Combined Checkpoint Inhibition Ushers in a New Era of CNS Therapy in Melanoma

Combined Checkpoint Inhibition Ushers in a New Era of CNS Therapy in Melanoma

Dr. Hussein Tawbi presents Abstract 9507.
Data from two phase II studies, the CheckMate 204 trial and the Anti-PD1 Brain Collaboration (ABC) trial, lend support to combined use of nivolumab and ipilimumab to yield responses in melanoma that has metastasized to the brain.

Results from these studies, reported during the Melanoma/Skin Cancers Oral Abstract Session on June 4, offer important insight into the utility of immunotherapy for the sizable proportion of patients with advanced melanoma who develop central nervous system (CNS) metastases—a population currently facing a great unmet need. Although immunotherapies have fundamentally altered and enhanced the treatment landscape for metastatic melanoma, these agents remain largely untested in patients with untreated brain metastases, as this population has typically been excluded from most melanoma clinical trials of immunotherapy.

CheckMate 204 Results

Hussein Abdul-Hassan Tawbi, MD, PhD, of The University of Texas MD Anderson Cancer Center, presented updated data from the prospective phase II CheckMate 204 trial being conducted at multiple U.S. sites (Abstract 9507). To be eligible, patients were required to have melanoma and at least one metastatic brain lesion measuring 0.5 to 3.0 cm. Exclusion criteria included symptomatic disease, whole-brain radiotherapy, prior treatment with checkpoint inhibitors, leptomeningeal disease, and use of steroids for 10 days or more. Prior stereotactic radiotherapy for up to three metastatic brain lesions was permitted, as was prior treatment with BRAF and MEK inhibitors.

Patients enrolled in the trial received nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks until disease progression or toxicity. Patients could also receive stereotactic radiotherapy for brain oligoprogression if assessable lesions remained.

Dr. Tawbi showed efficacy and safety data for 75 patients who were evaluable as of the March 2017 database lock. After a median follow-up duration of 9.2 months, approximately one-third of patients had received all four combined nivolumab/ipilimumab doses, and 56% went on to receive nivolumab maintenance, among whom a median of 12 nivolumab doses were delivered.

The intracranial objective response rate (ORR) was 55%, of which 21% of patients experienced complete response. When including patients with stable disease, the intracranial clinical benefit rate—the primary endpoint of the study—reached 60%. Extracranial responses largely matched the intracranial responses, as reflected by a 49% extra-cranial ORR.

Dr. Georgina V. Long presents Abstract 9508.
The 6-month progression-free survival (PFS) rate for intracranial disease exceeded 65%, and the median has not yet been reached.

The safety profile of the nivolumab/ipilimumab combination appeared to be consistent with earlier experiences in patients without metastatic brain metastases. Treatment-related grade 3/4 adverse events occurred in 52% of patients, and 31% of patients discontinued treatment because of adverse events. One patient died of treatment-related myocarditis.

The most common CNS-specific adverse event experienced by patients was headache, which occurred in 25%. Brain edema, intracranial hemorrhage, peripheral motor neuropathy, and syncope each occurred in 1% of patients.

“In patients with advanced melanoma and untreated melanoma brain metastases, nivolumab plus ipilimumab clearly demonstrates clinically meaningful efficacy,” Dr. Tawbi concluded. “We believe that this could become a new upfront treatment option.”

Looking forward, because the CheckMate 204 trial excluded patients with symptomatic disease and/or who required steroids, the investigators are now expanding the study to evaluate combined nivolumab/ipilimumab treatment in this patient subset.

ABC Results

Similar to CheckMate 204, the Australian ABC trial (Abstract 9508) was also a prospective phase II study that included patients with melanoma and asymptomatic brain metastases. But it differed in that participants were assigned to one of three treatment cohorts depending on their treatment history. As in CheckMate 204, prior treatment with BRAF and MEK inhibitors was permitted.

As Georgina V. Long, BSc, PhD, MBBS, FRACP, of the University of Sydney, explained, patients with no prior local brain therapy underwent random assignment to Cohort A and received the same nivolumab/ipilimumab regimen with nivolumab maintenance as in CheckMate 204 or to Cohort B that received just nivolumab 3 mg/kg every 2 weeks. Patients in whom local therapy had failed, who displayed neurologic symptoms, and/or who had leptomeningeal disease were assigned to Cohort C, which also received nivolumab 3 mg/kg every 2 weeks.

Dr. Lynn Mara Schuchter discusses Abstracts 9507 and 9508.
Dr. Long presented data for 67 of 76 evaluable patients based on a median follow-up duration of 16.4 months.

Patients with asymptomatic brain metastases who had not previously received local therapy had a favorable response to nivolumab and ipilimumab, and somewhat less to nivolumab alone. In Cohort A, which received the nivolumab/ipilimumab combination, the intracranial ORR reached 42%, the extracranial ORR 48%, and the 6-month intracranial PFS 46%. These rates were attenuated in Cohort B, which received nivolumab alone, as shown by an intracranial ORR of 20%, extracranial ORR of 30%, and 6-month intracranial PFS of 28%.

Dr. Long pointed out that nivolumab and ipilimumab demonstrated improved activity among patients who had not previously experienced disease progression on a BRAF or MEK inhibitor, offering hints at how targeted agents and immunotherapies may best be sequenced in the future. In Cohort A, 50% of patients with treatment-naive disease attained an intracranial ORR, compared with only 16% of patients previously treated with BRAF and MEK inhibitors.

Overall, the 16 patients who previously received local therapy or who had leptomeningeal melanoma had a poor response to nivolumab alone. The intracranial ORR was only 6%, the extracranial ORR 25%, and 6-month intracranial PFS 13%.

Again, as in CheckMate 204, no new or unexpected safety signals arose, and the incidence of adverse events was very similar to those seen in other phase III trials of nivolumab and ipilimumab. Four of the 67 patients (6%) experienced neurologic events—two with headache, one with radionecrosis, and one with seizure. No treatment-related deaths occurred.

“The combination of nivolumab and ipilimumab has high activity in melanoma brain metastases and may be considered for up-front therapy in such patients,” Dr. Long summarized.

A New Era of CNS Therapy in Melanoma

Discussant Lynn Mara Schuchter, MD, FASCO, of the University of Pennsylvania, agreed with the assessments of Dr. Tawbi and Dr. Long. In her discussion of the CheckMate 204 and ABC studies, she remarked that the data presented are sufficient to warrant upfront systemic therapy in patients with melanoma brain metastases to offer control of both intracranial and extracranial disease.

“Systemic therapy as initial treatment for patients with asymptomatic CNS melanoma metastases is an important new option for our patients and is practice changing,” Dr. Schuchter said.

–Kara Nyberg, PhD