Treating Advanced Melanoma With Immunotherapies

Treating Advanced Melanoma With Immunotherapies

Clinical Cases Focus on Patients Who Would Normally Be Excluded From Clinical Trials

Dr. John B. A. G. Haanen
Immunotherapies and targeted therapies have been approved for the treatment of metastatic melanoma based on clinical studies. However, in clinical practice, it is not easy to contextualize clinical study data. “Important issues arise when treating real-world patients with immunotherapies,” session chair John B. A. G. Haanen, MD, PhD, of the Netherlands Cancer Institute, said. For example, elderly patients and patients with brain metastases or rare tumors are typically not included in clinical trials, yet we see such patients routinely, Dr. Haanen explained. “New information from real-world data will help us make decisions in how to treat our patients,” he said.

Using a case-based approach with audience participation, three melanoma experts addressed how treatment is navigated in clinical practice and how risks and challenges may be addressed during the June 4 Clinical Problems in Oncology Session “Real-World Issues Using Immunotherapy and Targeted Therapies in Melanoma.”

In treating their patients, the physicians considered all available options—a PD-1 inhibitor alone or in combination with ipilimumab, BRAF/MEK inhibitors, chemotherapy, radiotherapy (for addressing brain metastases), or observation only following treatment discontinuation. Reimbursement issues were also considered.

After weighing the risks of treatment with available options, the panel concluded that it is possible to treat patients who typically fall out of the realm of the inclusion criteria of clinical trials in cutaneous melanoma.

Treating Elderly Patients With Immunotherapy

In practice, clinicians are faced with the conundrum of whether elderly patients can be treated and if it is possible to reinitiate therapy in a patient who has developed severe immune-related side effects.

Dr. Haanen’s first case was a frail 69-year-old woman who was referred for metastatic melanoma. The patient presented with asymptomatic brain metastases, multiple lung metastases, and liver metastases. Before exposing this frail patient to any of the approved immunotherapies (nivolumab, pembrolizumab, or ipilimumab), it was important to take several disease and patient factors into account—performance status, bulky disease, and LDH levels.

In the absence of BRAF-mutant disease, the risks posed with a combination approach with a PD-1 inhibitor and ipilimumab were considered to be significant for a frail patient. In clinical practice, treating brain metastases with radiotherapy before giving a PD-1 inhibitor is an option that is also considered.

The patient received an anti–PD-1 agent and had a good response in the brain and outside without significant side effects. Although she developed hypothyroidism and low-grade skin rash and itch, treatment is still ongoing.

The second case posed was that of a 51-year-old male with melanoma with metastases at multiple sites, including the lungs and liver. The patient had BRAF wild-type disease with an NRAS mutation. Although treatment with a MEK inhibitor or with single-agent immunotherapy was a possibility, treating with a combination of a nivolumab and ipilimumab was preferred.

After two courses of therapy, the patient developed four immune-mediated adverse events: grade 3 uveitis, grade 3 colitis, grade 2 hepatitis, and grade 2 skin rash and itch. Given the extent of adverse events, the only viable option was to discontinue treatment (vs. interruption) and manage the adverse events. Uveitis was managed with topical steroids. Colitis was managed with high-dose steroids for 5 days; with no resolution of colitis, the patient was treated with infliximab—an anti-TNF antibody.

After 6 weeks of discontinuing therapy, the patient developed type 1–like diabetes; he experienced an ongoing complete response 20 months later, as has been seen in clinical trials.

Sequencing BRAF/MEK Inhibitors and Immunotherapies

Dr. James M. G. Larkin
When a patient presents with BRAF-mutant melanoma, when is a clinician to use BRAF/MEK inhibitors over immunotherapies? James M. G. Larkin, MD, PhD, FRCP, of the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, addressed this question using two cases from his clinical practice as examples.

“The approval of PD-1 inhibitors changed the perception that immunotherapy took a long time to work,” Dr. Larkin told ASCO Daily News. However, in patients with high-burden disease and poor performance status, BRAF/MEK inhibitors are still the go-to agents, he said.

Dr. Larkin’s first case, a 67-year-old male, presented with fatigue, dyspnea, chest pain, and dysphagia over 2 months. He had an ECOG performance status of 2, with normal LDH levels. No disease was seen outside the thorax. Although a biopsy showed the presence of BRAF mutation, the result was not available when an urgent treatment decision was needed.

The patient received the combination of nivolumab and ipilimumab. After one dose, the patient presented with weakness, as well as numbness in the thighs and ataxia—a rare side effect of combination therapy. Liver enzymes were elevated to more than 10 times ULN. His inflammatory myeloradiculopathy responded well to steroids. A CT scan 2 weeks later indicated a partial response; however, treatment was discontinued, and the patient was under observation.

