Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death 1 (PD‐1) ligands. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single‐arm, open‐label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee‐assessed overall response rate was 34.8% (90% confidence interval, 20.8–51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment‐related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI‐142533.)
Summary
Background
Epstein‐Barr virus (EBV)‐associated T/natural‐killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors.
Objectives
To elucidate the prognostic factors of HV and HMB.
Methods
We studied clinicopathological manifestations, routine laboratory findings, anti‐EBV titres, EBV DNA load and EBV‐encoded gene expression, including expression of BZLF1, in 50 patients with classical HV (cHV), sHV, HMB only and HMB with HV (HMB + HV), and further analysed 30 patients who were available for follow‐up.
Results
The median age of disease onset was 5 years (range 1–74). A follow‐up study indicated that fatal outcomes were observed in three of eight patients with sHV, two of six patients with HMB only, and two of five patients with HMB + HV. The main causes of death were complications from haematopoietic stem‐cell transplantation and multiorgan failure. There were no fatalities among the 11 patients with cHV. Univariate analysis revealed two poor prognostic indicators: (i) onset age > 9 years and (ii) the expression of an EBV‐encoded immediate–early gene transcript, BZLF1 mRNA, in the skin lesions (P < 0·001 and P = 0·003, respectively).
Conclusions
No prognostic correlation was observed in EBV‐infected lymphocyte subsets, anti‐EBV antibody titres or EBV DNA load. Late onset and EBV reactivation are both related to more severe phenotypes of the disease, and thus may predict a poor prognosis.
The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase
II
study of nivolumab in untreated Japanese patients with stage
III
/
IV
or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (
ORR
), and secondary endpoints included overall survival (
OS
), progression‐free survival (
PFS
), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (
TRAE
), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase
II
study, 10 survived for over 3 years (41.7%). The
ORR
was 34.8% (90% confidence interval [
CI
]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the
ORR
was 66.7% (90%
CI
: 34.7, 88.3) for superficial spreading, 33.3% (90%
CI
: 11.7, 65.3) for mucosal, and 28.6% (90%
CI
: 10.0, 59.1) for acral lentiginous tumors. The median
OS
was 32.9 months, the 3‐year
OS
rate was 43.5%, and the 3‐year
PFS
rate was 17.2%. A long‐term response was observed in all the tumor types. The most common
TRAE
included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long‐term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.
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