COMMENTARY

Ipilimumab Plus Nivolumab for Melanoma Patients With Brain Metastases

Jeffrey S. Weber, MD, PhD

Disclosures

October 20, 2017

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist at the Perlmutter Cancer Center at the NYU Langone Medical Center in New York City. Today we'll be continuing to discuss abstracts from this year's American Society of Clinical Oncology (ASCO) meeting.

We'll be talking about two abstracts that relate to a critical need in the treatment of melanoma in patients with brain metastases.

One abstract was presented by Dr Hussein Tawbi on behalf of his co-investigators in the CheckMate 204 study.[1] This was a phase 2 study that accrued a total of 75 treated patients. Patients received standard doses of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg for four induction doses followed by maintenance nivolumab at 3 mg/kg, per the US Food and Drug Administration (FDA)-approved regimen that was approved a little over a year and a half ago. Inclusion criteria required that the patients have brain metastases within at least 5 mm up to 4 cm in size [Editor's note: The abstract states 0.5-3.0 cm], and patients could not be steroid-dependent or have significant evidence of cerebral edema. Almost all patients had extracranial disease.

The results of this trial showed a very impressive 55% intracranial response rate among all 75 patients, of whom about half had a BRAF mutation, by the way. All of them were immunotherapy naive. The extracranial response rate was an excellent 49%, for a total response rate overall between the intracranial and the extracranial areas of 53%. These are very impressive data.

Very impressive images were shown of large 3- to 4-cm masses that disappeared completely as there was a 20% intracranial complete response rate. This result is unprecedented in the absence of radiation. Of course, none of these patients were initially radiated. Among the total of 41 responses, 38 were ongoing at a median follow-up of 9 months. Again, every patient was evaluated with at least 6 months of follow-up, and the median was 9 months.

There's no question that there was a slight increase in the neurologic immune-related adverse events, which was 8% for grade 3/4. However, the overall immune-related adverse-event profile was not that much different from what we would see with patients who had no intracranial disease. The conclusion in these 75 patients was that the combination of ipilimumab and nivolumab in previously immunotherapy-naive patients could have very impressive and significant intracranial activity.

In the same session at the ASCO meeting, Dr Georgina Long from Sydney, Australia, presented data from a smaller study of 26 patients, who were previously immunotherapy naive and had brain metastases anywhere between 5 mm and 4 cm.[2] The data were virtually identical to those seen in the slightly larger CheckMate 204 study, in that patients who received combination immunotherapy of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg for four induction doses, followed by maintenance every other week with nivolumab at 3 mg/kg, had an excellent response rate of 42% intracranially. The response rate overall was about the same extracranially.

There were very few patients who had responses intracranially who did not have extracranial responses, and vice versa—again, similar to the CheckMate 204 study. The majority of patients, of course, had extracranial disease (approximately 80% of them), so these are very impressive data.

In this study, there was a comparison to nivolumab alone in the same category of patients who were immunotherapy naive and had CNS disease with or without extracranial disease. The intracranial response rate was a paltry 20% for nivolumab alone, with the overall response rate intra- and extracranially at about 30%, compared with 44% for the patients who received the combination. There was no long-term follow-up as in the CheckMate 204 study, but these data confirmed the response rates, including a 15% complete response rate in the brains of patients receiving the combination of ipilimumab with nivolumab at the FDA-approved doses.

Once again, it seems as if we're in a new era, where patients with intracranial or brain disease who have metastatic disease may do very well in the long term and have the same excellent response rates that we see in those with only extracranial disease. The long-term survival outcome data for these trials are eagerly awaited.

The next question is: Could we get away with not using radiation prior to initiation of immunotherapy in these patients? Neither trial was structured to answer that question. This will be the next question for future clinical trials in the area of metastatic melanoma.

Please feel free to write with comments or questions. I thank you for watching today. This is Dr Jeffrey Weber.

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