Nivolumab–Ipilimumab Benefits Continue At 5 Years For Asymptomatic Brain Melanoma Metastases

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: A 5-year update from the ABC Study of melanoma patients with asymptomatic brain metastases has been reported at the 2021 ASCO Annual Meeting, confirming that the addition of ipilimumab to first-line nivolumab therapy extends overall survival (OS). 

“Nivolumab combined with ipilimumab has high activity and durability in asymptomatic melanoma brain metastases, and may be considered for upfront therapy in such patients”, stated presenting author Georgina Long, from the University of Sydney in New South Wales, Australia. 

The randomised phase II trial used gadolinium-enhanced magnetic resonance imaging to assess intracranial disease with a baseline diameter of 5–39 mm in patients who were naïve to treatment with CTLA-4 and PD-1 or PD-L1-targeted therapies but may have previously received BRAF/MEK inhibitor therapy. 

Following on from positive findings reported after 3 years, the presenter updated the results after a median follow-up of 52.8 months (range, 43.3–71.5 months), with a best RECIST intracranial response from 12 weeks of treatment onwards of 51% for the 35 patients randomly assigned to receive combination therapy versus 20% for the 25 patients given nivolumab alone. This included complete responses in 26% and 16% of patients, respectively, and stable disease in a corresponding 6% and 0%. 

The median duration of intracranial response was not reached in any arm, remarked Georgina Long. 

When assessing the subgroup of drug treatment-naïve patients, intracranial response occurred in 59% of the 27 patients given nivolumab plus ipilimumab and 21% of the 19 patients given nivolumab alone, with complete responses in 30% versus 16% and stable disease in 7% versus 0%.  

The majority (83%) of study participants had extracranial melanoma metastases at baseline. Among these patients, 57% of the 30 given combination therapy achieved a RECIST response for extracranial disease versus 29% of 21 patients given nivolumab only, with complete responses in 13% and 19%, respectively. 

Intracranial progression-free survival (PFS) was a median 5.4 months with nivolumab plus ipilimumab versus 2.5 months with nivolumab alone, giving 5-year PFS rates of 46% and 15%, respectively. Among the drug-naïve patients, the corresponding durations were unreached versus 2.6 months with 5-year rates of 52% and 14%. 

Georgina Long noted that there was concordance between intracranial and extracranial response with regard to disease progression. “Any patient with an intracranial response did not have progression of disease extracranially”, she said, although “there were four patients who had an extracranial response with progression in the brain”. 

Intracranial PFS also correlated with intracranial best response, with a 5-year rate of intracranial PFS of 92% for those with a complete response versus 58% for those with only a partial response. 

Median OS was unreached among patients given nivolumab plus ipilimumab versus 26.1 months with nivolumab alone, with 5-year rates of 51% and 34%, respectively. 

Further analysis showed that patients alive at data cutoff were less likely than those who did not survive to have elevated LDH (38 vs 67%) and more than four brain metastases (24 vs 39%), as well as having a lower burden of extracranial disease (median 60.0 vs 71.0 mm). 

The presenter noted that combination-treated patients were less likely than nivolumab-only patients to subsequently receive local therapy to the brain (32 vs 62%) or ipilimumab plus PD-1 inhibitor therapy (5 vs 29%) but there were similar rates of BRAF/MEK-targeted therapy use (37 vs 43%). 

She also highlighted the “low” rate of radionecrosis in the small number of patients who received stereotactic radiosurgery after intracranial progression, ranging from 20% to 33% of patients. 

Noting that there was “no new toxicity” over the long-term follow-up of the study and no treatment-related fatal adverse events, Georgina Long summarised the trial findings as being “similar to studies of nivolumab plus ipilimumab in patients without active brain metastases”. 

She concluded that the ABC-X trial is now enrolling a new cohort of asymptomatic treatment-naïve patients with melanoma brain metastases to evaluate the use of upfront stereotactic radiosurgery to all brain metastases alongside nivolumab plus ipilimumab. 

Session discussant Sunandana Chandra, from Northwestern University in Chicago, Illinois, USA, agreed that the use of “local therapy up front, such as surgery or radiation, needs to be defined” in this patient population. 

She highlighted the unmet needs for asymptomatic melanoma brain metastases in patients unsuitable or unresponsive to nivolumab plus ipilimumab and those who have discordant intracranial and extracranial responses to treatment, as well as poor prognosis individuals with symptomatic or leptomeningeal metastases “for whom no standard of care therapy exists.” 

Reference  

Long GV, Atkinson V, Lo S, et al. Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol 2021;39(suppl 15; abstr 9508). DOI: 10.1200/JCO.2021.39.15_suppl.9508