Richard D. Carvajal, MD, director, Experimental Therapeutics, director, the Melanoma Service, Columbia University Medical Center, discusses the prognostic factors of uveal melanoma that differentiate it from other subsets of melanoma.

Uveal melanoma is biologically and clinically distinct from other melanoma subsets, Carvajal says. Regarding genomics, whereas the mutation burden of cutaneous melanoma is among the highest of all tumor types, uveal melanoma has 1 of the lowest mutation burdens, with low expression of biomarkers such as PD-L1, Carvajal says.

The clinical behavior of uveal melanoma is also different from other subsets because of its hepatotropic nature, a disease quality that is difficult to treat across tumor types, Carvajal notes. Since uveal melanoma is biologically aggressive, prone to metastasizing, and drawn to the immunosuppressive environment of the liver, many current therapies are suboptimal in the majority of patients, Carvajal concludes.

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Richard D. Carvajal, MD, discusses the prognostic factors of uveal melanoma that differentiate it from other subsets of melanoma.

Dr. Carvajal on Unique Prognostic Factors in Uveal Melanoma

Richard Carvajal, MD, Director of Experimental Therapeutics and Director of the Melanoma Service at Columbia University Medical Center, discusses the phase III SUMIT trial, a randomized, placebo-controlled, double-blind trial of selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma.

Ocular, or uveal melanoma as it is also known, is very treatment refractory when compared to cutaneous melanoma. Currently there are no approved systemic treatment options for patients with metastatic disease.

The SUMIT trial built on pre-clinical data and clinical data showing that MEK-inhibitor would be an effective data. The primary endpoint was progression-free survival (PFS).

However, the study demonstrated no different in median PFS between the experimental and control arms.

Dr. Richard Carvajal on Selumetinib/ Dacarbazine in Uveal Melanoma

Director, Experimental Therapeutics and Melanoma Service

	New York-Presbyterian Hospital/ Columbia University Medical Center

At a recent patient symposium, I had the opportunity to speak with a number of individuals affected by uveal melanoma, a rare and aggressive form of the disease that is clinically and molecularly distinct from its more common cutaneous counterpart. Unlike for advanced cutaneous melanoma, a disease for which there have been dramatic advances in treatment options, there is no FDA approved effective treatment option for metastatic uveal melanoma. Without the time pressures and relative formality associated with clinic, the discussions I had with the attendees focused less on clinical management options, and rather on the experience of being a patient with uveal melanoma or the challenges of caring for an individual with this disease. Fear and a sense of isolation are common themes raised by those affected by cancer; however, these emotions seemed amplified and were echoed repeatedly by those present at the symposium.

Although these emotions were partially allayed by the presentations by the researchers who discussed recent advances in our understanding and treatment of uveal melanoma, as well as by the nurses and social workers who spoke about managing the impact of this disease upon the patient and family, it was the opportunity for patients and family members to share their own experiences with the other symposium participants that was most effective in alleviating the fear and feeling of isolation. It was the knowledge that others were going through similar challenges to what they themselves were facing and the sense of community that rapidly developed over that weekend that the participants most appreciated.

The acknowledgment of the importance of community by those affected by rare cancers is reflected in the number of patient-established rare cancer support groups. For uveal melanoma, there is the Melanoma Research Foundation CURE OM (Community United for Research and Education of Ocular Melanoma) initiative, the Ocular Melanoma Foundation, OcuMelUK, the Eye Cancer Network, and others. For gastrointestinal stromal tumors, there is the Life Raft Group, the GIST Cancer Awareness Foundation, GIST Support UK, and GIST Support International. For neuroendocrine tumors, there is the NET Patient Foundation, the Carcinoid Cancer Foundation, and the Caring for Carcinoid Foundation.

The groups listed here are just examples of some of the many support groups available for patients and family members facing these and other rare tumors. These groups allow individuals to learn from one another, help each other navigate the complexities of our health system, identify potential treatment options, and provide emotional support. While similar organizations exist for those affected by more common cancers, the importance of these groups for those with rare cancers is augmented by the limited awareness by others regarding their diseases, the frequently more limited treatment options, and their own knowledge of the relatively limited funding and focus by the research community on finding a cure for their diseases.

The creation of rare cancer consortiums within the medical community to foster research in and enhance awareness of these malignancies, in many cases, has lagged behind the development of these patient and caretaker communities. While groups such as SARC, the CanLiv International Hepatobiliary Cancers Research Consortium, and the Lustgarten Foundation Pancreatic Cancer Research Consortium have successfully led significant research efforts in the fields of sarcoma, hepatobiliary malignancies, and pancreatic cancer, respectively, similar efforts either do not exist or are in their infancy for other rare cancers, such as adrenocortical cancer, small bowel cancers, thymomas, and many others.

Over the past several years, the uveal melanoma research community has been brought together due to the efforts of groups such as CURE OM and the International Rare Cancer Initiative (IRCI). CURE OM is the Melanoma Research Foundation’s initiative to increase awareness, education, treatment and research funding for uveal melanoma, and aims to meet these goals by providing grants, sponsoring biannual international scientific meetings, and forging partnerships with leading academic and industry organizations. Thus far, CURE OM has provided over $800,000 in grants specifically for uveal melanoma research.

