An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical ...predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice.
We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks.
As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio HR 0.29 P<0.001, HR 0.40 p=0.003, HR 0.29 P<0.001, HR 0.42 P=0.004, respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 P=0.004, Week6: HR 0.33 P=0.001) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 P=0.014, Week6: HR 0.51 P=0.046) had significantly better OS.
ALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.
A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this ...interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ‐glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval CI, 290–not reached NR) in the overall population, NR (95% CI, 305–NR) for cutaneous melanoma and 340 days (95% CI, 275–NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.
Skin cancer is most frequently diagnosed in the White population. However, its subtypes and epidemiology in Japan are understudied. We aimed to elucidate skin cancer incidence in Japan based on the ...National Cancer Registry, a new nationwide integrated population‐based registry. Data from patients diagnosed with skin cancer in 2016 and 2017 were extracted and classified by cancer subtypes. Data were analyzed using the World Health Organization and General Rules tumor classifications. Tumor incidence was calculated as the number of new cases divided by the corresponding total person‐years. Overall, 67,867 patients with skin cancer were included. The percentage of each subtype was as follows: basal cell carcinoma, 37.2%; squamous cell carcinoma, 43.9% (18.3% of which, in situ); malignant melanoma, 7.2% (22.1% of which, in situ); extramammary Paget's disease, 3.1% (24.9% of which, in situ); adnexal carcinoma, 2.9%; dermatofibrosarcoma protuberans, 0.9%; Merkel cell carcinoma, 0.6%; angiosarcoma, 0.5%; and hematologic malignancies, 3.8%. The overall age‐adjusted incidence of skin cancer was 27.89 for the Japanese population model and 9.28 for the World Health Organization (WHO) model. The incidences of basal cell carcinoma and squamous cell carcinoma were the highest (3.63 and 3.40 per 100,000 persons, respectively, in the WHO model) among skin cancers, whereas the incidences of angiosarcoma and Merkel cell carcinoma were the lowest (0.026 and 0.038 per 100,000 persons, respectively, in the WHO model). This is the first report to provide comprehensive information on the epidemiological status of skin cancers in Japan using population‐based NCR data.
The Japan NCR yielded data from 67,867 patients with skin cancer. The incidence of BCC and SCC was the first and second highest, respectively. The study may guide the development of needed treatments for skin cancers in Japan.
Skin toxicities are the most common side effects associated with the epidermal growth factor receptor inhibitor erlotinib, occurring in most patients receiving the drug. Clinical trials evaluating ...erlotinib for the treatment of non-small cell lung cancer have reported a range of skin disorders, the most common being acneiform rash, xeroderma (dry skin), pruritus, and paronychia. Although in the majority of cases these effects are mild and transient, they can have a considerable impact on a patient's quality of life and, if particularly severe and persistent, may necessitate treatment interruption or cessation and compromise treatment outcome. This coupled with recent evidence to suggest a positive correlation between the incidence and severity of rash and clinical outcome among erlotinib-treated patients with advanced or metastatic non-small cell lung cancer highlights the importance of adequately managing epidermal growth factor receptor inhibitor–related skin disorders. Clear treatment strategies are therefore necessary to ensure the prevention and optimal management of erlotinib-related skin toxicities thereby enabling patients to continue erlotinib treatment. In this review we present a practical approach for the treatment of erlotinib-related cutaneous side effects in Japanese patients with advanced non-small cell lung cancer providing details of specific treatment interventions, according to symptom severity, for each of the common skin disorders. In addition, the importance of preventive skin care measures–namely maintaining cleanliness, moisturization, and protection from external stimuli–in preventing the development of serious skin disorders is discussed and guidelines for the practice of proper skin care are presented.
We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma in ...real‐world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation‐positive advanced melanoma in our hospital (26 men and 24 women, aged 21–86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression‐free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long‐term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.
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.)
