Treating 'Out-of-the-Box' Melanoma Patients With Anti-PD-1s

Alexander M. Castellino, PhD

June 14, 2016

CHICAGO — Clinical trials that led to the approval of new therapies often have strict exclusion criterion, and so yield no data on how the drugs fare in patients with preexisting conditions. For that, data from the real-world setting are needed, and the latest to come in for the anti-PD-1 immunotherapies are data to show that they are safe and effective even in patients with preexisting autoimmune diseases.

Researchers reporting a retrospective study at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting say that the new data are reassuring and that preexisting autoimmune diseases should not preclude treatment with immunotherapy with the PD-1 inhibitors pembrolizumab (Keytruda, Merck & CO) and nivolumab (Opdivo, Bristol-Myers Squibb).

"In the real world, one frequently encounters patients with autoimmune disease who develop melanoma. In fact, these patients have the highest risk for developing cancers," presenter Alexander Menzies, MD, PhD, from the Melanoma Institute Australia, University of Sydney, told Medscape Medical News. "Our study shows that current immunotherapies are safe and work in many of these patients," he added.

Dr Menzies also suggested that the results of their study could be applied to other cancers, such as lung and renal cell, which can now be treated with immunotherapy.

Two melanoma experts not involved in the study welcomed the new findings.

"This is an important study and addresses important issues physicians face in clinical practice: how to treat patients who are typically excluded from clinical trials," Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News.

"An extension of this study is reevaluating eligibility and exclusion criteria for clinical trials," Dr Postow said. "Clinical trials are highly restrictive, and many patients do not have access to them. Determining the efficacy and safety of agents in high-risk patients in prospective studies informs clinical practice," he added.

"We can indeed treat patients with PD-1 blockade when they have low-grade or even moderate-grade autoimmunity, as well as those who had high-grade ipilimumab-related toxicity," Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University's Langone Medical Center, told Medscape Medical News. He indicated that in his own practice, he has seen similar patients, and he considers immunotherapy with nivolumab or pembrolizumab an option.

"A study such as this one expands the population of patients who can receive immunotherapy with PD-1 inhibitors," he noted.

Baseline Characteristics

For the study, Dr Menzies and colleagues retrospectively identified 119 patients with advanced melanoma who had been treated with anti-PD-1 immunotherapy and who either had preexisting autoimmune diseases (n = 52) and/or had experienced major immune-related adverse events (irAEs) when they received prior immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb).

The 52 patients with preexisting autoimmune disease had advanced disease: 85% had M1c disease, 35% had brain metastases, 48% had elevated lactate dehydrogenase (LDH), and 56% had an Eastern Cooperative Oncology Group performance status of 1 or more. "With these baseline characteristics, these patients are poor candidates for clinical trials," Dr Menzies said.

Disease was not active in 71% of patients, and 62% were not receiving treatment for their autoimmune disease, whereas 17% were being treated with steroids. The autoimmune diseases cover a wide spectrum: rheumatologic (52%), dermatologic (15%), gastrointestinal (12%), neurologic (10%), endocrine (8%), and respiratory (4%).

The other 67 patients who had prior ipilimumab toxicities also had advanced disease: 87% had M1c disease, 27% had brain metastases, 40% had elevated lactate dehydrogenase, and 63% had an Eastern Cooperative Oncology Group performance status of 1 or more. The toxicity was grade 3 in 76% of these patients, and grade 4 in 10%. Major irAEs experienced included colitis (42%) and endocrine-related (11%) and dermatologic-related (4%) events. Others included rheumatologic, ocular, hepatitic, neurologic, and hematologic events.

These irAEs were managed with oral steroids (46%), intravenous steroids (24%), and infliximab (22%). In all but one of these patients, the irAEs resolved before starting pembrolizumab or nivolumab.

Most of the patients received pembrolizumab (109 of 119), and the remaining 10 patients received nivolumab. Median follow-up was 4.6 months, with 72% of the patients having 3 or more months of follow-up.

Results in Patients With Preexisting Autoimmune Disease

Among the 56 patients with preexisting autoimmune diseases, 38% (20 patients) experienced flares after a median of 38 days. Flares were most commonly seen in patients with rheumatologic conditions, occurred most commonly with active disease, and tended to occur more in patients receiving immunosuppressants at the start of PD-1 inhibitor therapy, Dr Menzies indicated.

Immunosuppression with steroids was administered in 21% of patients, and steroid-sparing agents were administered in 12% of patients. In patients experiencing flares, PD-1 dosing was continued in 10 (20%) of 58 patients, was interrupted in 8 (15%) of 58 patients, and was permanently discontinued in 2 patients; irAEs were reported in 15 (29%) of 52 patients and were symptomatically managed in 8 patients (15%).

Overall response rate (ORR; complete or partial) was reported in 17 of 52 patients (33%), median progression-free survival was 6.2 months, and duration of response and overall survival were not reached at time of reporting. ORR was similar in patients who experienced flares (35%) compared with those who were flare free (31%).

