TLD-1, a novel liposomal doxorubicin, in patients with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).

BACKGROUND: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors. PATIENTS AND METHODS: We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m2, according to an accelerated titration design followed by a modified continual reassessment method. RESULTS: 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m2, RP2D was defined at 40 mg/m2. Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h. CONCLUSIONS: The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m2 administered every 3 weeks. (NCT03387917).

Neratinib as Extended Adjuvant Treatment of HER2-Positive/HR-Positive Early Breast Cancer Patients in Germany, Austria, and Switzerland: Interim Results of the Prospective, Observational ELEANOR Study.

Introduction: Prognosis of patients diagnosed with HER2+ early breast cancer (eBC) has substantially improved, but distant recurrences impacting quality of life and survival still occur. One treatment option for extended adjuvant treatment of patients with HER2+/HR+ eBC is neratinib, available in Europe for patients who completed adjuvant trastuzumab-based therapy within 1 year. The ELEANOR study is investigating the real-world use of neratinib in Germany, Austria, and Switzerland. Results from an interim analysis of the first 200 patients observed for ≥3 months are reported. Methods: The primary objective of this prospective, multicenter, observational study is to assess patient adherence to neratinib (defined as the percentage of patients taking neratinib on ≥75% prescribed days). Secondary objectives are patient characteristics and treatment outcomes. Results: At cut-off (May 2, 2022), a total of 202 patients had been observed for ≥3 months, with neratinib treatment documented for 187 patients (median age: 53.0 years; 67.9% at increased risk of disease recurrence). In total, 151 (80.7%) patients had received prior neoadjuvant treatment; of these, 82 (54.3%) patients achieved a pathologically complete response. Neratinib was initiated at a median 3.6 months after trastuzumab-based treatment, with 36.4% starting at a dose <240 mg/day. Treatment is ongoing for 46.0% of patients, with median treatment duration of 11.2 (interquartile range 0.9-12.0) months. Diarrhea was the most common adverse event (78.6% any grade, 20.3% grade ≥3); pharmacologic prophylaxis was used in 85.6% of patients. Conclusions: The pattern of anti-HER2 pretreatment observed reflected the current treatment for HER2+/HR+ eBC in Germany, Austria, and Switzerland. These interim results suggest that neratinib as an extended adjuvant is a feasible option after various anti-HER2 pretreatments and that its tolerability can be managed and improved with proactive diarrhea management.

Darolutamide Maintenance in Patients With Metastatic Castration-Resistant Prostate Cancer With Nonprogressive Disease After Taxane Treatment (SAKK 08/16).

PURPOSE: To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events. RESULTS: Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7% v 52.2%; P = .127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.91]; P = .017), and median event-free survival was 5.4 versus 2.9 months (HR, 0.46 [95% CI, 0.29 to 0.73]; P = .001). PSA 50% response rate was improved (22% v 4%; P = .014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR, 0.62 [95% CI, 0.3 to 1.26]; P = .181). Treatment-related adverse events were similar in both arms. CONCLUSION: SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

Effect of an interprofessional small-group communication skills training incorporating critical incident approaches in an acute care and rehabilitation clinic specialized for spinal cord injury and disorder.

