Soft-tissue sarcomas (STSs) are rare malignancies, accounting for approximately 1% of adult cancer. Metastatic disease carries a poor prognosis, and various efforts have been made to improve the ...prognosis of advanced STS, to date with little success. Immune checkpoint inhibitors (ICPIs) have substantially improved prognosis for many cancer types. Their role in the treatment of STS, however, remains unravelled.
The objective of the study is to assess the activity of ICPIs in the treatment of STS.
We performed a systematic review using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Furthermore, abstracts from European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and Connective Tissue Society Oncology (CTOS) congress were searched from 2017 until 2020. Prospective clinical trials investigating ICPIs, either monotherapy or combination therapy, in STS were available for inclusion. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and major toxicity. Cut-off for clinical activity was defined as an ORR of ≥0.15. Subgroup analysis was carried out as per treatment category, disease setting and histologic subtype, using a random effects model.
We identified 27 studies, including a total of 1012 patients (range 6–85) with more than 25 histologic subtypes. The pooled ORR was 0.14 (95% confidence interval CI 0.09–0.18), DCR was 0.55 (95% CI 0.43–0.66), mean PFS range was 1.8–11.5 months and mean OS was 6.1–34.7 months. The pooled ORR as per treatment category was 0.14 for anti-programmed cell death 1 (anti-PD1) monotherapy (95% CI 0.07–0.23), 0.16 for anti-PD1 + anti-cytotoxic T-lymphocyte–associated protein 4 (95% CI 0.06–0.29), 0.20 for anti-PD1 + tyrosine kinase inhibitor (95% CI 0.06–0.38), 0.20 for anti-PD1 + chemo (95% CI 0.06–0.38) and 0.08 for anti-PD1 + immunomodulator (95% CI 0.01–0.19). The pooled ORR as per disease setting was as follows: neoadjuvant treatment, 0.09 (0.00–0.25); advanced disease first line, 0.23 (0.15–0.32) and advanced pretreated, 0.13 (0.09–0.19). High response rates were seen in classic Kaposi sarcoma (CKS), alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (UPS) with ORR of 0.69 (95% CI 0.51–0.82), 0.35 (95% CI 0.27–0.44) and 0.20 (95% CI 0.15–0.27), respectively. Activity was limited in gastrointestinal stromal tumour (ORR 0.01 95% CI 0.0–0.08), uterine leiomyosarcoma (ORR 0.06 95% CI 0.02–0.18), leiomyosarcoma (ORR 0.10 95% CI 0.06–0.17) and liposarcoma (ORR 0.11 95% CI 0.07–0.17).
Clinical activity of ICPIs in STS is highly variable and depends on histologic subtype, disease setting and concomitant treatment strategy. Activity was high in CKS, ASPS and UPS. Early incorporation of ICPIs in combination with chemotherapy seems a promising strategy that warrants further interest. Translational research integrating molecular profile, biological behaviour and response to ICPIs should determine their role in treatment of STS.
•Immune checkpoint inhibitors are active in soft-tissue sarcoma, with a 14% objective response rate (ORR) for all combinations.•Responses vary by histologic subtype, with highest activity in classic Kaposi sarcoma, alveolar soft part sarcoma and undifferentiated pleomorphic sarcoma.•First-line anti-programmed cell death 1 + chemo combos have a 24% ORR, with manageable toxicity.•Immunoprofile and correlation to immune checkpoint inhibitor response are the key features to further development.
SummaryBackgroundTrastuzumab duocarmazine is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies ...showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. MethodsWe did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FindingsBetween Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3–4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two 1%) and dyspnoea (two 1%). The most common treatment-related adverse events (grades 1–4) were fatigue (48 33% of 146 patients), conjunctivitis (45 31%), and dry eye (45 31%). Most patients (104 71% of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4–48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8–46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3–67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2–30·2) of 16 patients with gastric cancer, four (25%, 7·3–52·4) of 16 patients with urothelial cancer, and five (39%, 13·9–68·4) of 13 patients with endometrial cancer. InterpretationTrastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FundingSynthon Biopharmaceuticals.
Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development ...for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 10
PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 10
cells (27.3); 62 mg, 0.272 pmol per 10
cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.