"Patients with preexisting autoimmune diseases can be successfully treated with PD-1 inhibitors. The response is as good as that seen in other patients. Even when the autoimmune disease flares, it can be managed," Dr Menzies said.

Commenting on the study, Dr Postow agreed. "This study has absolute relevance to clinical practice," he said. It shows that patients with preexisting autoimmune diseases can benefit from therapy with PD-1 inhibitors. Although about 40% of patients experienced flares, most exacerbations were low grade in nature and were treatable with immunosuppressive agents, he noted. "The efficacy seen in the study approximates to the efficacy we see in clinical trials," Dr Postow said. "PD-1 inhibitors should not be withheld from these patients who stand to benefit from immunotherapy," he noted.

Results in Patients With Prior irAEs

Among the 67 patients who had developed irAEs to prior ipilimumab, these events recurred in two patients (3%): colitis and arthritis. Other irAEs related to PD-1 inhibitors were reported in 23 (34%) of 67 patients: grade 1/2, 13%; grade 3, 18% (colitis, hepatitis, arthritis, myasthenia, pneumonitis, diabetic ketoacidosis); and grade 4, 3% (pneumonitis, hepatitis).

Clinically, irAEs were managed symptomatically (in 9% patients), with oral steroids (15%) and intravenous steroids (6%), among others. Of the 23 patients experiencing irAEs with PD-1 inhibitors, nine patients continued therapy, six patients had an interruption of treatment, and eight patients permanently discontinued the treatment. ORR was reported in 27 (40%) of 67 patients; median progression-free survival was 7.2 months, and duration of response and median overall survival were not reached.

This is similar to what has recently been reported by Dr Weber and colleagues ( Cancer Immunol Res. 2016;4:345).

"The slightly higher signal for grade 3/4 toxicities compared with rates seen in clinical practice indicates that these patients may need to be followed more closely following treatment with a PD-1 inhibitor," Dr Postow said.

With respect to treating patients with PD-1 inhibitors who experienced prior ipilimumab toxicities, Dr Postow noted that with the advent of PD-1 inhibitors, it is unlikely that many more of these patients will be seen in the future. "I would hope that most clinicians are offering PD-1 inhibitors first-line to patients with metastatic melanoma," he said.

However, he pointed out that the study may inform the clinical management of patients who discontinue because of irAEs with the combination of PD-1 inhibitor and ipilimumab. (At present, the combination of nivolumab and ipilimumab is approved for metastatic melanoma in both the United States and the European Union).

"This study makes me comfortable about restarting a patient on single-agent therapy with a PD-1 inhibitor if he or she has experienced immune-related adverse events with the combination of a PD-1 inhibitor and ipilimumab," he added.

Other Issues in Real-life Patients

Other issues that arise in patients encountered in clinic practice were discussed at a session during the ASCO annual meeting entitled "Real-World Issues Using Immunotherapy and Targeted Therapies."

Dr Menzies was among the experts on a panel that provided insights from case studies on the use of immunotherapies and targeted agents such as the BRAF/MEK inhibitor-targeted therapies in atypical cases with metastatic melanoma. Cases discussed included the frail elderly patient and patients with brain metastases, BRAF mutant disease, and mucosal melanoma.

The take-home message from that session was that for all patients with metastatic melanoma, available options should be considered by the management team on an individual basis: anti-PD-1 immunotherapy alone or in combination with ipilimumab, BRAF/MEK inhibitors alone or in combination, radiation therapy, chemotherapy, or only observation. Sequencing BRAF/MEK inhibitors with immunotherapy is not informed by prospective data, but is undertaken in clinical practice.

In several instances, reimbursement also becomes part of the equation, as there may be instances in which the combination of BRAF/MEK inhibitors or that of immunotherapies may not be reimbursed.

The experts on the panel indicated that in the absence of prospective data, clinicians have to make informed decisions in the management of patients with metastatic melanoma who typically fall out of the eligibility criteria of clinical studies, which advanced their use in clinical practice.

Dr Menzies reports receiving honoraria from Bristol-Myers Squibb and Novartis, a consulting or advisory role with MSD Oncology, and travel and accommodation expenses from Bristol-Myers Squibb. Dr Postow reports a consulting or advisory role with Amgen and Bristol-Myers Squibb, research funding from Bristol-Myers Squibb, and travel and accommodation expenses from Bristol-Myers Squibb. Dr Weber reports stock and ownership interests in Altor Biosciences, cCam Biosciences, and Celldex, as well as acting in a consulting and advisory role and receiving honoraria and travel and accommodation expenses from many different pharmaceutical companies, including AbbVie, Altor BioScience, Amgen, AstraZeneca, Bristol-Myers Squibb, cCam Biotherapeutics, Celldex, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Ichor Medical Systems, Lion Biotechnologies, Merck, Pieris, and Roche.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 9515. Presented June 4, 2016.

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