Nivolumab plus ipilimumab benefits patients with asymptomatic melanoma brain metastases
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Combination therapy with nivolumab plus ipilimumab conferred an OS benefit for patients with asymptomatic melanoma brain metastases, according to results of the open-label, phase 2 CheckMate 204 study published in The Lancet Oncology.
“Immunotherapy in melanoma has been excessively studied ... (but) all of the phase 3 studies completely excluded patients with any evidence of brain metastases,” Hussein A. Tawbi, MD, PhD, deputy chair of and professor in the department of melanoma medical oncology and director of melanoma clinical research and early drug development at The University of Texas MD Anderson Cancer Center, told Healio. “We were clear on the fact that these agents have the potential to be effective in the brain and we knew that about 40%of our patients from day 1 with metastatic melanoma will have metastatic disease to the brain, so we knew that this population needed better options.”
The analysis included 119 patients with measurable melanoma brain metastases (0.5 cm to 3 cm in diameter) screened, enrolled and treated at 28 study sites across the United States between Feb. 19, 2015, and Nov. 1, 2017.
Of them, 101 patients had asymptomatic brain metastases (median age, 59 years; interquartile range [IQR], 51-66; 67% men) and 18 had symptomatic metastases (median age, 59.5 years; IQR, 50-70; 72% men). Researchers grouped asymptomatic patients, who had an ECOG performance status of 0 or 1 and no neurologic symptoms or baseline corticosteroid use, into cohort A; they grouped symptomatic patients, who had an ECOG performance status of 0 to 2 with stable neurologic symptoms and possible treatment with low-dose dexamethasone, into cohort B.
Patients received 1 mg/kg nivolumab (Opdivo, Bristol Myers Squibb) plus 3 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) via IV every 3 weeks for four doses, followed by 3 mg/kg nivolumab every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity.
Median follow-up was 34.3 months (interquartile range, 14.7-36.4) for cohort A and 7.5 months (range, 1.2-35.2) for cohort B.
Intracranial clinical benefit rate, defined as complete and partial responses and stable disease lasting at least 6 months, served as the primary endpoint.
Results showed investigator-assessed intracranial clinical benefit in 58 patients (57.4%; 95% CI, 47.2-67.2) in cohort A and three patients (16.7%; 95% CI, 3.6-41.4) patients in cohort B, and objective response rates of 53.5% (95% CI, 43.3-63.5) in cohort A and 16.7% (95% CI, 3.6-41.4) in cohort B. Additionally, 33 patients in cohort A and three patients in cohort B had an intracranial complete response.
Tawbi and colleagues reported a 36-month intracranial PFS rate of 54.1% (95% CI, 42.7-64.1) and OS of 71.9% (95% CI, 61.8–79.8) in cohort A, and 36-month intracranial PFS of 18.9% (95% CI, 4.6-40.5) and OS of 36.6% (95% CI, 14-59.8) in cohort B.
“If you think about [patients with brain metastases] before any new, novel therapy came along, before checkpoint inhibitors, the 1-year survival was 20%. And by 3 years it would dip significantly below 10%. So, the idea that 72% of patients are alive at 3 years is quite wonderful,” Tawbi told Healio.
Tawbi noted that at about 3 years of follow-up, the intracranial activity of the immunotherapy combination continued to show a “truly surprising” high rate of durable responses, with 85% of intracranial responses in asymptomatic patients ongoing at the time of data cutoff.
“In landmark analysis, we looked to see if patients had a response in the brain at 12 weeks,” Tawbi said. “And in those patients who had an intracranial response at 12 weeks, the OS rate at 3 years was 92%. So now when I’m treating a patient with nivolumab plus ipilimumab in the clinic, I don’t have to wait 3 years to tell them that they’re doing OK; after 12 weeks, if they’re responding, I’m going to say, ‘your chance at survival is more than 90%.’”
Tawbi and colleagues reported one treatment-related death due to myocarditis in cohort A. The most common grade 3 to grade 4 treatment-related adverse events in cohort A included increased alanine aminotransferase (15%) and aspartate aminotransferase (15%). Researchers observed no serious treatment-related adverse events in more than one patient in cohort B.
Tawbi said goals of future research include getting more patients to respond and to investigate new approaches in symptomatic patients requiring steroids (only 22% responded in the current study, he said).
“The third issue, and it’s not a minor issue, is that the ipilimumab-nivolumab combination has a toxicity rate of about 55%,” Tawbi added. “Interestingly, that toxicity wasn’t any different in patients with brain metastases vs. in patients without. Still, 55% is a lot. My hope is to be able to find newer approaches that would be that effective but potentially less toxic.”
Tawbi and colleagues have similar work underway assessing the combination of relatlimab (BMS-986016, Bristol Myers Squibb) and nivolumab.
“That combination, in patients without brain metastases, seems to have a PFS similar to ipilimumab-nivolumab with only an 18.9% rate of grade 3 to grade 4 toxicity,” Tawbi said. “We’re hoping that may give us some advantage here, as well.”
For more information:
Hussein A. Tawbi, MD, PhD, can be reached at Department of Melanoma Medical Oncology, Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; email: htawbi@mdanderson.org.
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