Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can ...potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.
To assess safety and objective response rate of durvalumab combined with tremelimumab.
The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.
Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.
Safety and tolerability and efficacy measured by objective response rate.
Among the 267 patients (220 men 82.4%), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.
In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.
clinicaltrials.gov Identifier: NCT02319044.
In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) ...receptor, MK-4830, as monotherapy and in combination with pembrolizumab.
Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.
Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.
This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.
Summary
Purpose
The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated ...dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy.
Methods
Patients with advanced solid tumors (
N
= 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (
n
= 43) had tumor samples with
PIK3CA
and/or PTEN alterations.
Results
The most common cancers were colorectal (
n
= 31) and breast cancer (
n
= 21). Median number of prior antineoplastic regimens was four (range: 1–12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (
18
F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit.
Conclusion
Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.
Circulating biomarkers have emerged as valuable surrogates for evaluating disease states in solid malignancies. Their relative ease of access and rapid turnover has bolstered clinical applications in ...monitoring treatment efficacy and cancer progression. In this review, the roles of various circulating biomarkers in monitoring treatment response are described. Non-specific markers of disease burden, tumor markers (eg CA 125, CEA, PSA, etc.), circulating tumor cells, nucleic acids, exosomes, and metabolomic arrays are highlighted. Specifically, the discovery of each of these markers is reviewed, with examples illustrating their use in influencing treatment decisions, and barriers to their application noted where these exist. Finally, opportunities for future work using these circulating biomarkers are discussed.
Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not ...historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.
Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. ...Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.
The goals and objectives of phase 1 clinical trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose-toxicity profile of the ...investigational agent. Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient ways to design and implement early clinical trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 design, multi-institutional phase 1 studies, accelerated titration designs, continual reassessment methods, the study of specific target patient populations, and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The "fail early and fast" approach is acceptable if the appropriate patient population is evaluated in the phase 1 trial. The approaches outlined in this overview address the merits, advantages, disadvantages, and obstacles encountered during first in human studies.
Summary Objectives To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC). Methods OPC treated with ...RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(−) cohorts. Results Median follow-up was 3.9 years. The DM rate were similar (11% vs. 15% at 3-years, p = 0.25) between the HPV(+) ( n = 457) vs. the HPV(−) ( n = 167) cases. While almost all (24/25) HPV(−) DM occurred within 2-years following RT (1 was at 2.1 years), 7/54 (13%) of HPV(+) DM were detected beyond 3 years (up to 5.3 years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(−). Post-DM survival rates were 11% vs. 4% at 2-years ( p = 0.02) for the HPV(+) vs. HPV(−) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1). Conclusions Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(−) patients: it may occur after a longer interval, often with a “disseminating” phenotype, and a small number may have prolonged survival after salvage for DM.
Abstract
Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein-Barr virus infection and has a high ...propensity for regional and distant metastases, while it is very sensitive to radiation and chemotherapy. A common feature of Epstein-Barr virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive programmed death-ligand 1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a clinical trial planning meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care, and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco regionally advanced, nonmetastatic NPC; widely metastatic NPC; and either local recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this clinical trial planning meeting and provides a road map for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This road map, though specific for NPC, may also be applicable to other virally driven cancers that have similar ability to evade the host’s immune system.
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