With increasing dyspnea and progressive disease, the patient was started on the BRAF/MEK inhibitor combination of dabrafenib and trametinib, which was well tolerated. On restaging, tumor shrinkage was observed. Currently, the patient has stable disease 5 months after treatment with the targeted agents.

Dr. Larkin’s second case was a 26-year-old physician-in-training. He presented with cough and acute abdominal pain and had a prior history of melanoma to the scalp. His performance status was good; LDH was approximately 3 to 4 times ULN. Disease was seen in the spleen, liver, and lung. Liver biopsy revealed BRAF-mutant melanoma.

With a high disease burden, elevated LDH, and a desire for a rapid clinical response, the patient was started on dabrafenib, as the combination with a MEK inhibitor was then not reimbursed. The patient showed a rapid clinical response; LDH normalized within 2 weeks. Ongoing response was seen at 8 months, but a routine brain MRI showed brain lesions.

Only when disease progressed beyond the brain, dabrafenib was discontinued, and pembrolizumab was initiated because the combination of nivolumab and ipilimumab was not reimbursed. The patient developed progressive CNS symptoms, which were treated with high-dose steroids. Whole-brain radiotherapy was given 2 weeks later for symptomatic brain disease. Pembrolizumab was stopped when new lesions were seen in the cervical lymph nodes and tonsils; steroid dose could not be weaned below the moderate dose.

The patient self-paid for the combination of nivolumab and ipilimumab. After 2 cycles, response was seen in the cervical lymph nodes and brain.

These cases highlight the use of whole-brain radiation therapy given at lower doses and whether high-dose steroids, anti-inflammatory drugs, may dampen the efficacy of immunotherapy.  

A Role for Immunotherapies in Patients With Mucosal Melanoma, Autoimmune Disease

In presenting his case studies, Alexander M. Menzies, BSc(Med), MBBS, FRACP, PhD, of the Melanoma Institute Australia, Royal North Shore Hospital, and The University of Sydney, addressed unique cases encountered in clinical practice that are also typically excluded from clinical trials—patients with mucosal melanoma and autoimmune disease.

Dr. Menzies’ first case was a 40-year old woman who presented with pelvic bleeding and a pelvic mass. A diagnosis of primary mucosal melanoma of the vagina and cervix was made. Surgery was undertaken for excision of the primary melanoma, but the margins were positive, and two of the 16 lymph nodes tested positive.

Adjuvant immunotherapeutic approaches have not been studied in mucosal melanoma, but with technical incomplete resection, this was considered to be unresectable stage III disease—appropriate for immunotherapies, Dr. Menzies said. For resected melanoma with positive margins, several options may be considered in clinical practice: observation, radiotherapy, or treatment with interferon, ipilimumab, or an anti–PD-1 inhibitor. Other options include a combination of radiotherapy with the immune therapies.

In practice, the patient received adjuvant radiotherapy and seven cycles of pembrolizumab (not approved for adjuvant treatment). She developed mild cough, hemoptysis, had elevated LDH levels. An MRI indicated lung and liver metastases. A KIT mutation was also identified.

Several options were considered—immunotherapy, ipilimumab alone or in combination with nivolumab, and imatinib (targeting KIT). However, imatinib is associated with low response rates and short progression-free survival. Pooled data from clinical trials suggest that PD-1 immunotherapies have the highest response rates, especially in combination with ipilimumab. For bleeding lung metastases, systemic therapy, surgery, and the combination of radiotherapy and immunotherapy (given sequentially or together) are options to be considered.

The patient received radiotherapy to the lungs and the combination of ipilimumab and nivolumab. The patient did not experience any pneumonitis. However, after 6 weeks, a mixed response was observed. The cough improved, and hemoptysis resolved. Although the patient showed a response in the irradiated lung, there was some progressive disease in the liver and additional lung metastases. The patient continues on combination immunotherapy.

Dr. Menzies’ second case posed a significant challenge—an elderly patient with an autoimmune disease. The patient, an 84-year-old man, with a past history of cutaneous melanoma, ulcerative colitis (16 years), and prostate cancer, presented with hip pain and anorexia. Multiple imaging modalities determined a pelvic mass, liver metastases, and four asymptomatic brain metastases. “Such a patient would never be included in a clinical trial,” Dr. Menzies said.

After considering options for managing systemic disease, local iliac metastasis, and brain metastases, the management team settled on radiotherapy to the iliac mass given in combination with a PD-1 inhibitor, pembrolizumab, and not sequentially. The patient developed no gastrointestinal toxicity, and a 12-week restaging scan showed a response in and outside the brain. Nine months later, the patient now has a near-complete response in the brain and extracranially.

“We should not be afraid to give immunotherapy to patients with autoimmune disease,” Dr. Menzies told ASCO Daily News. “Autoimmune diseases do not necessarily flare with immunotherapies.”

                                                                                                                                                —Alexander Castellino, PhD