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9th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® - PER Pulse™ Recap




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PER Pulse™ Recap
Medical Crossfire® is a roundtable discussion series designed to address topics of interest to medical oncologists. In this installment of the series, which was part of the of 9th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®, moderator Dr. Jeffrey S. Weber asked expert panelists Drs. Keith T. Flaherty and Jedd D. Wolchok to comment on the use of immunotherapy, targeted therapy, and combination/sequencing therapy in metastatic melanoma (MM). The thought leaders also discussed less common melanomas (ie, mucosal, acral, and uveal) and provided commentary on two case studies.



PER Pulse™ Recap
PER Pulse™ Recap
Medical Writer: Kathleen Wildasin, MA



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PER Pulse™ Recap
9th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®

The following PER Pulse™ Recap summarizes Dr. Wolchok’s perspectives on several immunotherapy topics, including the role of ipilimumab in MM, management of immune-related adverse events (AEs), evidence supporting an abscopal effect, and use of concurrent or sequenced CTLA-4 and PD-1/PD-L1 blockade.

PER Pulse™ Recap

The discussion pertaining to the role of ipilimumab in MM first focused on survival as a way to measure responses. Dr. Wolchok made the point that the proportion of patients who achieve an objective response or long-term stable disease with ipilimumab is about 20% to 25%. Furthermore, recent data from a pooled analysis of more than 4800 patients showed that just over 20% of patients were alive more than 3 years after ipilimumab therapy, suggesting that long-term survival may be possible with this immunotherapy. Given these data, Dr. Wolchok suggested that oncologists may interpret responses differently now than they did in the past. "We’re not so much focused on quantifying the number of patients who have a radiographic response, but rather those who live for an extended period of time," he said.

Dr. Wolchok also commented on retreatment with ipilimumab. He stated that although retreatment is not part of the FDA indication for ipilimumab, data from a phase III trial demonstrated that patients who initially derived benefit from the four labeled doses of ipilimumab without severe toxicity could respond again if retreated at the time of progression. He also made the point that, in some patients, the second response may be of a greater magnitude than that previously achieved.

Dr. Wolchok explained that the immune-related AEs that have been reported with ipilimumab are best classified as tissue-specific inflammatory events, most commonly involving the skin or gastrointestinal (GI) tract in the form of dermatitis, pruritis, and enterocolitis. Because enterocolitis can be serious or fatal if not treated in a timely manner, appropriately managing evolving GI symptoms, such as diarrhea, is critically important.

In his discussion of the abscopal effect, Dr. Wolchok defined the concept and shared a patient anecdote. The abscopal effect is a phenomenon in which treating one tumor with regional therapy (eg, radiation, cryoablation, or radiofrequency ablation) triggers a systemic immune attack on untreated metastases in other areas of the body. As an example of this phenomenon, Dr. Wolchok described a patient with MM who slowly progressed while receiving ipilimumab in a phase II trial. The progression included not only symptomatic pain and enlargement of the index lesion, but also the appearance of many new lesions in the spleen. In this patient, radiation therapy to the dominant lesion led to the regression of numerous untreated metastases. Because of this abscopal effect, his patient continues to have a durable response to date. Dr. Wolchok also noted that the abscopal effect has been documented in the literature, not only with ipilimumab, but also with high-dose interleukin 2. He added that several prospective clinical trials are currently under way to further elucidate the potential benefits of the abscopal effect.

According to Dr. Wolchok, data support the idea that blockade of the PD-1 pathway can elicit responses in a substantial number of patients with MM, even those who have progressed after ipilimumab therapy. Furthermore, recent data suggest that concurrently blocking CTLA-4 and PD-1 is feasible, with an acceptable safety profile. This finding has led to the initiation of phase II and phase III clinical trials that aim to determine whether concurrent blockade of these checkpoints is better than blockade of either one alone. Dr. Wolchok went on to say that the AEs observed with concurrent therapy in the phase I trial were not unlike those observed with ipilimumab or the PD-1-/PD-L1-blocking antibodies alone. Although more patients who received concurrent therapy had multiple AEs, Dr. Wolchok said that none of the side effects were beyond the skill set of a practicing oncologist.



