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Nivolumab with higher ipilimumab dose shows promising efficacy for bladder cancer
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Nivolumab showed durable antitumor activity among patients with metastatic urothelial carcinoma, both alone and combined with ipilimumab, according to extended follow-up from the CheckMate 032 study.
Nivolumab (Opdivo, Bristol-Myers Squibb) combined with high-dose ipilimumab (Yervoy, Bristol-Myers Squibb) yielded the greatest antitumor activity of all regimens evaluated and had a tolerable safety profile.
“The approval of single-agent PD-1 checkpoint inhibitors for bladder cancer in 2017 was an important step forward, but it will take combination therapies to extend the impact of these drugs to more of our patients,” Padmanee Sharma, MD, PhD, professor in the department of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center, said in a press release.
In the open-label, multicohort phase 1/phase 2 study, Sharma and colleagues evaluated patients aged at least 18 years with platinum-pretreated, unresectable, histologically or cytologically confirmed, locally advanced or metastatic urothelial carcinoma. Eligible patients had demonstrated disease progression after undergoing one or more platinum-based chemotherapies.
The researchers treated patients with nivolumab monotherapy (n = 78), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1; n= 104), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3; n = 92). Patients remained on these regimens until disease progression or intolerable toxicity.
Investigator-determined objective response rate served as the primary outcome.
Researchers previously reported interim and initial results from the study. The current analysis includes extended follow-up for all three treatment arms, with a minimum follow-up of 37.7 months for nivolumab monotherapy, 38.8 months for NIVO3+IPI1 and 7.9 months for NIVO1+IPI3.
Results showed the nivolumab monotherapy group attained an ORR of 25.6% (95% CI, 16.4-36.8) and a complete response of 10.3%.
ORRs reached 26.9% (95% CI, 18.7-36.5) with a complete response of 7.7% for NIVO3+IPI1, and 38% (95% CI, 28.1-48.8) with a complete response of 6.5% for NIVO1+IPI3. All groups achieved a median duration of response exceeding 22 months.
Median PFS was 2.8 months in the nivolumab monotherapy group, 2.6 months in the NIVO3+IPI1 group and 4.9 months in the NIVO1+IPI3 group. Median OS was 9.9 months in the nivolumab monotherapy group, 7.4 months in the NIVO3+IPI1 group and 15.3 months in the NIVO1+IPI3 group.
In total, 84.6% of patients in the nivolumab monotherapy and NIVO3+IPI1 groups experienced an any-grade adverse event, as did 80.4% of the NIVO1+IPI3 group.
Grade 3 or 4 treatment-related adverse events occurred in 26.9% of patients in the nivolumab monotherapy group, 30.8% in the NIVO3+IPI1 group and 39.1% in the NIVO1+IPI3 group.
The ORR of 38% in the NIVO1+IPI3 group exceeded prior rates observed in studies of single-agent immunotherapies, the researchers noted. Those rates ranged from 13.4% to 21.1% for metastatic bladder cancer.
“The durable higher response rate with NIVO1+IPI3 found in this study is most encouraging and also indicates that different tumor types may require different doses to elicit improved efficacy,” Sharma said. “The combination for metastatic renal cell cancer uses a lower dose of ipilimumab, but bladder cancer may require ipilimumab at the higher dose. This should be an important consideration.” – by Jennifer Byrne
Disclosures: Bristol-Myers Squibb sponsored the CheckMate 032 study. Sharma reports stock and other ownership interests, consultant/advisory roles with, and patents, royalties and other intellectual property with Bristol-Myers Squibb, Constellation Pharmaceuticals, Jounce Therapeutics and Neon Therapeutics. Please see the study for all other authors’ relevant financial disclosures.
Perspective
Back to TopQian Qin, MD, and Che-Kai Tsao, MD
PD-1/PD-L1 checkpoint inhibitors have become a standard-of-care treatment for metastatic urothelial carcinoma. Despite the approval of five checkpoint inhibitors in recent years, only a subset of patients derive clinical benefit from this therapeutic approach. As evident in other malignancies, concurrent CTLA-4 blockade with ipilimumab plus nivolumab has resulted in better antitumor activity, but applicability of the treatment has been somewhat limited by associated adverse effects. In CheckMate 032, Sharma and colleagues evaluated the safety and efficacy of this combination approach with an expansion cohort of patients with platinum-treated metastatic urothelial carcinoma.
Although the study design precluded direct comparison, the NIVO1+IPI3 cohort showed the highest ORR compared with the NIVO3 and NIVO3+IPI1 arms. In an exploratory subgroup analysis, the NIVO1+IPI3 cohort with PD-L1 expression greater than 1% showed a more significant ORR of 58.1%. These results are encouraging compared with the ORR of PD-1/PD-L1 monotherapy. Increased response durability and OS also were observed in the NIVO1+IPI3 cohort compared with others in the study.
Higher incidence of serious adverse events, particularly with higher doses of ipilimumab, is one concern, as it has been observed in patients with other malignancies. In this population of patients with platinum-treated metastatic urothelial carcinoma, any-grade treatment-related adverse events were similar in the three arms. When examining the two combination arms, NIVO1+IPI3 was associated with higher incidence of grade 3 to grade 4 treatment-related adverse events compared with NIVO3+IPI1, but the rate of treatment-related discontinuation was similar.
Importantly, there were no observed treatment-related deaths, and most high-grade immune-related adverse events resolved with immune-modulating treatments.
Despite these promising results, the small sample size should preclude definitive conclusions at this time. Randomized, prospective validation will be needed to determine optimal dosing, validate clinical benefit and assess long-term safety. This will help define an evolving paradigm in determining the optimal selection and sequence of treatment for patients with metastatic urothelial carcinoma.
References:
Bellmunt J, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.36.6_suppl.410.
Hellman MD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801946.
Motzer RJ, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(19)30413-9.
Wolchok JD, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1709684.
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