Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab

Abstract

Purpose: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued.

Patients and methods: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation.

Results: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative.

Conclusion: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Trial registration: ClinicalTrials.gov NCT00730639.

Fig 1.

Kaplan-Meier curves of (A) overall survival and (B) progression-free survival in 107 nivolumab-treated patients with melanoma and (C) response duration in 33 objective responders. Analysis includes patients from all dose cohorts. (A) Patients with melanoma had 1- and 2-year overall survival rates of 62% and 43% and a median overall survival of 16.8 months. (B) Progression-free survival rates were 36% and 27% at 1 and 2 years, and the median was 3.7 months. (C) The median duration of response in 33 responding patients was 24 months. Open circles indicate censored events defined for progression-free survival as the time to the last tumor assessment before the date of data analysis for patients without disease progression or death, and for overall survival as the time to the last known alive date before the date of data analysis for patients without a death. NE, not estimable.

Fig 2.

Characteristics of tumor regression in patients with melanoma receiving nivolumab therapy. (A) Maximum reduction or minimum increase in the sum of target lesion measurements compared with baseline in all treated patients with tumor measurements during treatment (n = 97). Responses were observed at all dose levels. Horizontal line at +20% indicates the threshold for defining progressive disease according to RECIST. Horizontal line at −30% indicates threshold for defining objective response (partial tumor regression) in the absence of new lesions or nontarget disease progression according to RECIST. (B) Response kinetics in patients receiving nivolumab at 1 mg/kg (n = 31) or 3 mg/kg (n = 17). Baseline tumor measurements are standardized to zero. Tumor burden is measured as the sum of the longest diameters of target lesions. Triangles indicate first occurrence of a new lesion. Vertical line at 96 weeks indicates the protocol-defined maximum duration of continuous nivolumab therapy. Horizontal line at −30% marks the threshold for defining objective response (partial tumor regression) according to RECIST. Blue curves indicate three unconventional immune-related response patterns in the 1 mg/kg dose cohort that did not meet RECIST criteria (eg, persistent reduction in target lesions in the presence of new lesions or regression following initial progression). Objective responses, unconventional responses, and stable disease persisted following treatment discontinuation in some patients. (C) Durability of tumor regressions in patients with melanoma who had objective responses to nivolumab therapy according to conventional RECIST criteria. Among 107 patients, 33 (31%) responded, including six (35%) of 17 who received nivolumab at 0.1 mg/kg, five (28%) of 18 at 0.3 mg/kg, 11 (31%) of 35 at 1 mg/kg, seven (41%) of 17 at 3 mg/kg, and four (20%) of 20 at 10 mg/kg. Blue bars indicate the time to and duration of response while on treatment; gold bars indicate response duration after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. Vertical line at 96 weeks indicates maximum planned duration of continuous nivolumab therapy. Reasons for treatment discontinuation with ongoing response included investigator-assessed complete response (n = 2), attainment of maximum treatment duration (n = 5), adverse events (n = 6), and other (eg, withdrew consent or investigator decision [n = 4]).

Fig 2.

Characteristics of tumor regression in patients with melanoma receiving nivolumab therapy. (A) Maximum reduction or minimum increase in the sum of target lesion measurements compared with baseline in all treated patients with tumor measurements during treatment (n = 97). Responses were observed at all dose levels. Horizontal line at +20% indicates the threshold for defining progressive disease according to RECIST. Horizontal line at −30% indicates threshold for defining objective response (partial tumor regression) in the absence of new lesions or nontarget disease progression according to RECIST. (B) Response kinetics in patients receiving nivolumab at 1 mg/kg (n = 31) or 3 mg/kg (n = 17). Baseline tumor measurements are standardized to zero. Tumor burden is measured as the sum of the longest diameters of target lesions. Triangles indicate first occurrence of a new lesion. Vertical line at 96 weeks indicates the protocol-defined maximum duration of continuous nivolumab therapy. Horizontal line at −30% marks the threshold for defining objective response (partial tumor regression) according to RECIST. Blue curves indicate three unconventional immune-related response patterns in the 1 mg/kg dose cohort that did not meet RECIST criteria (eg, persistent reduction in target lesions in the presence of new lesions or regression following initial progression). Objective responses, unconventional responses, and stable disease persisted following treatment discontinuation in some patients. (C) Durability of tumor regressions in patients with melanoma who had objective responses to nivolumab therapy according to conventional RECIST criteria. Among 107 patients, 33 (31%) responded, including six (35%) of 17 who received nivolumab at 0.1 mg/kg, five (28%) of 18 at 0.3 mg/kg, 11 (31%) of 35 at 1 mg/kg, seven (41%) of 17 at 3 mg/kg, and four (20%) of 20 at 10 mg/kg. Blue bars indicate the time to and duration of response while on treatment; gold bars indicate response duration after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. Vertical line at 96 weeks indicates maximum planned duration of continuous nivolumab therapy. Reasons for treatment discontinuation with ongoing response included investigator-assessed complete response (n = 2), attainment of maximum treatment duration (n = 5), adverse events (n = 6), and other (eg, withdrew consent or investigator decision [n = 4]).

Fig 3.

Partial response of locally advanced unresectable primary melanoma to nivolumab therapy in a 34-year-old man with xeroderma pigmentosum. Tumor had progressed through prior treatment with high-dose interleukin-2. (A) Pretreatment magnetic resonance imaging scans show right facial tumor eroding the zygomatic bone and extending into the orbit (gold arrows). (B) Immediate pretreatment core-needle tumor biopsy of the facial mass shows melanoma cells (single arrow) adjacent to infiltrating lymphocytes (double arrows). (C) A partial response was observed after 4 months (two cycles) of nivolumab therapy at 0.3 mg/kg every 2 weeks. This patient remains in partial response 2 years after treatment initiation. (D) Post-treatment core-needle biopsy shows fibrosis and infiltrating lymphocytes (double arrows); no tumor was present in this specimen. Hematoxylin and eosin stain; original magnification, ×200.

Fig 4.

Partial response of metastatic melanoma to nivolumab, with continued tumor regression after drug discontinuation. This 59-year-old woman previously had experienced disease progression following high-dose interleukin-2, temozolomide, and sorafenib therapies. She received nivolumab 10 mg/kg every 2 weeks and achieved a partial tumor regression at 2 months. Treatment was discontinued at 8 months (four treatment cycles) as a result of exacerbation of an upper extremity neuropathy. Tumor regression continued after drug discontinuation. Computed tomographic scanning was performed with oral contrast but without intravenous contrast dye. Gold arrows indicate melanoma metastases involving (A) the right adrenal gland, (B) small bowel, and (C) mesenteric lymph nodes.