We conducted the present single‐arm, open‐label, multicenter, phase 2 study to evaluate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Nivolumab administered at a dose of 3 mg/kg once every 2 weeks was tolerable and demonstrated favorable anti‐cancer activity. In addition, patients with BRAF wild‐type and those with BRAF mutant melanoma both experienced response.
Nivolumab, a monoclonal antibody against human programmed death 1, was approved for the treatment of melanoma in July 2014 in Japan. Because the Japanese phase II studies (ONO‐4538‐02, ONO‐4538‐08) ...enrolled small numbers of melanoma patients, post‐marketing surveillance (PMS; JapicCTI‐163 272) was conducted to collect safety data in a larger patient population. We report data for melanoma patients who received nivolumab between July 4, 2014 and February 28, 2017. Data collected included baseline characteristics, laboratory tests, treatment‐related adverse events (TRAE), and overall survival (OS). Of 2069 enrolled patients, 2008 patients were included in the safety analysis population. There were 1030 (51.3%) males, the median age was 69 years, and 269 patients (13.4%) had a performance status of ≥2. The primary tumor sites were cutaneous (34.4%), mucosal (34.2%), acral lentiginous (18.6%), others (6.8%), and unknown (6.3%). TRAE occurred in 62.1% of patients, the most common being hypothyroidism (14.0%), increased aspartate aminotransferase (8.5%), and increased alanine aminotransferase (6.9%). TRAE of special interest in ≥5% of patients were thyroid dysfunction (24.9%), hepatic dysfunction (20.6%), infusion reactions (11.4%), colitis/severe diarrhea (6.3%), and interstitial lung disease (ILD; 5.0%). Several types of TRAE of special interest, which included myasthenia gravis/myocarditis/myositis/rhabdomyolysis (0.9%), venous thromboembolism (0.2%), immune thrombocytopenic purpura (0.1%), and encephalitis (0.0%), were observed in this PMS. Although these TRAE were not reported in previous studies (ONO‐4538‐02, ONO‐4538‐08, CheckMate 066, and CheckMate 037), they have been listed in the current Risk Management Plan. History of ILD and male sex were risk factors for ILD in a multivariable analysis. Age <75 years was a risk factor for hepatic dysfunction. At 12 months, median OS was not reached. In conclusion, these results suggested that there was no concern requiring additional precautions for the safety of nivolumab in Japanese patients with melanoma other than the safety information in the Risk Management Plan.
Background
In the previous report of the Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society, we tabulated data on patients with malignant melanoma who had been ...registered at major medical institutions (22 institutions on average) in Japan over 5-year periods from 1987 to 1991 (group A) and from 1992 to 1996 (group B). In the present study, patients registered from 1997 to 2001 (group C) were investigated and the data were compared with findings obtained by the subsequent follow-up of groups A and B.
Methods
The numbers of melanoma patients registered were: 545 in group A (1987–1991), 699 in group B (1992–1996), and 821 in group C (1997–2001). Because the International Union Against Cancer (UICC) TNM and stage classifications for malignant melanoma were changed substantially in 2002, analyses in the present investigation were performed according to the new classifications. The Kaplan-Meier method was used to draw survival curves, and the log-rank test was used to assess the significance of differences in survival. In addition, the numbers of patients with various kinds of skin malignancies, including not only malignant melanoma but also basal cell carcinoma, squamous cell carcinoma, mycosis fungoides, actinic keratosis, Bowen’s disease, and Paget’s disease, registered at approximately 100 medical institutions in Japan from 1987 to 2001, were also investigated and data were tabulated.
