A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. RESULTS: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. CONCLUSIONS: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Choice of surgery in intestinal-type adenocarcinoma of the sinonasal tract: a long-term comparative study.

PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.

Comparison of different estimated glomerular filtration rates for monitoring of kidney function in oncology patients.

Background: Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and ß-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. Methods: We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Results: Cr remained constant during TKI treatment (P = 0.7753), whereas a significant decrease in CSTC (from week 2 onward, P < 0.0001) and BTP (at weeks 2 and 4, P = 0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P < 0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P = 0.2262), CSTC (P = 0.7341), and BTP concentrations (P = 0.3592). Conclusion: GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.

Infrared Spectroscopy: A New Frontier in Hematological Disease Diagnosis.

Hematological diseases, due to their complex nature and diverse manifestations, pose significant diagnostic challenges in healthcare. The pressing need for early and accurate diagnosis has driven the exploration of novel diagnostic techniques. Infrared (IR) spectroscopy, renowned for its noninvasive, rapid, and cost-effective characteristics, has emerged as a promising adjunct in hematological diagnostics. This review delves into the transformative role of IR spectroscopy and highlights its applications in detecting and diagnosing various blood-related ailments. We discuss groundbreaking research findings and real-world applications while providing a balanced view of the potential and limitations of the technique. By integrating advanced technology with clinical needs, we offer insights into how IR spectroscopy may herald a new era of hematological disease diagnosis.

Monoclonal antibodies against GFRα3 are efficacious against evoked hyperalgesic and allodynic responses in mouse join pain models but, one of these, REGN5069, was not effective against pain in a randomized, placebo-controlled clinical trial in patients with osteoarthritis pain.

The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund's Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.

Assessment of pharmacokinetics, safety, and tolerability following twice-daily administration of molnupiravir for 10 days in healthy participants.

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) that has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [n = 6], 600 mg [n = 6], and 800 mg [n = 12]) or matching placebo (n = 8) every 12 h (q12h) for 10.5 days. Blood was collected to evaluate the PKs of NHC in plasma and of its active metabolite, NHC-triphosphate (NHC-TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well-tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose-related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC-TP. Accumulation was minimal (<1.2) for NHC and ~2- to 2.5-fold for NHC-TP. Plasma NHC PKs was generally dose proportional, and PBMC NHC-TP PKs was less than dose proportional over the dose range studied. NHC and NHC-TP PK support twice-daily administration. Overall, molnupiravir administered at up to 800 mg q12h for 10.5 days was generally well-tolerated in healthy participants with dose-linear PKs, supporting the evaluation of longer molnupiravir dosing up to 10 days in future clinical trials.

Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours.

BACKGROUND: Bromodomain and extraterminal domain (BET) inhibitors have demonstrated efficacy in solid tumours and haematological malignancies. BI 894999 is a novel oral BET inhibitor that has demonstrated potent antitumour activity in preclinical studies. PATIENTS AND METHODS: 1367.1 was an open-label, Phase Ia/Ib dose-finding study evaluating BI 894999 once daily in patients with advanced solid tumours (Schedule A: 0.2, 0.5, 1.0, 1.5, 2.0, and 5.0 mg, Days 1-21/21-d cycle; Schedule B: 1.5, 2.0, and 2.5 mg, Days 1-15/21-d cycle; Schedule C: loading dose 5.0, 6.0, or 7.0 mg on Day 1 followed by maintenance dose 2.5, 3.0, or 3.5 mg, Days 2-7 and 15-21/28-d cycle); 77 patients were enrolled. NCT02516553. RESULTS: Grade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25, and 9/31 patients for Schedules A, B, and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8%, and 9.7% for Schedules A, B, and C, respectively. Other DLTs occurring in ≥1 patient were troponin T increase (13.6%), hypophosphataemia (4.5%), and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0%, and 29.0% of patients for Schedules A, B, and C, respectively. A partial response was achieved in 9.5% and 4% of patients with Schedules A and B, respectively. The best response with Schedule C was stable disease. CONCLUSION: The 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial.

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Incidence, evolution and risk factors of hypophosphatemia in patients with solid tumors receiving ferric carboxymaltose: a retrospective cohort study.

