Pembrolizumab and Bevacizumab for Melanoma Brain Metastases

Host Dr. Davide Soldato and guest Dr. Harriet Kluger discuss the JCO article "Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Harriet Kluger. Dr. Kluger is a professor of medicine at Yale School of Medicine, Director of the Yale SPORE in Skin Cancer, and an internationally recognized expert in immuno-oncology for melanoma and renal cell carcinoma. She leads early-phase and translational trials that pair novel immunotherapies with predictive biomarkers to personalized care. Today, Dr. Kluger and I will be discussing the article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases." In this study, Dr. Kluger and colleagues evaluated four cycles of pembrolizumab plus the anti-VEGF antibody bevacizumab followed by pembrolizumab maintenance in patients with asymptomatic non-hemorrhagic melanoma brain metastases that had not previously received PD-1 therapy. Thank you for speaking with us, Dr. Kluger. Dr. Harriet Kluger Thank you for inviting me. The pleasure is really all mine. Dr. Davide Soldato So to kick off our podcast, I just wanted to ask if you could outline a little bit the biological and clinical rationale that led you to test this type of combination for patients with untreated brain metastases from metastatic melanoma. Dr. Harriet Kluger Back in approximately 2012, patients who had untreated brain metastases were excluded from all clinical trials. So by untreated, I mean brain metastases that had not received local therapy such as surgery or radiation. The reason for it was primarily because there was this fear that big molecules wouldn't penetrate brain lesions because they can't pass the blood-brain barrier. Turns out that the blood-brain barrier within a tumor is somewhat leaky and drugs sometimes can get in there. When PD-1 inhibitors were first identified as the next blockbuster class of drugs, we decided to conduct a phase 2 clinical trial of pembrolizumab monotherapy in patients with untreated brain metastases. We actually did it also in lung cancer, and we could talk about that later on. Responses were seen. The responses in the brain and the body were similar. They were concordant in melanoma patients. Now, at approximately that time, also another study was done by the Australian group by Dr. Georgina Long, where they did a randomized trial where patients who didn't require immediate steroid therapy received either nivolumab alone or nivolumab with ipilimumab, and the combination arm was substantially superior. Subsequently, also, Bristol Myers Squibb also conducted a large phase 2 multicenter trial of ipilimumab and nivolumab in patients with untreated brain metastases. And there, once again, they saw that the responses in the brain were similar to the responses in the body. Now, somewhere along the line there, we completed our anti-PD-1 monotherapy trial. And when we looked at our data, we still didn't have the data on ipilimumab and nivolumab. And our question was, "Well, how can we do better?" Just as we're always trying to do better. We saw two really big problems. One was that patients had a lot of perilesional edema. And the other one was that we were struggling with radiation necrosis in lesions that were previously Gamma Knifed. The instance of radiation necrosis was in excess of 30%. So the rationale behind this study was that if we added bevacizumab, maybe we could treat those patients who had some edema, not requiring steroids, but potentially get them on study, get that PD-1 inhibitor g