Results
The nationwide survey of Japanese patients with malignant skin tumors from 1987 to 2001 showed that the most prevalent skin tumor was basal cell carcinoma, which increased year by year, followed by squamous cell carcinoma, and then by malignant melanoma. The following results were obtained from the data for melanoma patients registered at major institutions from 1987 to 2001. (1) The overall 10-year survival rates for melanoma patients in each chronological group were ranked as: group C > B > A, although only the difference between groups C and A was statistically significant. (2) The male-to-female ratio ranged from 1: 0.97 to 1: 1.14, and the survival rate of female patients was higher than that of male patients (the 140-month survival rate was 70.6% in females and 60% in males). (3) Assessment of the age distribution showed that the number of patients increased rapidly from ages 40–49 years and reached a peak at around 60 years in all three groups. (4) The sole of the foot was the most common site of melanoma in both males and females, while melanomas on the lower limbs were also prevalent in females. (5) Acral lentiginous melanoma (ALM) was the most common type in all three groups, accounting for nearly 50% of the patients in each group. The number of patients with superficial spreading melanoma (SSM) increased steadily over time and exceeded the number of patients with nodular melanoma (NM) in group C. The prognosis of NM was the worst, while that of SSM was the most favorable. (6) The proportion of stage I patients was larger in group C than in groups A and B, but no significant difference among the groups was observed in the proportions of stage II, III, and IV patients. For patients in stage III, the overall survival rate was higher in group C than that in group A or B, while there was no apparent difference in survival between the groups for patients in stage I or II. For patients in stage IV, the survival rate in group C was slightly lower than that in group A or B. (7) In group C, the overall survival rates for substages III A, B, and C were ranked as III A > III B > III C. (8) The overall survival rates for stage IV M1a, M1b, and M1c were ranked as M1a > M1b > M1c. In group C, the overall survival rate of stage IV patients with a normal serum lactic dehydrogenase (LDH) level was higher than that of patients with elevated LDH values. (9) Evaluation of the effects of some therapeutic procedures (prophylactic lymph node dissection and chemotherapy with and without interferon-beta) on the survivals of patients with melanoma was inconclusive and suggested the need for more studies in this area.
Conclusion
In Japan, the number of patients with malignant skin tumors has increased year by year. The prognosis of patients with advanced malignant melanoma remains extremely poor, but that of patients in stage III has shown an improvement.
Treatment with immune checkpoint inhibitors has improved prognosis among patients with cutaneous melanoma, but there are still unmet medical needs in Japan, especially for mucosal melanoma and acral ...lentiginous melanoma (ALM) subtypes. Ipilimumab, a fully human monoclonal antibody that specifically blocks cytotoxic T‐lymphocyte‐associated antigen 4 and potentiates antitumor T‐cell response, was approved in Japan in 2015 for the treatment of radically unresectable malignant melanoma. This postmarketing surveillance (prospective, non‐interventional, multicenter, observational study) evaluated the safety (occurrence of adverse drug reactions ADR) and efficacy (overall survival OS) of ipilimumab in a real‐world setting in Japan. All patients with radically unresectable malignant melanoma undergoing treatment with ipilimumab in Japan during the registration period between August 2015 and February 2017 were enrolled. In total, 547 patients were analyzed; 67.5% were 60 years old or more, 85.7% had an Eastern Cooperative Oncology Group performance status of 0–1, 50.3% had melanoma of the skin (mainly of the ALM subtype) and 73.5% had negative BRAF mutation status. Most patients had experienced recurrence and received multiple treatments. The overall incidence of ADR and serious ADR was 69.5% and 40.8%, respectively. The most common ADR and serious ADR were liver disorder, colitis and diarrhea. The most common ADR of special interest were liver‐related ADR (22.5%), skin‐related ADR (22.1%), gastrointestinal‐related ADR (20.3%) and endocrine system‐related ADR (16.3%). Most of these events had recovered or were in remission by the last evaluation. The median OS was 7.52 months (95% confidence interval, 6.47–8.74). Median OS was 6.31 and 8.44 months in patients with mucosal melanoma and melanoma of the skin; 9.43 and 3.75 months in patients with and without ADR; and 10.32 and 6.11 months in patients with and without serious ADR, respectively. Ipilimumab was tolerable and showed efficacy in improving OS for these patients.
Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, ...in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib.
The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride.
In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed.
Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR.
ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.
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