In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that ...neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.
In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.
Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks).
GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.
Clinicaltrials.gov NCT00356460.
Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised ...that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma.
In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0–1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742.
Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 23%), diarrhoea (n=5 10%), fatigue (n=5 10%), and increased alanine aminotransferase concentration (n=4 8%). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 29%), increased alanine aminotransferase concentration (n=9 17%) or aspartate aminotransferase concentration (n=7 13%), hypothyroidism (n=7 13%), and fatigue (n=6 12%). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0–84·4) patients achieved an objective response (complete or partial response).
The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331).
Pfizer Inc.
Introduction
Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely ...used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk.
Materials and Methods
This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib.
Results
34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome.
Conclusions
The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.
Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of ...TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (
n
= 24) were collected and analyzed from patients (
n
= 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients (
n
= 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFβ.
Abstract Background After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance, thus follow up is highly variable among institutions and ...individual providers. The NCCN recommends routine clinical exam and consideration of imaging for stage IIB-IIIC every 3-12 months with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits. Methods We retrospectively reviewed 369 patients with Stage II and III melanoma treated at Ohio State University from 2009-2015 who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 months after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow up after surgery and were excluded. Results The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical exam. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical exam only while 61% (76/125) were followed with at least 2 serial chest x-rays. The median time to first chest x-ray after NED status was 4.7 months (n=76), median time to second chest x-ray after NED status was 12.7 months (n=76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 months for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% (95% CI: 0.88-.99)) versus those followed with at least 2 serial x-rays (96% (95% CI: 0.89-0.98). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 months. Fifty percent of recurrences were detected by imaging in asymptomatic patients while 50% (14/28) had recurrence detected on imaging associated clinical findings. Eighty seven percent (106/122) of stage IIC/IIIA-C patients were followed with at least 2 serial whole body PET/CT scans or whole body CT scans plus brain MRI; median time between NED status and second scan was 10.3 months. Of stage IIC/IIIA-C patients with recurrence, 57% (16/28) went on to surgical resection of the recurrence while 11 (39%) patients received B-RAF inhibitor therapy, immune blockade therapy, or combination therapy. Conclusion For stage IIA and IIB melanoma, surveillance chest x-rays did not improve survival compared to physical exam alone. However, for stage IIC and IIIA-C melanoma, where the recurrence rates are higher, routine whole body imaging detected 50% of recurrences leading to additional surgery and/or treatment with novel systemic therapies for the majority of patients. Detection of melanoma recurrence is important and specific sub stage should be used to stratify risk and define appropriate follow up.
Despite recent advances in oncologic therapy, an important proportion of patients with primary cancer will develop distant metastasis. The standard therapy for metastatic cancer is systemic therapy, ...which typically does not yield excellent response rates for most solid tumors. Data in the literature support the existence of a state of limited metastasis or oligometastasis. Favorable outcomes have been observed in selected patients with oligometastases that are treated with local ablative therapies, which include surgical extirpation, stereotactic body radiation therapy, and radiofrequency ablation. Lung and liver are the two most common sites of oligometastases considered for local ablative therapy and this Review will focus on the role of local therapy in oligometastases that arise in these organs.
We conducted a study to evaluate the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection of distant metastases from renal cell carcinoma (RCC).
Twenty-four ...patients with histologically proven clear-cell RCC undergoing surgical evaluation for possible resection of recurrent disease were investigated. All patients had suspected distant metastases based on conventional anatomic imaging techniques (computed tomography and magnetic resonance imaging). A total of 36 distant metastatic sites were identified. Pathology for all sites was obtained by biopsy or after surgical resection.
Histologically documented distant metastases from RCC were present in 33 sites (21 patients). Overall sensitivity, specificity, and positive predictive value of FDG-PET for the detection of distant metastases from RCC was 63.6% (21 of 33), 100% (three of three), and 100% (21 of 21), respectively. The mean size of distant metastases in patients with true-positive FDG-PET was 2.2 cm (95% CI, 1.7 to 2.6 cm) compared with 1.0 cm in patients with false-negative FDG-PET (95% CI, 0.7 to 1.4 cm; P =.001).
FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy.
Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in ...immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN-α or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-α- and IL-2-stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-α, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 μM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-α or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5-20 μM), IL-2 (2-24 nM), and IFN-α (10(1)-10(6) U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-α- and IL-2-regulated genes and inhibited NK cell production of IFN-γ, RANTES, MIP1-α, and MIG in response to IFN-α stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-α treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells.
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