Aim: To investigate the impact of site-specific inter-professional small-group communication skills training (CST) that incorporates critical incident approaches to learning on patient satisfaction with communication. Setting: Rehabilitation clinic specialized for spinal cord injury/disorder (SCI/D). Methods: Retrospective observational cohort study design using patient and health-professional self-report data. Data for patient satisfaction with communication were collected in 2014 (existing records) and each year from 2015 to 2021 (post-program; volunteers) using the MECON survey. Results: Fifteen basic (n = 161 participants), 16 refresher (n = 84), and five short (n = 17) CST seminars were conducted. Overall, 262 employees (105 physicians, 63 nurses, 36 physio- and occupational therapists, and 58 others) participated; 92 participants (response rate 37.6%) responded to feedback surveys. They rated the seminars positive concerning the alternation between theory, discussion, and practical exercise in 91.3%, and rated the length of the training ideal in 80.2%. Post-program patient satisfaction overall increased from 83.1% (confidence interval (CI) 2.6%) to 90% (CI 0.8%; R2 = 0.776; p= 0.004). It was higher in specific communication-related topics: "receiving information" (81.1%, CI 3.1-90.2%, CI 1.0%; p = 0.003), "being able to bring in concerns" (83%, CI 1.0-90.8%; R2 = 0.707; p = 0.009) and "being treated with respect" (89.4%, CI 2.6-94.4%, CI 0.8%; R2 = 0.708; p = 0.004). Practice implications: Inter-professional CST is feasible and well accepted by professionals from various professional groups. During seven years of continuous training, independent patient ratings of satisfaction with professional communication have improved significantly. Participants attest to the training's high credibility and usefulness in everyday life.

SAKK 19/17: safety analysis of first-line durvalumab in patients with PD-L1 positive, advanced nonsmall cell lung cancer and a performance status of 2.

INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.

RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward?

BACKGROUND: There is no established systemic treatment option for unresectable osteosarcoma progressing after standard chemotherapy. A recently published clinical trial has demonstrated some activity of sorafenib in this situation. Preclinical research suggests a role for the inhibition of the receptor activator of nuclear factor-ĸB ligand (RANKL), but no clinical data have been reported so far. CASE REPORT: A 37-year-old man was diagnosed with unresectable osteoblastic, osteoblastoma-like osteosarcoma in the C7/Th1 vertebra. The tumour progressed locally despite two lines of chemotherapy and stereotactic radiotherapy. On treatment with sorafenib and denosumab, a complete metabolic remission was achieved and is ongoing for over 18 months. Immunohistochemistry revealed an overexpression of RANK and RANKL in the patient's primary tumour. DISCUSSION: This is the first report of activity achieved by the combination of the tyrosine kinase inhibitor sorafenib and the RANKL inhibitor denosumab in a patient with osteosarcoma. It confirms preclinical data on RANK/RANKL inhibition in osteosarcoma and could serve as a hypothesis-generating approach for clinical trials in this patient population.

Epidermal growth factor receptor mutation in a patient with squamous cell carcinoma of the lung: who should be tested?

We report the case of a 64-year-old ex-smoker with metastatic poorly differentiated squamous cell carcinoma (SCC) of the lung and an epidermal growth factor receptor (EGFR) mutation in exon 21 (p.L858R) who achieved prolonged clinical benefit from treatment with an EGFR tyrosine kinase inhibitor (TKI). The initial diagnosis of SCC of the lung obtained by bronchoscopic biopsy was based on immunohistochemical staining only with positivity for cytokeratin (CK) 5/6 and p63 because morphological diagnosis was not possible. Patients with non-small cell lung cancer (NSCLC), not otherwise specified (NOS) favouring SCC are usually not tested for the presence of EGFR mutations, and therefore may not receive EGFR TKI therapy. A bronchoscopic rebiopsy showed small nests of undifferentiated tumour cells with weak immunoreactivity of some tumour cells for CK5/6, p63 and no positivity of some tumour cells for thyroid transcription factor-1. These findings suggested a mixed squamous/glandular immunophenotype that has been missed at the initial biopsy. Our clinical case illustrates the problem of tumour heterogeneity encountered in small bronchoscopic biopsies and the difficulties of evaluating the histological subtype in poorly differentiated carcinomas. Initial bronchoscopy should be performed by an experienced pulmonologist who attempts to obtain sufficient material from different areas of the tumour. In the era of targeted therapy, a remote smoking history in a patient with NOS favouring SCC should also lead to EGFR mutation testing to allow highly effective therapy to be offered to mutation-positive patients.

PET/CT of the abdomen: optimizing the patient breathing pattern.