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PER Pulse™ Recap
9th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®

The following PER Pulse™ Recap summarizes Dr. Flaherty’s perspectives on the efficacy, safety, and dosing of small-molecule inhibitors in the treatment of BRAF-mutated melanoma.

PER Pulse™ Recap

Dr. Flaherty began the discussion by stating that the two BRAF inhibitors currently approved for the treatment of advanced melanoma -- vemurafenib and dabrafenib -- are similar in terms of efficacy, especially with regard to the initial antitumor effect, but are associated with different side effects. He summarized the safety profiles of the two agents as follows:

  • Vemurafenib can cause photosensitivity, which increases the risk of developing sunburn, even with a small amount of sun exposure. In addition to photosensitivity, other common vemurafenib-associated toxicities include rash and arthralgia. Each of these toxicities is usually mild or moderate, but in some patients, treatment modification (ie, dose interruption or dose reduction) is needed. In clinical trials, about 40% of patients treated with vemurafenib have required some type of treatment modification to continue therapy.
     
  • Dabrafenib is not associated with as much photosensitivity, but has been shown to cause fever in more patients than vemurafenib for reasons that remain to be elucidated. In addition to fever, other dabrafenib-associated side effects include rash and arthralgia. As with vemurafenib, dose interruption and dose reduction are the most plausible strategies for managing these toxicities. Cutaneous squamous cell carcinoma (SCC) also has been reported in 10% to 25% of patients with MM treated with dabrafenib. In such cases, the usual strategy is to treat the cutaneous SCC lesions and retain dabrafenib therapy.

Dr. Flaherty went on to say that performing skin exams and partnering with a dermatologist before and during BRAF inhibitor therapy are good strategies in patients with a personal history of cutaneous SCC or skin damage from the sun. In addition, he stated that scanning patients every 6 to 8 weeks is an important part of management, especially in asymptomatic patients, to determine when the disease has become resistant to therapy.

Appropriate patient selection is an important consideration when using BRAF inhibitors. According to Dr. Flaherty, patients with BRAF wild-type MM do not typically respond to these agents. When asked whether all eligible patients with BRAF-mutated melanoma should receive BRAF inhibitors as first-line therapy, Dr. Flaherty stated that data are lacking to implement such a strategy. He went on to say that patients with a BRAF mutation have multiple treatment options and that clinicians must consider the prospect of two lines of therapy – both a frontline and backup approach. For example, if a patient has symptomatic, burdensome disease, a BRAF inhibitor, with its rapid onset of action, might be the best treatment option to improve symptoms and potentially prolong survival. In contrast, ipilimumab, which has a somewhat slower onset of action, might be an appropriate frontline choice in a patient with more indolent disease to achieve a durable treatment effect. In such a case, a BRAF inhibitor could potentially still be used effectively as second-line therapy.

With respect to combining BRAF inhibitors with MEK inhibitors, Dr. Flaherty noted that both types of inhibitors target the same pathway, which probably explains why, as single agents, they have similar efficacies. Emerging data indicate, however, that dual blockade of this pathway with BRAF and MEK inhibitors may provide more robust responses, but additional clinical trial data are needed to confirm these early findings. 

Dr. Flaherty believes that further study also is needed to determine whether BRAF inhibitors should be continued beyond disease progression. He stated that if a patient has no other treatment options and is still asymptomatic, treatment continuation can be considered; however, if a patient reaches the point of symptomatic progression, the argument for treatment continuation is more difficult to make.

"If a patient has not yet seen ipilimumab specifically, as the other FDA-approved survival-impacting therapy, it is absolutely critical to have a really short trigger in terms of moving that patient over to ipilimumab therapy," he said.

According to Dr. Flaherty, the rationale behind discontinuous dosing of BRAF inhibitors is sufficient to warrant consideration for conducting prospective clinical trials. Although he feels that it is reasonable to assess the scientific evidence, which suggests that the benefit of therapy could be modestly extended with on-treatment and off-treatment periods, he stressed that the current clinical evidence showing improved survival with BRAF inhibitors is based on continuous dosing.



Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

This activity is not approved for AMA PRA Category 1 Credit™.

Funded entirely by Physicians' Education Resource®, LLC.






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