Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses the rationale for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with melanoma who have brain metastases.

Patients with melanoma brain metastases, approximately 20% to 25% of the overall population of patients with advanced disease, have a poor prognosis, says Long. Despite this, they are often excluded from clinical trials. This unmet need served as the basis for a phase II trial (NCT02374242), in which investigators evaluated the combination of nivolumab and ipilimumab versus nivolumab alone in patients with previously untreated melanoma and brain metastases, explains Long.

According to the design of the trial, patients were randomized to 1 of 2 cohorts: cohort A with the combination (n = 35), or cohort B with nivolumab alone (n = 25). Investigators included a third cohort for patients with brain metastases who had failed local therapy, had neurological symptoms, and/or had leptomeningeal disease (n = 16), says Long. However, responses to nivolumab monotherapy were modest in this cohort, concludes Long.

Videos

Georgina V. Long, BSc, PhD, MBBS, FRACP, discusses the rationale for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with melanoma who have brain metastases.

Dr. Long on Rationale for Nivolumab/Ipilimumab in Patients With Melanoma Who Have Brain Mets

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses how to efficiently enroll patients with melanoma who have brain metastases in clinical trials. 

Often, patients with brain metastases are excluded from clinical trials, says Long. Alternatively, investigators could create separate studies that only include patients with brain metastases. This could be an effective strategy because many patients with melanoma also have brain metastases. 

Alternatively, Long suggests designing clinical trials in which patients with brain metastases would be evaluated in a separate cohort in the same protocol as patients without brain metastases. This is likely the most efficient way to develop therapies for this subgroup of patients, says Long.

Georgina V. Long, BSc, PhD, MBBS, FRACP, discusses how to efficiently enroll patients with melanoma who have brain metastases in clinical trials. 
 

Dr. Long on Including Patients With Melanoma Who Have Brain Mets on Clinical Trials 

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses the sequence of local therapy in patients with melanoma who have brain metastases.

There is a lot of debate in the field of melanoma regarding the optimal sequence of local therapy for patients with brain metastases, says Long, specifically, whether patients should receive systemic therapy upfront or local therapy followed by systemic therapy. Although patients with brain metastases have a poor prognosis, it is the entire burden of disease that causes mortality as opposed to the intercranial disease alone.

Therefore, investigators have launched a trial which will randomize patients with brain metastases to receive the combination of frontline ipilimumab (Yervoy) and nivolumab (Opdivo) plus stereotactic radiosurgery versus the combination immunotherapy plus local therapy at the time of progression. The results will determine whether local therapy is best used upfront or as salvage therapy, concludes Long.

Georgina V. Long, BSc, PhD, MBBS, FRACP, discusses the sequence of local therapy in patients with melanoma who have brain metastases.

Dr. Long on Sequencing Local Therapy in Patients With Melanoma Who Have Brain Mets

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses the long-term data from the phase II ABC study (NCT02374242), in which investigators are comparing the efficacy of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) versus single-agent nivolumab in patients with melanoma brain metastases. 

For the trial, patients with asymptomatic brain metastases with no prior local brain treatment were randomized to either cohort A or cohort B. Patients in cohort A received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks with a maximum of 4 doses, then nivolumab 3 mg/kg every 2 weeks. Those in cohort B were given nivolumab 3 mg/kg every 2 weeks. Patients in cohort C had brain metastases, failed local therapy, had neurological symptoms, and/or had leptomeningeal disease, received nivolumab 3 mg/kg every 2 weeks. Prior treatment with a BRAF inhibitor was permitted.

When patients who were previously treated with BRAF or MEK inhibitors were excluded, response rates were much higher at 59% with the combination immunotherapy versus 21% with nivolumab monotherapy, says Long. Of the 8 patients who had received prior treatment with BRAF or MEK inhibitors, only 2 responded to the combination immunotherapy regimen. As such, the take-home message is that the combination of nivolumab plus ipilimumab is highly active in patients with multiple untreated asymptomatic melanoma brain metastases, but efficacy diminishes if patients had prior treatment with BRAF or MEK inhibitors, she concludes.

Georgina V. Long, BSc, PhD, MBBS, FRACP, discusses the long-term data from the phase II ABC study , in which investigators are comparing the efficacy of nivolumab in combination with ipilimumab versus single-agent nivolumab in patients with melanoma brain metastases. 
 

Dr. Long on Nivolumab/Ipilimumab in Patients With Melanoma Who Have Brain Mets

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses the results of the pooled analysis of parts 1 and 2 of the phase III COMBI-i study.

The COMBI-i trial is exploring the combination of targeted therapy and immunotherapy—specifically, dabrafenib (Tafinlar) and trametinib (Mekinist) plus an anti—PD-1 drug called spartalizumab. In parts 1 and 2, researchers evaluated 36 patients who were given a full dose of all 3 drugs together. The triplet therapy induced a response rate of 78%. Only one patient progressed on the treatment, says Long. Notably, the median progression-free survival was above 20 months with the triplet, which compares favorably to what has been observed with either a PD-1 inhibitor alone or the combination of dabrafenib and trametinib.

In terms of adverse events, pyrexia was more extensive with the triplet therapy than with the combination of dabrafenib and trametinib alone; however, this is being explored further in part 3 of the trial, says Long. In part 3, patients will be randomized to receive either the triplet therapy or dabrafenib and trametinib alone. To date, the toxicity appears to be very manageable with proper patient and physician education, concludes Long.

Dr. Long on the Results of the Pooled Analysis of the COMBI-i Trial in Melanoma

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses results from the 5-year analysis of the combination of dabrafenib and trametinib in patients with 

Long presented the 5-year pooled data of the phase III COMBI-v and COMBI-d trials at the 2019 ASCO Annual Meeting. In both trials, investigators tested the combination versus a BRAF inhibitor alone. The COMBI-d trial looked at the combination compared with dabrafenib alone, while the COMBI-v trial looked at the combination compared with vemurafenib alone, says Long. The analysis encapsulated over 500 patients who received the combination. Data showed a 5-year overall survival (OS) rate of 34%. In certain populations, the 5-year OS rate exceeded 50%, adds Long.

The rate of progression-free survival (PFS) was approximately 50% in patients who achieved a complete response (CR), suggesting that the majority of patients who have a CR do not progress, explains Long. Furthermore, patients with a normal baseline lactate dehydrogenase level and less than 3 sites of metastases do very well. These data suggest that targeted therapy could potentially lead to cure; at the least it induces good long-term control in a proportion of patients. In the intent-to-treat population, just less than 20% of patients are progression-free at 5 years.

Georgina V. Long, BSc, PhD, MBBS, FRACP, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discusses results from the 5-year analysis of the combination of dabrafenib and trametinib in patients with BRAF V600E-mutant melanoma.

Georgina V. Long, BSc, PhD, MBBS, FRACP

Articles

Dr. Long on Rationale for Nivolumab/Ipilimumab in Patients With Melanoma Who Have Brain Mets

Dr. Long on Including Patients With Melanoma Who Have Brain Mets on Clinical Trials

Dr. Long on Sequencing Local Therapy in Patients With Melanoma Who Have Brain Mets

Dr. Long on Nivolumab/Ipilimumab in Patients With Melanoma Who Have Brain Mets

Dr. Long on the Results of the Pooled Analysis of the COMBI-i Trial in Melanoma

Dr. Long on Dabrafenib/Trametinib in BRAF V600E-Mutant Melanoma