Nivolumab/Ipilimumab Combo Leads to Durable Responses in Metastatic Melanoma With Asymptomatic Brain Mets

Hussein Abdul-Hassan Tawbi, MD, PhD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to durable intracranial responses in patients with metastatic melanoma and asymptomatic brain metastases, according to data from the phase II CheckMate-204 study presented at the 2019 ASCO Annual Meeting.¹

Long-term follow-up of the combination showed an objective response rate (ORR) of 54% and a clinical benefit rate (CBR) of 58% at a median follow-up of 20.6 months in patients with asymptomatic brain metastases; median progression-free survival (PFS) and overall survival (OS) had not yet been reached in the asymptomatic cohort. In a symptomatic brain metastases cohort that was added to the study, the ORR and the CBR were each 22%, and the median PFS for intracranial lesions was 1.2 months.

“We have confirmed the durable intracranial responses observed in patients with asymptomatic brain metastases and we believe, at this point, that this supports the use of nivolumab and ipilimumab as the first-line therapy for those patients,” said Hussein Abdul-Hassan Tawbi, MD, PhD, associate professor, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, in a presentation during the meeting.

Brain metastases are a major cause of morbidity and mortality from melanoma. More than half of patients with metastatic melanoma will experience ≥1 brain metastasis during the course of their disease. Historically, these patients have poor median OS.

The population with symptomatic brain metastases is more difficult to treat, although some symptomatic patients can benefit from nivolumab plus ipilimumab, said Tawbi.

Strategies to manage brain metastases had been limited to radiation and surgery. In patients with asymptomatic melanoma-related brain metastases who do not require steroids, immunotherapy has proven to be tolerable and has clinical benefit: single-agent nivolumab has an ORR of 16% in the central nervous system (CNS),² and both single-agent nivolumab and pembrolizumab monotherapy have a CNS ORR of approximately 20%.^3,4

CheckMate-204 was a multicenter, phase II trial that was conducted to investigate the efficacy and safety of nivolumab combined with ipilimumab in patients with melanoma and brain metastases. To be eligible, patients had to have ≥1 measurable nonirradiated brain metastasis of 0.5 to 3.0 cm. Prior radiation was permitted, as long as it was delivered to <3 sites and as long as 1 lesion remained not radiated. Prior treatment with BRAF/MEK inhibition was permitted, but no prior checkpoint inhibitors were allowed in the metastatic setting.

Patients were enrolled into 1 of 2 cohorts: an asymptomatic cohort in whom their last dose of steroids was ≥10 days before starting induction therapy (cohort A) and those with neurologic symptoms whether or not they were receiving steroid therapy (cohort B). In both cohorts, patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by 3 mg/kg of nivolumab every 2 weeks until disease progression or toxicity. The primary endpoint was intracranial CBR, defined as the proportion of patients with complete response (CR) plus partial response (PR) plus stable disease (SD) ≥6 months).

Cohort A Results

Previously, clinically meaningful intracranial efficacy was reported for the nivolumab/ipilimumab combination in 94 patients with asymptomatic brain metastases not requiring steroid therapy. The intracranial CBR was 57% and the median PFS had not been reached at 14 months of follow-up.⁵ Updated safety and efficacy were reported here for 101 asymptomatic patients (cohort A), with a median follow-up of 20.6 months.

Patients in cohort A had a median age of 59.0 years. Two-thirds (67%) of these patients had a BRAF mutation and 27% had an NRAS mutation. Forty-one (41%) patients had a lactate dehydrogenase level (LDH) above the upper limit of normal (ULN), and 11 (11%) had an LDH >2 multiplied by ULN. Of the 100 patients who had PD-L1 testing, PD-L1 expression was ≥1% in 54% and <1% in 46%. Nine percent of patients had prior radiation. The median sum of intracranial target lesion diameters was 15 mm. Twenty-two percent of patients had ≥3 brain lesions.

Results showed that the ORR in cohort A was 54%, with a 29% CR rate and a 26% PR rate. Four patients had SD, leading to a CBR of 58%. Extracranial efficacy was concordant with intracranial efficacy, said Tawbi.

The median time to response was 1.6 months, “essentially the first time we checked with magnetic resonance imaging at 6 weeks,” he said. “The median duration of response has not been reached, as would be expected, since 87% of the responses are ongoing at the time of this analysis.”

The 6-month PFS rate was 63% and the 1-year OS rate was 82%. These results are paralleled and confirmed in a recently published Australian study,³ Tawbi noted.

Cohort B results

Results for 18 patients enrolled in cohort B were also reported at the 2019 ASCO Annual Meeting. Patients in this cohort were required to have an ECOG performance status of 0 to 2 and their maximum dose of steroids was required to be 4 mg of dexamethasone or its equivalent. The median age was 59.5 years, 50% had a BRAF mutation, and 50% had an NRAS mutation. Nearly half (47%) of patients had an LDH level >ULN, and 12% had an LDH level >2 multiplied by ULN. Of the 10 patients who had PD-L1 expression tested, 60% had PD-L1 expression ≥1%. No patient received prior radiation.

Whereas the median sum of intracranial target lesions was 15 mm in cohort A, it was 26 mm in cohort B. Approximately 39% of patients in cohort B had ≥3 brain lesions, and 11 of the 18 (61%) patients were on steroid therapy at the time of initiation of therapy.

Of the 4 responses in cohort B, 2 were a CR and 2 were a PR. As in cohort A, extracranial and intracranial responses were concordant. One responder was on steroid therapy at baseline. The median time to intracranial response was 4.1 months, and the median duration of response has not been reached; 3 of 4 (75%) responses are ongoing. The median OS is 8.7 months.

The median number of nivolumab and ipilimumab doses was 1. Moreover, the 4 responders have entered the maintenance phase of treatment, said Tawbi.

Safety summary

Regarding safety, the rates of grade 3/4 treatment-related adverse events (TRAEs) were 54% in cohort A and 56% in cohort B, which are consistent with observations in patients without brain metastases, Tawbi said. Grade 3/4 treatment-related nervous system AEs occurred in 7% and 17%, respectively, and led to study discontinuation in 2% and 0%, respectively. Overall, TRAEs led to discontinuation in 19% of cohort A and 0% of cohort B.

References

1. Tawbi HA-H, Forsyth PAJ, Hodi S, et al. Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). J Clin Oncol. 2019;37(suppl; abstr 9501). meetinglibrary.asco.org/record/173427/slide.
2. Margolin K, Emstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459-465. doi: 10.1016/S1470-2045(12)70090-6.
3. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672-681. doi: 10.1016/S1470-2045(18)30139-6.
4. Kluger HM, Chiang V, Mahajan A, et al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J Clin Oncol. 2019;3752-60. doi: 10.1200/JCO.18.00204.
5. Tawbi HA, Forsyth PA, Algazu A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379:722-730. doi: 10.1056/NEJMoa1805453.