IRCI is a joint initiative between the National Institute for Health Research (NIHR) Cancer Research Network (NCRN) and Cancer Research UK (CR-UK) in the United Kingdom, the National Cancer Institute (NCI) in the United States, and European Organisation for Research and Treatment of Cancer (EORTC), and the Institut National Du Cancer (INCA) in France. The aim of this initiative is to facilitate the development of international clinical trials for patients with rare cancers in order to boost the progress of new treatments for these patients. Uveal melanoma is one of the nine cancers initially targeted for the IRCI efforts, and the IRCI uveal melanoma committee meets twice yearly to coordinate international research efforts in this disease.

As defined by the National Institutes of Health (NIH), each rare cancer affects fewer than 200,000 individuals in the United States at any one time; however, approximately half of all individuals diagnosed with malignancy are diagnosed with a rare cancer. Outcomes for patients with these rare cancers are generally inferior to those diagnosed with more common cancers. Thus, it is critical that research aimed specifically at understanding and improving outcomes for patients affected by each rare cancer is supported and promoted. It is equally critical that those of us whose research focuses on rare cancers learn from our patients who have long recognized the importance of community.

It is only through the development of effective collaborations between clinicians and researchers focused on rare cancers within the United States and internationally, industrial partners, and those affected by rare cancers that the progress toward our goal of cure for these diseases will be most rapidly achieved.

Articles

Richard D. Carvajal, MD discusses the significance of researching, understanding, and improving outcomes for patients with rare cancers. 

Community and the Care of Patients With Rare Cancers

	Richard D. Carvajal, MD, Director, Experimental Therapeutics and Melanoma Service New York-Presbyterian Hospital/ Columbia University Medical Center, discusses the challenge of using vaccines for cancer therapy.

Vaccines have been explored in cancer for over 100 years, but incorporating them has been difficult, says Carvajal.

Numerous phase 2 trials have shown positive results, but many phase 3 vaccine trials have been negative. This is often due to a vaccine achieving the intended result on the immune system, but that result not translating into an anti-cancer response, explains Carvajal. Reasons for this vary, but include the target antigen not being immunologically relevant.

Richard D. Carvajal, MD, Director, Experimental Therapeutics and Melanoma Service New York-Presbyterian Hospital/ Columbia University Medical Center, discusses the challenge of using vaccines for cancer therapy.

Dr. Carvajal on Vaccine Challenges in Cancer Therapy

Richard D. Carvajal, MD, medical oncologist, Memorial Sloan-Kettering Cancer Center, describes the design of a phase II study of selumetinib versus temozolomide in uveal melanoma with GNAQ/GNA11 mutations.

It is challenging to conduct definitive trials in rare diseases, Carvajal says, and a lot of thought went into this trial's design. The trial design required the accrual of 80 patients and allowed 120 patients with the mutation. Over the course of three years, 98 patients were accrued across 15 sites.

The primary endpoint of the trial was progression-free survival (PFS). Final data showed that PFS doubled: 7 weeks with chemotherapy compared with 15.9 weeks with selumetinib (hazard ratio = 0.46).

There was also an increased response rate in patients treated with selumetinib, demonstrating biologic activity. Carvajal notes that about half of the patients treated with the drug experienced tumor shrinkage and 7 patients experienced major tumor shrinkage. In the context of the history of trials in this disease, response rates over 5% are very rare, Carvajal says.

Dr. Carvajal on the Design of a Trial in Uveal Melanoma

Richard D. Carvajal, MD, medical oncologist, Memorial Sloan-Kettering Cancer Center, discusses the background of the investigation of selumetinib for advanced uveal melanoma.

In 2008, Carvajal says, two independent laboratories identified frequent mutations in gnaq and Gna11 in uveal melanoma. These genes encode for G alpha subunits, which function to mediate signaling from cell surface receptors to downstream signaling pathways. With these mutations, Carvajal says, growth pathways, including the MAP kinase pathway, are activated. Researchers hypothesized that the inhibition of that MAP kinase pathway, perhaps at the level of MEK, could lead to clinical efficacy for selumetinib.

Researchers conducted a series of preclinical experiments to demonstrate that MEK inhibition works. Preclinical data showed that patients with uveal melanoma treated on prior studies with selumetinib experienced benefit, which led to the development of another trial to more definitively assess the benefits of MEK inhibition in this disease.

Dr. Richard D. Carvajal on the Investigation of Selumetinib

Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, describes the success of MEK inhibition using the agent selumetinib in patients with advanced uveal melanoma.

The trial exploring selumetinib was the first to discover an effective agent for patients with advanced uveal melanoma. Even though the MEK inhibitor trametinib was recently approved, Carvajal believes clinical trials are still the most appropriate area for treatment with MEK inhibitors in uveal melanoma.

View more from the 2013 ASCO Annual Meeting

Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, describes the success of MEK inhibition in patients with advanced uveal melanoma using the agent selumetinib. 

Richard D. Carvajal, MD