Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations.

BACKGROUND: Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. METHODS: Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. RESULTS: Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 µg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. CONCLUSIONS: The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

Multimethod imaging, staging, and spectrum of manifestations of metastatic melanoma.

The incidence of melanoma has been steadily increasing. Imaging plays an important role in tumour assessment as metastatic melanoma can involve multiple organs. Computed tomography (CT) is currently the most widely used technique for tumour staging, surveillance and assessment of therapeutic response, but ultrasound, magnetic resonance imaging (MRI) and positron-emission tomography (PET)-CT also play important roles in the imaging of this tumour. In this article, we review the pathways of spread, staging according to the recently updated TNM classification, pathology, typical and atypical imaging features at common and uncommon sites, and treatment of metastatic melanoma.

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma.

PURPOSE: High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma. METHODS: For PK analysis, 32 patients received peginterferon α-2b 6 µg/(kg week) subcutaneously for 8 weeks (induction) then 3 µg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied. RESULTS: Peginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision. CONCLUSIONS: Peginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity.

Clinical results using biochemotherapy as a standard of care in advanced melanoma.

Phase II studies of biochemotherapy in metastatic melanoma patients have reported response rates of 47-63%. Even though these were highly selected patients, we were intrigued by these promising response rates and began using this regimen as standard care in advanced melanoma patients. We report the results of the first 65 patients with AJCC stage IV melanoma (n = 57) or unresectable stage III (n = 8) melanoma treated with concurrent biochemotherapy at Memorial Hospital. Treatment was repeated every 3 weeks and patients were assessed for antitumour effects after every other cycle. The overall response rate among the 63 patients evaluable for response was 29% (three complete responses, 15 partial responses). The median duration of responses was 3.7 months. The response rate among previously treated and previously untreated patients was 6% and 38%, respectively. The estimated median survival for all patients was 8.5 months; the median survival for previously untreated patients was 9.2 months. Tumour response did not correlate with survival. Our experience, which is a retrospective evaluation, does not provide support for the routine use of biochemotherapy as standard treatment. The low response rate among previously treated patients indicates that biochemotherapy is not useful as second-line therapy.

Treatment of malignant pleural effusions with tunneled long-term drainage catheters.

PURPOSE: To assess the effectiveness of tunneled pleural catheters (TPCs) in the treatment of malignant pleural effusions (MPEs). MATERIALS AND METHODS: Twenty-eight patients with symptomatic MPEs had 31 hemithoraces treated with TPCs placed under image guidance. Chemical sclerotherapy had failed in two patients and two had symptomatic locules. Drainage was accomplished by intermittent connection to vacuum bottles. Pleurodesis was considered achieved when three consecutive outputs were scant and imaging showed no residual fluid. RESULTS: All catheters were successfully placed. Dyspnea improved in 94% (29 of 31 hemithoraces) at 48 hours and 91% (20 of 22 patients) at 30 days. Control of the MPE was achieved in 90% of hemithoraces (28/31), although five required ancillary procedures. Pleurodesis occurred in 42% (13 of 31) of hemithoraces, including both that underwent an earlier attempt at chemical sclerotherapy and one treated locule. Continued drainage without pleurodesis controlled the effusion in 48% (15 of 31). In only 7% was hospital time necessary for care related to the TPC. Early, transient catheter-related pain was common, but only three complications (in two patients) occurred. Neither of these altered patient care. CONCLUSIONS: Regardless of whether pleurodesis is achieved, TPCs provide effective long-term outpatient palliation of MPEs.

Staging work-up and post-treatment surveillance of patients with melanoma.

Strategies based on evidence are required to accurately stage and effectively follow patients with melanoma. The goal of staging is to define the extent of disease at the time of presentation to direct and assign prognosis. Patient surveillance is performed to assess treatment results and detect recurrences amenable to further treatment. Staging and surveillance require careful use of resources to be cost effective. This article addresses preoperative staging and post-treatment surveillance of patients with melanoma and outlines a method of follow-up based on available data.

