor targets that can stimulate immune responses, which is one of the major bottlenecks in developing a new generation of adoptive T-cell therapy,’ Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI, said in a press release. ‘The two targets identified in this study play important roles in cancer cell proliferation.’ ”

Editor’s note: In order to improve new treatments so that more people can benefit from them, it is useful to figure out why they are particularly successful for certain patients. In this story, researchers wished to know why two people with metastatic melanoma experienced complete disappearance of their tumors in response to a treatment called adoptive T-cell transfer. In adoptive T cell transfer, immune system cells are collected from either the patient’s tumor or the blood supply near the tumor. In the laboratory, these cells are multiplied to produce high numbers of ‘killer’ T cells, which are then infused back into the patient, where they are able to recognize and attack cancer cells. It was found that the two patients with exceptionally good responses had two genetic mutations in their tumor cells that the T cells were able to attack directly. The discovery could help researchers learn how to make adoptive T cell transfer more effective for more people.

European Commission Approves Mekinist for Metastatic Melanoma

“The European Commission has given marketing authorization for trametinib as monotherapy for unresectable or metastatic melanoma in adults with a BRAF V600 mutation, GlaxoSmithKline announced.

“Trametinib (Mekinist), a kinase inhibitor that targets MEK1/MEK2 activation and kinase activity, has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy. Before taking trametinib, patients must have confirmation of a BRAF V600 mutation using a validated test.”

Editor’s note: The European Commission (the executive body of the European Union) has approved the drug trametinib (brand name Mekinist) as a treatment for unresectable or metastatic melanoma in adults whose tumors have a mutation called V600 in the BRAF gene. The approval is based on promising results for the drug in a clinical trial.

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…

PD-1 Antibody Demonstrated Encouraging Activity in Metastatic Melanoma

“Heavily pretreated patients with metastatic melanoma who received the humanized anti-PD-1 monoclonal antibody pidilizumab demonstrated encouraging rates of 12-month OS, according to results of a phase 2 study presented at the ASCO Annual Meeting.

“ ‘Activity was previously seen [with pidilizumab] in two lymphoma populations in phase 2 studies,’ researcher Michael B. Atkins, MD, deputy director of Georgetown-Lombardi Comprehensive Cancer Center in Washington, and professor of oncology and medicine at Georgetown University School of Medicine, said during a presentation. ‘Correlative studies in those lymphoma populations supported a PD-1/PD-L1–linked mechanism of action, and importantly there was no change or an increase in PD-1–positive CD4 and CD8 lymphocytes and CD14 monocytes following the drug, excludingantibody-dependent cellular cytotoxicity of PD-1–positive cells as a consequence of therapy.’ “

Editor’s note: Pidilizumab is a new drug that that might benefit people with metastatic melanoma who have already been heavily treated. A recent clinical trial testing it in volunteer patients found some promising results, but further studies will be needed to see how to use pidilizumab most effectively, in terms of dosage and combining it with other drugs. Pidilizumab is an “anti-PD-1” immunotherapy, meaning that it interacts with a protein called PD-1 to boost a patient’s own immune system to fight cancer. Learn more about immunotherapy treatments for melanoma at our Need to Know blog.

UPDATE 1-Bristol Immunotherapy Prolongs Survival in Melanoma Trial

“A late-stage trial testing Bristol-Myers Squibb Co’s cancer immunotherapy nivolumab in advanced melanoma patients was halted early after it was determined that the drug was likely to prolong survival, the company said on Tuesday…”

“The 418-patient Phase III study, called CheckMate -066, was testing nivolumab as an initial, or first line, therapy for patients with advanced melanoma, the deadliest form of skin cancer.”

Editor’s note: In a clinical trial with volunteer patients, researchers have been testing a new drug called nivolumab to see if it is a good first treatment for people with advanced melanoma. Nivolumab is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. In the clinical trial, some of the patients were being treated with nivolumab, and some with a standard chemotherapy drug called dacarbazine. Nivolumab showed so much better results than dacarbazine that the trial was ended early, and the patients who had been taking dacarbazine were switched to nivolumab.