The aim of this study was to evaluate the respiration position, which is optimal for co-registration of abdominal CT images, and the corresponding positron emission tomography (PET) scan in a new combined PET/CT system. Ten patients (5 men, 5 women; age 57.7+/-15.3 years, age range 34-80 years) underwent imaging for tumor staging on a combined PET/CT scanner (Discovery LS, GE Medical Systems, Milwaukee, Wis.). The PET emission images were acquired during normal shallow breathing and during CT scanning the patients performed four different breathing tasks: free breathing (FB); maximum inspiration (MaxInsp); maximum expiration (MaxExp); and normal expiration (NormExp). NormExp was defined as the respiratory level that was reached when the patient first inhaled and then exhaled without forcing expiration, and then held the breath in this position. Movements of the spleen, liver, left and right kidney, and the bladder were measured by using the promontory of the sacrum as a reference point and measuring the distance from this point to the abdominal organs in the PET and CT images by two independent observers. Statistical comparison of the measured distances between the CT scans and the PET scan were made using a Wilcoxon signed-rank test with Bonferroni correction. Repeated-measures analysis of variance served for the assessment of intraobserver and interobserver agreement. There was no significant difference between NormExp and FB indicating that both respiration protocols are suitable for PET/CT image co-registration of abdominal studies. In contrast, the MaxExp and MaxInsp protocol are not suitable. The NormExp and FB respiration protocol are both suitable for the co-registration of abdominal PET/CT studies. In most patients the mismatch of abdominal organs will be lower than the resolution of the final co-registered PET/CT image.

PET-CT image co-registration in the thorax: influence of respiration.

Because anatomical information on fluorine-18 fluorodeoxyglucose (FDG) whole-body positron emission tomography (PET) images is limited, combination with structural imaging is often important. In principle, software co-registration of PET and computed tomography (CT) data or dual-modality imaging using a combined PET-CT camera has an important role to play, since "hardware-co-registered" images are thereby made available. A major unanswered question is under which breathing protocol the respiration level in the CT images of a patient will best match the PET images, which represent summed images over many breathing cycles. To address this issue, 28 tumour patients undergoing routine FDG PET examinations were included in this study. In ten patients, PET and CT were performed using a new combined high-performance in-line PET-CT camera without the need for repositioning of the patient, while in 18 patients imaging was performed on separate scanners located close to each other. CT was performed at four respiration levels: free breathing (FB), maximal inspiration (MaxInsp), maximal expiration (MaxExp) and normal expiration (NormExp). The following distances were measured: (a) between a reference point taken to be the anterior superior edge of intervertebral disc space T10-11 and the apex of the lung, (b) from the apex of the lung to the top of the diaphragm, (c) from the apex of the lung to the costo-diaphragmatic recess and (d) from the reference point to the lateral thoracic wall. Differences between CT and corresponding PET images in respect of these distances were compared. In addition, for each of 15 lung tumours in 12 patients, changes in tumour position between PET and CT using the same protocol were measured. CT during NormExp showed the best fit with PET, followed by CT during FB. The mean differences in movement of the diaphragmatic dome on CT during NormExp, FB, MaxInsp and MaxExp, as compared with its level on PET scan, were, respectively, 0.4 mm (SD 11.7), -11.6 mm (13.3), -44.4 mm (25.5) and -9.5 mm (25.6). CT acquired in MaxExp and MaxInsp is not suitable for image co-registration owing to the poor match of images in MaxInsp and because of difficulties with patient performance in MaxExp. With reference to lung lesions, NormExp showed the best results, with a higher probability of a good match and a smaller range of measured values in comparison with FB. Image misregistration in combined PET-CT imaging can be minimized to dimensions comparable to the spatial resolution of modern PET scanners. For PET-CT image co-registration, the use of a normal expiration breath-hold protocol for CT acquisition is recommended, independent of whether combined PET-CT systems or stand-alone systems are used.