Systemic chemotherapy.

The main use of systemic chemotherapy in metastatic melanoma remains palliative. Dacarbazine (dimethyl-1-triazeno imidazole-4-carboxamide [DTIC]) is the standard chemotherapy agent for advanced disease. The combination chemotherapy and biochemotherapy regimens have achieved higher response rates, but have not led to durable remission or improved survival. The field of systemic therapy remains in need of a more effective and less toxic treatment strategy.

Colonic melanoma, primary or regressed primary.

Primary melanoma originating in the gastrointestinal tract is very rare and the majority of these tumors arise in the mucosa of the anus or rectum. A case of solitary colonic melanoma in a 79-year-old man is described with a review of pertinent literature. The surgically excised neoplasm was evaluated by routine histology and immunohistochemistry stains. Pathologic examination of the excised cecal mass revealed an 8 x 5-cm tan-pink mass with a central green-black necrotic area. Histologically, there were solid sheets of S100- and HMB-45-positive pigmented cells extending from the mucosal ulcerated surface through the bowel wall. The patient had no evidence of cutaneous or ocular primary melanoma. He remained free of recurrent disease 5 years after surgical resection of the colonic melanoma. The unique pathologic features and clinical outcome support the diagnosis of primary colonic melanoma in this patient.

New approaches in the treatment of metastatic melanoma: thalidomide and temozolomide.

Although melanoma is a relatively chemoresistant malignancy, systemic chemotherapy remains the primary treatment for metastatic melanoma. The observation of vasculogenic mimicry in aggressive melanoma has prompted investigation into using an antiangiogenic agent to enhance the antitumor activity of chemotherapy in metastatic melanoma. Thalidomide (Thalomid) exhibits antiangiogenic activity and other biological modulatory effects that may provide additive or synergistic antitumor effects when given concurrently with chemotherapy. A phase I/II study of thalidomide and temozolomide in the treatment of metastatic melanoma is in progress. Preliminary results of this combination therapy have shown significant antitumor activity, including some striking responses in brain metastases.

Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma.

BACKGROUND: Guidelines for follow-up of melanoma patients are not established. In 1987, a follow-up protocol was instituted at the Yale Melanoma Unit to improve upon the detection of disease recurrence in patients with American Joint Committee on Cancer Stage I-III cutaneous melanoma. The follow-up protocol consists of a patient education program and a surveillance schedule based on stage of disease. METHODS: The authors retrospectively reviewed the records of 373 patients who were seen and followed according to the surveillance protocol in the Yale Melanoma Unit between January 1988 and December 1994 to determine 1) the time interval between the initial visit and recurrence; 2) the most common method of detecting recurrences; 3) whether the surveillance schedule or the patient detects more recurrences, i.e., asymptomatic recurrences versus symptomatic recurrences; 4) whether there is any survival difference between asymptomatic and symptomatic recurrences. RESULTS: The 5-year overall survival rates for Stage I, II, and III patients were 95%, 72%, and 52%, respectively. Of the 78 recurrences, 44 (56%) were detected by physician-directed surveillance examinations and 34 (44%) by patients. Most recurrences were found within the first (47%) or second (32%) year of follow-up. The estimated 6-month hazard rates for death or recurrence were 0.0044, 0.0088, and 0.0278 for Stage I, II, and III patients, respectively. The group of asymptomatic patients with recurrence had a survival advantage over the symptomatic recurrence group. In addition, patients with locoregional recurrence had better survival than those with distant recurrence. CONCLUSIONS: Although many recurrences arise rapidly and are recognized early by patients, in this study more than half were found by surveillance examinations before symptoms were manifest. Based on the hazard ratio for recurrences, the authors recommend the following surveillance schedules in addition to the patient education program for detection of recurrences: 1) Stage I, annually; 2) Stage II, every 6 months for Years 1-2 and annually thereafter; 3) Stage III, every 3 months for Year 1, every 4 months for Year 2, and every 6 months for Years 3-5; 4) at Year 6 and beyond, all patients should have surveillance annually, due to the risk of late recurrence and/or metachronous multiple primaries.