Background
Acute and late toxicity after intensity‐modulated radiotherapy (IMRT) for head and neck cancer (HNC) impacts on patient quality of life; yet, very late toxicity data remain scarce. This ...study assessed dysphagia, xerostomia, and neck fibrosis 3‐8 years after IMRT.
Methods
A retrospective analysis using generalized estimated equations was performed on 60 patients with HNC treated with fractionated IMRT between 2000 and 2015 who had a follow‐up ≥8 years. Toxicity was scored using LENT‐SOMA scales.
Results
A trend towards a nonlinear global time effect (P = .05) was noted for dysphagia with a decrease during the 5 years post‐treatment and an increase thereafter. A significant decrease in xerostomia (P = .001) and an increase in neck fibrosis (P = .04) was observed until 8 years.
Conclusions
Dysphagia, xerostomia, and neck fibrosis do not appear stable over time and remain highly prevalent in the very late follow‐up. Our findings support the need for prospective trials investigating very late toxicity in patients with HNC.
Summary Background Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck ...(SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1–4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov , number NCT00460265. Findings Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8–12·2) in the panitumumab group and 9·0 months (8·1–11·2) in the control group (hazard ratio HR 0·873, 95% CI 0·729–1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6–6·6) in the panitumumab group and 4·6 months (4·1–5·4) in the control group (HR 0·780, 95% CI 0·659–0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 19% of 325 included in safety analyses vs six 2% of 325), diarrhoea (15 5% vs four 1%), hypomagnesaemia (40 12% vs 12 4%), hypokalaemia (33 10% vs 23 7%), and dehydration (16 5% vs seven 2%). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months 95% CI 9·7–13·7 vs 8·6 months 6·9–11·1; HR 0·73 95% CI 0·58–0·93; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months 7·3–12·9 vs 12·6 months 7·7–17·4; 1·00 0·62–1·61; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 95% CI 0·47–1·04). Interpretation Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. Funding Amgen Inc.
This randomized trial of the treatment of advanced head and neck cancer tested the efficacy of adding cetuximab, an antibody against the epidermal growth factor receptor, to standard therapy ...(platinum-based chemotherapy). As compared with standard chemotherapy alone, cetuximab plus chemotherapy prolonged median overall survival by almost 3 months.
In the treatment of advanced head and neck cancer, cetuximab plus chemotherapy prolonged median overall survival by almost 3 months.
Platinum-based chemotherapy consisting of either cisplatin or carboplatin is the usual first-line treatment for inoperable recurrent or metastatic squamous-cell carcinoma of the head and neck. Cisplatin is often combined with fluorouracil, but the results of this treatment are far from satisfactory.
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Head and neck cancer cells often express the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome.
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Cetuximab (Erbitux, developed by Merck Darmstadt, under license from ImClone) is an IgG1 monoclonal antibody that inhibits ligand binding to the EGFR
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and stimulates antibody-dependent cell-mediated cytotoxicity.
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It also enhances the activity of a . . .
Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a ...tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary radiation or chemotherapeutics, often present low response rates. As a result, there is an unmet need for novel therapeutic approaches. Nowadays, target-based therapies (e.g., small inhibitors and immunotherapy) are used by the medical oncologist for possible treatment of advanced SGMs. Based on recent published trials, some novel treatments may provide additional disease control for some patients. However, sample sizes are small, the general findings are unsatisfactory, and a lot of uncertainties remain to be elucidated. Nevertheless, research shows that patients do not benefit from blind administration of systemic treatments and therefore a more personalized approach is highly needed. The aim of this review paper is to summarize the most recent advances in the biological understanding and molecular pathways of salivary gland cancers, the association of these pathways with the current treatments used and their implications for more personalized targeted-based therapies.
The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in ...patients with CD70 expressing advanced malignancies.
Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (
= 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.
Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies.
This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies.
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Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), ...is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.
The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.
Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval CI: 2.7–NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5–1.8) and 6.7 months (95% CI: 3.0–9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).
Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
•This study demonstrates the feasibility of UPSTREAM, a biomarker-driven trial for SCCHN.•This is the first trial of monalizumab monotherapy in SCCHN.•Disease stabilization was observed in 23% of the patients.•Patients previously exposed to PD-(L)1 inhibitors had a higher median OS.
Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure ...prophylaxis (PrEP).
Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level.
In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal.
In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6 cells) were above the PK threshold for all dose levels.
Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.
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