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SummaryAntibody–drug conjugates (ADCs) are a relatively new class of highly potent molecules which combine the targeting properties of monoclonal antibodies with the cell destructive properties of cytotoxic agents in order to reduce systemic exposure and toxicity of the latter. Gemtuzumab–ozogamicin was the first-in-class drug approved by the US Food and Drug Administration (FDA) in 2000, but later approval was withdrawn. In the meantime, the number of these types of drugs available for clinical use is rapidly evolving. This review gives a brief overview of currently approved ADCs, with special consideration of pharmaceutical aspects

Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of early administration of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to 4 weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Regarding serum levels of CTX-1, changes over time averaged -0.45 ng/mL (95% confidence interval [CI] -0.72, -0.18) for the denosumab group and 0.29 ng/mL (95% CI -0.01, 0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged -0.74 ng/mL (95% CI -1.14, -0.34; p = 0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged -5.60 ng/mL (95% CI -11.2, -0.04; p = 0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (-1.77 mmol/L [95% CI -3.48, -0.06; p = 0.044]). No adverse events could be attributed to the study medication. The investigation proved that a single application of denosumab early after admission to an ICU prevents acute immobilization-associated increase in bone resorption among previously healthy individuals. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Background: Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Methods: Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to four weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Results: Regarding serum levels of CTX-1, changes over time averaged -0.45 ng/ml (95%CI: -0.72, -0.18) for the denosumab group and +0.29 ng/ml (95%CI: -0.01, +0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged -0.74 ng/ml (95%CI: -1.14, -0.34; p=0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged -5.60 ng/ml (95%CI: -11.2, -0.04; p=0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (-1.77 mmol/l (95%CI: -3.48; -0.06; p=0.044). No adverse events could be attributed to the study medication. Conclusion: The investigation proved that a single application of denosumab early after admission to an ICU prevents any immobilization-associated increase in bone resorption among previously healthy individuals.

SummaryThis article is a brief overview of drugs, which are of use in the treatment of constipation and diarrhoea in palliative care. Whereas most of the drugs mentioned are widely used and known, the aspect of gastrointestinal symptoms as side effect of pharmacological treatments is often underestimated. Therefore, the article highlights the approach of deprescribing, as a tool to reduce both, pill burden and symptoms.

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.

Background Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial. Methods Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^2 plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS). Results Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7–11.6) and the median OS 21.3 months (95% CI 6.3–31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia. Conclusion DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.

Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)–positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, −4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m2) in combination with docetaxel (50 mg/m2) plus cetuximab (500 mg/m2) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7–14.2) and 6.3 months (95% CI 5.7–6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.

e12114 Background: Her2-positive (Her2pos) breast cancer (BCa) is the second most lethal subtype of BCa. The treatment of Her2-positive BCa was revolutionized due to the dual use of trastuzumab and pertuzumab (T+P) in recent years both in the neoadjuvant and the palliative setting. Although several years have passed after initial approval of these drugs, single-center outcome data as reported by clinicians is sparse. In this retrospective study, we set to assess outcomes measures at our institution, Austria’s largest academic hospital, for the use of T+P in early and metastasized BCa. Methods: We acquired records on combined pertuzumab and trastuzumab orders from our intramural drug order software (CATO, Cato Research, Durham, NC, USA) for the time period of May 2013 to March 2018. Further, using electronic patient histories, we described both the neoadjuvant and palliative patient groups by assessment of body weight/size, tumor stage, histology including immunohistochemistry (IHC), lines of oncological therapies received, ejection fraction (EF) drops>10%, deaths and most importantly the outcomes measures pathological complete response (pCR, neoadjuvant cohort) rate and progression-free survival (PFS, palliative cohort). Results: 120 breast cancer patients were given dual therapy with T+P. The neoadjuvant cohort contained 63 patients, while the palliative cohort included 57 patients. All patients included were female. Full histology including IHC data was available for 47 of 63 patients in the neoadjuvant cohort and 30 of 57 patients in the palliative cohort. BMI was 25.6 and 23.3, respectively, on average. The mean age was 54 years in the neoadjuvant and 56 years in the palliative cohort. 73.6% (39/53) and 65.9% (29/44) of tumors were ER positive as determined by IHC. While neoadjuvant patients obtained an average of 6.5 cycles, patients within the palliative cohort received a mean of 17.3 cycles of T+P. 0 and 17 deaths were observed in the respective cohorts. Data on pCR and PFS was available for 95.2% and 91.2% of patients, respectively. The pCR rate within the neoadjuvant cohort was 46.7% (28/60), and mean PFS across all treatment lines of the palliative cohort was 10.2 months. Conclusions: We report retrospective single-center outcome data for the combined use of trastuzumab and pertuzumab in both early and metastatic Her2pos BCa in line with previously published data.