Therapeutic Approach for Recurrent Metastatic Melanoma

Michael A. Davies, MD, PhD:The use of PD-L1 testing is really an emerging area in the care of patients with metastatic melanoma. Multiple studies have shown that patients who have a positive test for PD-L1 expression by immunohistochemistry seem to have better outcomes when treated with immunotherapy with anti-PD-1 antibodies. That’s a place that we’re really starting to look at the use of the PD-L1 antibodies and whether this helps to guide the decision to use single-agent PD-1 inhibitor therapy or combination therapy with anti-PD-1 and anti-CTLA4. Probably the most compelling data that we have about the role of PD-L1 testing are from the CheckMate-067 study, a randomized phase III trial in which metastatic melanoma patients were treated with single-agent ipilimumab, single-agent nivolumab, or combined therapy with ipilimumab and nivolumab.

Initial clinical results from this study demonstrated that the ipilimumab/nivolumab combination had a very high response rate of almost 60%, but this was somewhat balanced by the fact that it also had a very high rate of toxicity, with greater than 50% of patients having grade 3 or grade 4 toxicities. Single-agent PD-1 was also highly effective, with a response rate of approximately 45% in only patients experiencing grade 3 to grade 4 autoimmune toxicities. Patients treated with ipilimumab in the study had a response rate of approximately 20% and about 25% grade 3/grade 4 autoimmune toxicities. Both nivolumab alone and the ipilimumab/nivolumab combination had response rates that were much higher than we’re seeing with ipilimumab alone, and each of those regimens in previous randomized clinical trials have shown superior response rate safety and overall survival compared to single-agent ipilimumab. So, on a day-to-day basis, physicians are left with the decision about whether to treat patients with single-agent PD-1 therapy or the ipilimumab/nivolumab combination.

In data that were recently reported at the 2017 AACR Annual Meeting, we finally heard the results of overall survival at 2 years for patients enrolled in the study. This showed that overall for patients with 2 years of follow-up, the overall survival rate with ipilimumab/nivolumab was 64%, and with nivolumab alone, it was 59%. When the results were looked at separately in patients who were positive for PD-L1, their 2-year overall survival rates were actually nearly identical for single-agent nivolumab and the ipilimumab/nivolumab combination. And in contrast, for patients who had a negative PD-L1 test, they were actually seen to have approximately a 10% to 11% improvement in overall survival at 2 years with the ipilimumab/nivolumab combination compared to single-agent nivolumab. This suggests that the PD-L1 test may help to identify patients who get much more additive benefit from the ipilimumab/nivolumab combination, despite its increased toxicities. However, most of these data are really coming from a single study, and there are multiple PD-L1 tests that are available currently. So, this remains an area of research that will need to be studied further in the future.

One of the key factors in guiding therapeutic selection for patients are their medical comorbidities. And indeed, in this case, this is a patient who had undergone a nephrectomy and has an elevated creatinine consistent with impaired renal function. At this point in time, we still have very limited data available about the safety and use of most of our approved therapies in patients with abnormal organ function. So, this is an area where, again, we just monitor patients very closely. At this point, we really don’t have any absolute contraindications to starting any of the available therapies in this patient, but certainly this is a patient where their renal function will have to be followed quite closely as they go through their therapy.

So, for patients who present with metastatic melanoma with the wild-typeBRAFgene, at this point in time for patients who are eligible to receive it, the standard of care remains FDA-approved immune therapies. While, again, these new therapies represent a tremendous advance over previously existing therapies, we do also consider enrollments in clinical trials for these patients. To date, we have no therapy that’s 100% effective in all patients. In addition, we also consider clinical trials for patients who have failed standard therapies in the second-line and third-line settings.

Transcript edited for clarity.

June 2010

• A 73-year-old Caucasian male presented to his physician with a right pre-auricular pigmented lesion, 8 mm-diameter
• PMH: arterial hypertension, dyslipidemia, hyperuricemia and hypothyroidism, for which he has been medically treated
• He is a non-drinker and a former smoker
• In 2002, he had undergone a right nephrectomy for a spontaneous retroperitoneal hematoma. Consequently, he has chronic renal insufficiency
  • Creatinine, 1.8 mg/dL
  • GFR, 40 mL/min
• He otherwise maintains full autonomy in his daily activities and personal care
• He subsequently underwent surgical resection. Pathologic assessment revealed an ulcerated melanoma
  • Breslow index 0.8 mm
  • Clark level of III (pT1b, Stage IB)
• Since his surgery, he remains active and continues golfing 3 times per week

June 2016

• On routine follow-up, the patient presents with moderate asthenia that limited his daily activity, without other relevant clinical symptoms (ECOG PS 1)
• Physical examination did not detect any relevant findings
• Remarkable laboratory findings: Urea, 70 mg/dL; Creatinine 1.76 mg/dL; AST, 59 UI/L; ALT 52 UI/L; GGT 363 UI/L; Alk Phos, 204; LDH, 820 UI/L
• Full-body CT scan revealed the presence of pulmonary and hepatic nodules, no evidence of brain metastases
• He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications
  • Pathology revealed metastatic melanoma
  • Mutation testing:BRAF-negative