ASCO Daily News

Source: ASCO Daily News, June 2016

Treating Advanced Melanoma With Immunotherapies

Clinical Cases Focus on Patients Normally Excluded From Clinical Trials

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,” said session chair John B. A. G. Haanen, MD, PhD, of the Netherlands Cancer Institute.

For example, elderly patients and patients with brain metastases or rare tumors are typically not included in clinical trials, yet oncologists see such patients routinely, Dr. Haanen explained. “New information from real world data will help us make decisions regarding how to treat our patients,” he said.

During the June 4 Clinical Problems in Oncology Session “Real-World Issues Using Immunotherapy and Targeted Therapies in Melanoma,” three melanoma experts discussed how treatment is navigated in clinical practice and how risks and challenges may be addressed. The session featured real patient cases and audience participation.

The presenting 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 with these agents.

Treating Elderly Patients With Immunotherapy

Clinicians face 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 patient discussed during the session was a frail 69-year-old woman referred for metastatic melanoma. The patient presented with asymptomatic brain metastases, multiple lung metastases, and liver metastases. Before exposing the patient to any of the approved immunotherapies (nivolumab, pembrolizumab, or ipilimumab), physicians must consider several disease and patient factors including performance status, bulky disease, and lactate dehydrogenase (LDH) levels.

In the absence of BRAF-mutant disease, the risks with a combination approach with a PD-1 inhibitor and ipilimumab are considered substantial for a frail patient. In clinical practice, treating brain metastases with radiotherapy before giving a PD-1 inhibitor is another option.

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

The second case study involved a 51-year-old male with melanoma who had 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.

Six weeks after 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

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 patient 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 the 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 patient discussed, a 67-year-old male, presented with fatigue, dyspnea, chest pain, and dysphagia over 2 months. He had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with normal LDH levels. No disease was seen outside the thorax. Although a biopsy showed the presence of a 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 the upper limit of normal (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 underwent observation.

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

Dr. Larkin’s second patient was a 26-year-old physician-in-training. He presented with cough and acute abdominal pain and had a prior history of melanoma of 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 started on dabrafenib, as the combination with a MEK inhibitor was not then 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 was dabrafenib discontinued. Pembrolizumab was then initiated because the combination of nivolumab and ipilimumab was not reimbursed. The patient developed progressive central nervous system 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; the steroid dose could not be weaned below the moderate dose.

The patient paid for the cost of the combination of nivolumab and ipilimumab himself. After two cycles, response was seen in the cervical lymph nodes and brain.

These patient cases highlight the use of whole-brain radiation therapy given at lower doses and examine whether high-dose steroids and 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 with pelvic bleeding and a pelvic mass. The patient was diagnosed with primary mucosal melanoma of the vagina and cervix. 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 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 and hemoptysis and 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 needing consideration.

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 remains on combination immunotherapy.

Dr. Menzies’ second patient posed a substantial 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. The treatment was not given sequentially. The patient developed no gastrointestinal toxicity, and a 12-week restaging scan showed a response in the brain and systemically. 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 the ASCO Daily News. “Autoimmune diseases do not necessarily flare with immunotherapies.”

–Alexander Castellino, PhD

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