Antoni Ribas, MD, PhD, professor of medicine, University of California, Los Angeles, director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center, discusses immune-related adverse events (irAEs) in melanoma.

With immune checkpoint inhibition, physicians have to be aware of the potential irAEs, which may include autoimmune reactions or inflammatory toxicities, says Ribas. Over time, physicians have become more comfortable with using these agents. As such, physicians have been able to better recognize and manage irAEs with earlier intervention strategies, some of which may include immunosuppressive agents, such as corticosteroids.

In terms of the therapies themselves, single-agent PD-1/PD-L1 therapy shows a lower frequency of irAEs compared with when it is used in combination with CTLA-4 inhibitors. In general, combination immunotherapy shows a higher rate of toxicity, says Ribas. Most recently, the FDA approved the PD-1 inhibitor pembrolizumab (Keytruda) as adjuvant therapy for patients with high-risk stage III melanoma with lymph node involvement following complete resection. Nivolumab (Opdivo) and ipilimumab (Yervoy) also hold indications in this setting.

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Dr. Ribas on Immune-Related Adverse Events in Melanoma

Antoni Ribas, MD, PhD, professor of medicine, University of California, Los Angeles, director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center, discusses the potential for combination immunotherapy and radiation in the treatment of patients with melanoma.

The goal of this combination, Ribas says, is to achieve the abscopal effect, which is when radiation is directed toward 1 lesion and there is a systemic effect throughout the body. Based on recent data published in the New England Journal of Medicine, researchers believe this is effect is boosted when added to immune checkpoint blockade.

However, Ribas notes that this is not something that is commonly seen in the clinic. When you radiate a progressive tumor that is also being treated with PD-1 or CTLA-4 checkpoint inhibitors, most of the time you will see synergy, but not the abscopal effect, he says. Preclinical data with mouse models initially suggested the potential for this, but in the last 50 years researchers have not quite been able to reach that end goal. Ribas concludes that physicians need to better understand the immune effects of radiation therapy, as there are benefits and limitations to its use.

Dr. Ribas on Combination Immunotherapy and Radiation in Melanoma

Antoni Ribas, MD, PhD, a professor of medicine, surgery, and molecular and medical pharmacology at the University of California, discusses selecting patients for immunotherapeutic agents in melanoma.  

Right now, besides PD-L1, there are limited biomarkers available to select patients, says Ribas.

To better understand potential biomarkers, there must first be a better understanding of the presence of immune cells in the tumor and of the T-cells that are triggering PD-L1 expression, says Ribas. There will also have to be an understanding of what those T-cells are, says Ribas.

It will also have to be determined if T-cells are recognizing tumor antigens, and if the tumor is something the immune system can recognize because it has high mutational loads and has a certain genetic profile that is permissive to an immune system, says RIbas.

Dr. Antoni Ribas on the Search for Immunotherapy Biomarkers in Melanoma 

Antoni Ribas, MD, PhD, professor of Hematology and Oncology and director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center, discusses triplet therapies for patients with melanoma and the sequencing challenges associated with the approvals of additional agents in the field.

Though current immunotherapy regimens are showing significant activity in patients, Ribas says the response rate is not 100%; therefore, there needs to be investigations of other ways to modulate the immune system. Patients who benefit from PD-1 monotherapy should not receive any more, as it will lessen treatment-related toxicities, he adds. 

However, the majority of patients will require multiple-drug regimens, or sequential use of different agents, to elicit more durable responses. Future research will be able to demonstrate the optimal sequence of these various agents. 

Dr. Ribas on Triplet Regimens in Melanoma

Antoni Ribas, MD, PhD, the director of the Tumor Immunology Program Area at UCLA's Jonsson Comprehensive Cancer Center, discusses the efficacy of ipilimumab for the treatment of melanoma.

Ipilimumab blocks CTLA-4, which is a negative regulator of the immune system, and is important in the activation step of the immune system.

When the immense system is being activated, CTLA-4 has its brake effect. If the brake effect is released, Ribas says, immune system cells may be able to target the cancer, while others may target other tissues, creating some risk.

PD-1 is at the defector stage of the immune system, Ribas says, and releasing PD-1 is more likely to achieve a rapid response and be more targeted to the T cells that are cancer-specific.

Dr. Ribas on the Efficacy of Ipilimumab in Melanoma

Antoni Ribas, MD, PhD, the director of the Tumor Immunology Program Area at UCLA's Jonsson Comprehensive Cancer Center, discusses preliminary results of an ongoing trial investigating the anti-PD-1 antibody lambrolizumab in patients with advanced melanoma.

Clinically meaningful activity was observed in a substantial number of patients in the trial, Ribas explains. The overall response rate by RECIST criteria was 38% with 90% of patients experiencing durable responses. At the highest dose, response was 52%. Most of the adverse events with lambrolizumab were minimal, Ribas suggests.

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Antoni Ribas, MD, PhD, from UCLA's Jonsson Comprehensive Cancer Center, discusses preliminary results of an ongoing trial investigating the anti-PD-1 antibody lambrolizumab in patients with advanced melanoma. 

Dr. Ribas on Anti-PD-1 Agent Lambrolizumab in Melanoma

Antoni Ribas, MD, Department of Medicine, Division of Hematology-Oncology; Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), describes a phase I/II trial that plans to combine the BRAF inhibitor vemurafenib (Zelboraf) and the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy) for patients with 

Indirect evidence from previous clinical trials seems to support the efficacy of this combination, Ribas explains. The rationale behind the trial is that treatment with ipilimumab will take advantage of the vulnerability created by BRAF inhibition with vemurafenib, which does not affect the immune system. Ribas believes the combination may result in either the prolongation of survival or a more durable response to therapy.

The goal of the phase I portion of the trial is to examine the safety and tolerability of the combination. The phase II portion aims for a primary endpoint of overall survival. At this point, it is still largely unknown whether there will be any interactions between the two classes of agents. For more information, visit 

Antoni Ribas, MD, from the UCLA Jonsson Comprehensive Cancer Center, discusses a phase I/II trial combining vemurafenib and ipilimumab for metastatic melanoma.

Dr. Ribas on Combining Vemurafenib and Ipilimumab

Antoni Ribas, MD, Department of Medicine, Division of Hematology-Oncology; Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), describes the unique combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, which both inhibit activating mutations in the mitogen-activated protein kinase (MAPK) pathway.

Both dabrafenib and trametinib are being investigated as single agents and in combination for patients with metastatic melanoma who harbor 

 gene mutations. Research into the two drugs as monotherapies and in combination was presented at the American Society of Clinical Oncology (ASCO) annual meeting in June and is published in 

The unique combination of dabrafenib and trametinib prevents the development of MAPK-driven acquired resistance. Additionally, the combination is able to block the formation of the secondary cutaneous squamous cell carcinomas that are common with single agent BRAF inhibitors. The unique ability to increase antitumor activity while decreasing toxicities is an uncommon trait for a combination therapy, Ribas notes.

Further data on the combination of trametinib and dabrafenib was presented at the European Society for Medical Oncology (ESMO) congress held in Vienna, Austria, from September 28 - October 2, 2012. 

Dr. Antoni Ribas, from UCLA Jonsson Comprehensive Cancer Center, on the Benefits of MAPK Inhibition With Dabrafenib and Trametinib

Antoni Ribas, MD, PhD

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