Renal cell carcinoma: a paradigm of lanthanic disease.

Renal cell carcinoma is characterized by varied and sometimes obscure manifestations, which include unusual metastatic sites and paraneoplastic and vascular syndromes. In this review, uncommon metastatic sites and their clinical significance are discussed, particularly the thyroid, nasal structures, vagina, and gastrointestinal sites. Paraneoplastic syndromes appear to be related predominantly to cytokines or immunologic mechanisms. Vascular syndromes are related to the tendency of the tumor to spread by direct venous extension and to complications related to the vascularity of the tumor or its metastases. The recognition of unusual manifestations of renal cell carcinoma is important because these syndromes may lead to the diagnosis. Moreover, paraneoplastic syndromes and vascular findings may not indicate unresectability or incurability.

A clinical-pharmacological evaluation of percutaneous isolated hepatic infusion of doxorubicin in patients with unresectable liver tumors.

A dose escalation study of hepatic arterial infusion of doxorubicin during hemodynamic isolation of the liver (the Delcath system) was conducted to: 1) study the pharmacokinetics of regional doxorubicin therapy, and 2) define therapeutic efficacy in the treatment of unresectable liver tumors. Eighteen patients with unresectable primary or metastatic tumor in the liver were treated with 57 procedures. Pharmacokinetic studies were performed on all treatments. Hepatic extraction ratio of doxorubicin remained constant at 60.3+/-12.1%. independent of the dose escalation. The calculated intrahepatic concentration of doxorubicin ranged from 30 to 88 microg/ml when the dosage of doxorubicin was escalated from 50 to 120 mg/m2. Dose-limiting systemic toxicity (grade 4 myelosuppression) was observed at 120 mg/m2. Twelve of 14 patients who received more than one treatment at 90 or 120 mg/m2 were evaluable for disease response: there were 4 partial responses, 3 minor responses, I stable disease, and 4 progressive disease. The median overall survival of responders was 23 months, and for nonresponders it was 8 months. We have demonstrated a dose-response effect of hepatic infusion of doxorubicin at 90 and 120 mg/m2 in advanced hepatic malignancies. The isolated hepatic perfusion system improves the therapeutic index of doxorubicin and provides pharmacologic justification for its use in the treatment of unresectable hepatic malignancies, especially metastatic melanoma and sarcoma.

Molecular basis for thymidine modulation of the efficacy and toxicity of alkylating agents.

The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in mice previously was shown to be markedly enhanced by co-administration of thymidine. We have examined the cellular mechanisms underlying the augmentation effect of thymidine. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma or L1210 leukemia cells in vitro. Instead, thymidine appeared to augment the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice, which specifically rejected a secondary challenge with the B16/F10 tumor. Thus, development of an antitumor immune response is facilitated by thymidine in BCNU-induced immunosuppressed mice. These preclinical studies suggested that combination therapy with alkylating agents and thymidine may be a more efficacious and less toxic anticancer therapy. The potential efficacy of the sequential administration of dacarbazine (DTIC), BCNU, and thymidine in patients with advanced malignant melanoma was investigated. As predicted from animal studies, sequential administration of DTIC, BCNU, and thymidine is a relatively nontoxic therapy for metastatic melanoma. This treatment induced durable responses in up to 35% of patients, and hence is superior to many commonly used toxic combination chemotherapies. The mechanism of action, although not well characterized, is thought to be mediated through protection of the cellular immune process, as well as organ function, from alkylating agent toxicity through modulation of DNA repair enzymes such as O(6)-alkylguanine-DNA alkyltransferase in normal tissue. Thus, thymidine is a biomodulator, which not only protects patients from hematologic, pulmonary, and hepatic toxicities associated with DTIC and BCNU chemotherapy, but also potentiates therapeutic efficacy.