Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study.

PURPOSE: Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. PATIENTS AND METHODS: We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. RESULTS: Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. CONCLUSION: The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma, with deep and sustained confirmed responses.

Adjuvant Ipilimumab in High-Risk Uveal Melanoma.

Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting in locally advanced cutaneous melanoma. We performed a Phase I/II clinical trial of adjuvant ipilimumab in high-risk primary uveal melanoma with distant metastasis-free survival (DMFS) as the primary objective. A total of 10 patients with genomically high-risk disease were treated: three at a dose of 3 mg/kg and seven at 10 mg/kg. Two of the seven patients at the higher dose had to discontinue therapy secondary to grade 3 toxicity. At 36 months follow-up, 80% of patients had no evidence of distant disease (95% CI, 58.7⁻100). With recent advancements in CTLA-4 inhibition, PD-1 inhibition, and combined checkpoint blockade, immunotherapy is a promising avenue of treatment in uveal melanoma. Further clinical trials are needed to elucidate the role of immunotherapy in the adjuvant setting.

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

In the version of this article originally published, there was an error in Fig. 2b. RECIST ORR and pCR were both listed as 25%. RECIST ORR was actually 73%, and pCR was 45%. Also, an author's name was incorrect in the author list. Danny K. Wells should have been listed as Daniel K. Wells. The errors have been corrected in the print, HTML and PDF versions of this article.

Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.

In the version of this article originally published, there was an error in Fig. 1. In the neoadjuvant phase column, the n values for arms A and B were both reported to be 20. The n values for arms A and B were actually 12 and 11, respectively. Also, the URL underlying the accession code in the data availability section was incorrect. The URL was originally https://www.ebi.ac.uk/ega/studies/EGAS00001002698. It should have been https://www.ebi.ac.uk/ega/studies/EGAS00001003178. The errors have been corrected in the print, HTML and PDF versions of this article.

A phase I study of TPI 287 in combination with temozolomide for patients with metastatic melanoma.

TPI 287 is a synthetic taxane derivative with structural modifications allowing for central nervous system penetration and potential circumvention of multidrug resistance efflux pump mechanisms. The aim of this phase I study was to determine the maximum tolerated dose of the combination of TPI 287 and temozolomide in metastatic melanoma. Patients with stage IV unresectable or recurrent stage III melanoma were eligible. Stable untreated or treated brain metastases were allowed. Patients with previous taxane exposure were excluded. TPI 287 was administered intravenously on days 1, 8, and 15 and temozolomide was taken orally daily on days 1-5 of a 28-day cycle. Responses were assessed every two cycles according to WHO criteria. A total of 21 patients were enrolled. The maximum tolerated dose of the combination at this schedule was determined to be 125 mg/m intravenous of TPI 287 and 110 mg/m of oral temozolomide. The dose-limiting toxicity was neuropathy and six patients experienced grade III neuropathy. All patients were evaluable for tumor response. There were no complete responses; there were two partial responses and seven patients had stable disease (overall response rate 9.5% and disease control rate 42.9%). Three patients had stable disease in the brain despite progressive extracranial disease. The combination of TPI 287 and temozolomide is well tolerated in patients with metastatic melanoma, with the exception of neuropathy. The central nervous system penetration of both agents makes this a rational combination for further testing in primary and metastatic brain lesions.