OBJECTIVES: Ferric carboxymaltose (FCM) is increasingly used in the management of cancer-related anemia, yet it may cause hypophosphatemia. This retrospective study describes the incidence, evolution and risk factors of hypophosphatemia in a cohort of patients with solid tumors receiving FCM. METHODS: Serum phosphorus concentration was assessed longitudinally using a random intercepts model. The probability of developing hypophosphatemia, as graded by CTCAE version 4.0, was investigated using a multi-state model. Transition hazards were modeled non-parametrically and semi-parametrically by a Cox model. Causal marginal risk differences between baseline interventions on serum phosphorus and/or FCM dose were obtained via G-computation. RESULTS: In 174 ambulatory patients with solid tumors receiving FCM at two university hospitals between October 2020 and September 2021, the risk of developing moderate-to-severe hypophosphatemia was 36.0% (95% confidence interval (CI) 28.2-43.9%) and peaked within 16 days after first FCM administration. The average duration of moderate-to-severe hypophosphatemia was 12.4 days. After adjustment for confounders, lower baseline serum phosphorus (adjusted hazard ratio (aHR) 0.88 per 0.1 mmol/L increase, 95% CI 0.79-0.98) and higher FCM dose (first dose: aHR 1.12 per 1 mg/kg increase, 95% CI 1.01-1.25; second dose: aHR 1.06 per 1 mg/kg increase, 95% CI 1.00-1.13) significantly increased the hazard of moderate-to-severe hypophosphatemia. CONCLUSION: Approximately one out of three ambulatory patients with solid tumors may develop moderate-to-severe hypophosphatemia after FCM administration. Baseline serum phosphorus and FCM dose may be modifiable risk factors that should be considered for intervention in order to mitigate the risk of hypophosphatemia.

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

BACKGROUND: 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). SETTING: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.

The Therapeutic Landscape of Salivary Gland Malignancies-Where Are We Now?

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.

Concordance, Correlation, and Clinical Impact of Standardized PD-L1 and TIL Scoring in SCCHN.

BACKGROUND: The clinical significance of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression has been thoroughly researched in squamous cell carcinoma of the head and neck (SCCHN). To address the impact of intra- and intertumoral heterogeneity in these biomarkers, we explored the concordance of PD-L1 combined positive score (CPS) and stromal TILs in different paired tissue sample types, while evaluating their internal relationship and prognostic impact. METHODS: A total of 165 tissue blocks from 80 SCCHN patients were reviewed for TILs and PD-L1 CPS. Concordance between paired tissue samples was evaluated, and their association with several clinicopathological variables, overall survival (OS), and disease-free survival (DFS) was determined. RESULTS: Biopsies and paired resection material were severely discordant in 39% and 34% of samples for CPS and TIL count, respectively, of which CPS was underscored in 27% of biopsies. In paired primary tumor-metastatic lesions, the disagreement was lower for CPS (19%) but not for TIL count (44%). PD-L1 CPS was correlated with prolonged OS when calculated from tissue acquirement, while extended OS and DFS were observed for high TIL density. CONCLUSION: Intertumoral and, especially, intratumoral heterogeneity were confounding factors when determining PD-L1 CPS and TIL count on paired tissue samples, indicating the increasing necessity of assessing both biomarkers on representative tissue material. Although TILs hold valuable prognostic information in SCCHN, the robustness of PD-L1 as a biomarker in SCCHN remains ambiguous.

Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: Ready for Prime Time?

The evaluation of tumor-infiltrating lymphocytes (TILs) has received global attention as a promising prognostic cancer biomarker that can aid in clinical decision making. Proof of their significance was first shown in breast cancer, where TILs are now recommended in the classification of breast tumors. Emerging evidence indicates that the significance of TILs extends to other cancer types, including head and neck cancer. In the era of immunotherapy as a treatment choice for head and neck cancer, assessment of TILs and immune checkpoints is of high clinical relevance. The availability of the standardized method from the International Immuno-oncology Biomarker Working Group (IIBWG) is an important cornerstone toward standardized assessment. The aim of the current article is to summarize the accumulated evidence and to establish a clear premise for future research toward the implementation of TILs in the personalized management of head and neck squamous cell carcinoma patients.

The use of national reimbursement reports to support formulary decisions of the hospital's Drug and Therapeutics Committee: a comparative analysis.

Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access to patients by compiling a formulary on rational grounds. An evolving landscape of innovative molecules challenges timely formulary adaptation after national reimbursement. Aim To integrate national reimbursement reports in the hospital's appraisal, thereby promoting access for patients without delay. Method For 2019, the rationale for new molecules at Ghent University Hospital, Belgium, was compared with the public assessment report of the National Institute for Health and Disability Insurance, assessing a medicine in a specific indication following a reimbursement request by the manufacturer. Decision criteria (therapeutic value and cost) between matching medicines in both databases (national & hospital) were retrospectively compared [no (%), mean (SD)]. Results Two-hundred public reports and 30 formulary decisions were analysed (with antineoplastic & immunomodulating as most prevalent class: 41.0% resp. 36.7%). National decision often concerned hospital-only medicines (89; 44.5%) without patient co-payment (101; 50.5%). Of 13 matched medicines (same indication), time delay between national decision and formulary admission was on average 3.1 (SD 2.3) months. Comparative analysis showed that assessment in both committees was mostly based on the efficacy endpoints of Randomised Controlled Trials. Literature used in hospital appraisals was of more recent publication date: + 0.78 (SD 2.2) years. Using public reports as a horizon scan could enable quick identification of new indications. Conclusion To speed up patient access, the scientific evidence of national reimbursement reports can be used for the purpose of hospital formulary decisions.

Mental Health and Quality of Life among Patients with Cancer during the SARS-CoV-2 Pandemic: Results from the Longitudinal ONCOVID Survey Study.

PURPOSE: This longitudinal survey study aimed to investigate the self-reported outcome measures of COVID-19 peritraumatic distress, depression, anxiety, stress, quality of life (QOL), and their associated factors in a cohort of cancer patients treated at a tertiary care hospital during the SARS-CoV-2 pandemic. METHODS: Surveys were administered at four time points between 1 April 2020 and 18 September 2020. The surveys included the CPDI, DASS-21, and WHOQOL-BREF questionnaires. RESULTS: Survey response rates were high (61.0% to 79.1%). Among the 355 participants, 71.3% were female, and the median age was 62.2 years (IQR, 53.9 to 69.1). The majority (78.6%) were treated with palliative intention. An important proportion of the participants reported symptoms of COVID-19 peritraumatic distress (34.2% to 39.6%), depression (27.6% to 33.5%), anxiety (24.9% to 32.7%), and stress (11.4% to 15.7%) at any time point during the study period. We did not find clinically meaningful mental health and QOL differences during the study period, with remarkably little change in between the pandemic's first and second wave. We found no consistent correlates of mental health or QOL scores, including cancer type, therapy intention, and sociodemographic information. CONCLUSION: This cohort of cancer patients showed considerable resilience against mental health and QOL deterioration during the SARS-CoV-2 pandemic.

Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers.

BACKGROUND AND AIMS: Polyhexamethyl biguanide (PHMB), a widely used topical treatment for Acanthamoeba keratitis (AK), is unlicensed with no formal safety assessment. This study evaluated its safety and tolerability. METHODS: A prospective, randomised, double-masked controlled trial in 90 healthy volunteers. Subjects were treated with topical 0.04%, 0.06%, 0.08% PHMB or placebo (vehicle) 12× daily for 7 days, then 6× daily for 7 days. The rates of dose-limiting adverse events (DLAEs) leading to interruption of dosing, mild adverse events (AEs) (not dose limiting) and incidental AEs (unrelated to treatment) were compared. The primary outcome was the difference between treatments for DLAE rates. RESULTS: 5/90 subjects developed DLAE within <1-4 days of starting treatment; 2/5 using PHMB 0.06% and 3/5 PHMB 0.08%. These resolved within 1-15 days. There were no significant differences in DLAE between treatment groups. Mild AEs occurred in 48/90 subjects (including placebo). There was no trend for an increased incidence of any AE with increasing concentrations of PHMB, except for corneal punctate keratopathy with PHMB 0.08%, which fully resolved within 7-14 days. CONCLUSION: These findings are reassuring for PHMB 0.02% users. They also suggest that higher PHMB concentrations may show acceptable levels of tolerance and toxicity in AK subjects, whose susceptibility to AE may be greater than for the normal eyes in this study. Given the potential benefits of higher PHMB concentrations for treating deep stromal invasion in AK, we think that the use of PHMB 0.08% is justified in treatment trials. TRIAL REGISTRATION NUMBER: NCT02506257.

Cytoreductive nephrectomy and exposure to sunitinib - a post hoc analysis of the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial.

OBJECTIVE: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm. PATIENTS AND METHODS: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used. RESULTS: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm. CONCLUSIONS: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit.

Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody-drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors.

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. RESULTS: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. CONCLUSIONS: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study.

BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.