Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.

Medicine Access Programmes: what do patients think - a patient-reported outcome study on ribociclib in metastatic breast cancer in Australia.

This study evaluated patient-reported outcomes (PROs) of Medicine Access Programmes (MAPs) for Australian metastatic breast cancer patients on ribociclib. Limited patient awareness of MAP enrolment was identified, emphasising the need for improved education and consent processes. Most patients expressed gratitude for accessing non-funded medications and perceived enhanced medication adherence as a key benefit. Integrating PRO data with real-world registry data provides comprehensive insight for future MAP development.

Telepharmacy for outpatients with cancer: An implementation evaluation of videoconsults compared to telephone consults using the CFIR 2.0.

Background: Medication history telepharmacy consults are conducted prior to patients commencing their systemic anti-cancer therapy. At the study institution, this has historically been carried out as an unscheduled telephone consult. However, due to challenges with telephone consults, a scheduled videoconsult model was established. Funding, time efficiency, and completion rate for videoconsults compared to telephone consults have been examined previously. Objective: The aim of this study was to determine staff perceptions of the factors that influence implementation, including enablers and barriers, for videoconsults compared to telephone consults, to inform model sustainability. Methods: Semi-structured interviews were conducted with staff (n = 14) involved with the videoconsult service, or who provided care for patients who had a videoconsult. Interviews were coded for positive or negative influence and strength using the Consolidated Framework for Implementation Research (CFIR) 2.0, to understand which constructs influence implementation. Results: Thirty-nine of the 79 constructs, from across four domains were identified as influences for the telephone and videoconsult models. Six constructs were strongly differentiating for videoconsults over telephone consults. Of the 25 positively influencing constructs for the videoconsult model, strongest ratings (+2) were given for innovation advantages, critical incidents, support persons assisting in the consult, financing related to funding reimbursement, and telehealth coordinator capability and motivation. Barriers unique to the videoconsult model included the many steps that were involved, compatibility with workflows, and pharmacist resource. Similarities and differences unique to each model were identified. Conclusion: Findings demonstrated a number of strongly differentiating constructs highlighting superiority of the videoconsult model. However, implementation of both models had multiple enablers and barriers that may influence adoption. The potential of a hybrid service, using both telephone consults and videoconsults, may help optimise delivery of services.

NeoAdjuvant pembrolizumab and STEreotactic radiotherapy prior to nephrectomy for renal cell carcinoma (NAPSTER): A phase II randomised clinical trial.

Background: Surgery remains the standard of care for localised renal cell carcinoma (RCC). Nevertheless, nearly 50% of patients with high-risk disease experience relapse after surgery, with distant sites being common. Considering improved outcomes in terms of disease-free survival with adjuvant immunotherapy with pembrolizumab, we hypothesise that neoadjuvant SABR with or without the addition of pembrolizumab before nephrectomy will lead to improved disease outcomes by evoking better immune response in the presence of an extensive reserve of tumor-associated antigens. Methods and analysis: This prospective, open-label, phase II, randomised, non-comparative, clinical trial will investigate the use of neoadjuvant stereotactic ablative body radiotherapy (SABR) with or without pembrolizumab prior to nephrectomy. The trial will be conducted at two centres in Australia that are well established for delivering SABR to primary RCC patients. Twenty-six patients with biopsy-proven clear cell RCC will be recruited over two years. Patients will be randomised to either SABR or SABR/pembrolizumab. Patients in both arms will undergo surgery at 9 weeks after completion of experimental treatment. The primary objectives are to describe major pathological response and changes in tumour-responsive T-cells from baseline pre-treatment biopsy in each arm. Patients will be followed for sixty days post-surgery. Outcomes and significance: We hypothesize that SABR alone or SABR plus pembrolizumab will induce significant tumor-specific immune response and major pathological response. In that case, either one or both arms could justifiably be used as a neoadjuvant treatment approach in future randomized trials in the high-risk patient population.

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.

An evaluation of telephone versus videoconference consults for pre-treatment medication history taking by cancer pharmacists.

INTRODUCTION: The primary aim was to compare the successful completion rates of pre-treatment medication history consults conducted by pharmacists with patients either via an unscheduled telephone consult (current standard care) or a scheduled videoconference consult model. Secondary aims were to examine pharmacist perceptions of the telephone and videoconference consults and explore patient (+/- support person) perceptions of videoconference consults. METHOD: Completion data were collected and compared for the two modalities. In addition, pharmacists commented on any positive/negative factors impacting all consults. For the final 35 participants completing a videoconference consult, patients, support people, and pharmacists involved, completed a survey exploring perceptions and satisfaction. RESULTS: A significantly higher completion rate (p < 0.0001) was found for the videoconferencing model, with 94% (76 of 81) completed successfully compared to 72% (76 of 105) of the unscheduled telephone consults. Pharmacists reported multiple factors impacting the success of the telephone consults including scheduling issues and patient factors. Survey responses revealed that 100% of patients/support people and 82% of pharmacists reported satisfaction with videoconference consults. Surveyed participants noted some technical issues, however, the 'ability to show/view medication containers and/or labels' and 'convenience of scheduled time' were benefits of the videoconference model. DISCUSSION: Results indicate that pre-treatment medication history consults should be offered via videoconference to maximise success.

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic clear cell renal cell carcinoma (ccRCC) but is limited by a lack of prospective clinical trial data. OBJECTIVE: The RAPPORT trial evaluated the safety and efficacy of total metastatic irradiation followed by short-course anti-programmed death receptor-1 immunotherapy in patients with oligometastatic ccRCC. DESIGN SETTING, AND PARTICIPANTS: RAPPORT was a single-arm multi-institutional phase I/II trial (NCT02855203). Patients with two or fewer lines of prior systemic therapy and one to five oligometastases from ccRCC were eligible. INTERVENTION: A single fraction of 20 Gy SABR (or if not feasible, ten fractions of 3 Gy) was given to all metastatic sites, followed by pembrolizumab 200 mg administered Q3W for eight cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The endpoints were adverse events (AEs), disease control rate (DCR) for at least 6 mo, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was used for time-to-event endpoints. Freedom from local progression (FFLP) was assessed per lesion adding patient as a cluster effect. RESULTS AND LIMITATIONS: Thirty evaluable patients, with a median age of 62 yr, were enrolled. The median follow-up was 28 mo. There were 44% of patients with intermediate-risk and 56% with favorable-risk disease. Eighty-three oligometastases were irradiated (median three per patient): eight adrenal, 11 bone, 43 lung, 12 lymph node, and nine soft tissue. Four patients (13%) had grade 3 treatment-related AEs: pneumonitis (n = 2), dyspnea (n = 1), and elevated alkaline phosphatase/alanine transaminase (n = 1). There were no grade 4 or 5 AEs. FFLP at 2 yr was 92%. ORR was 63% and DCR was 83%. Estimated 1- and 2-yr OS was 90% and 74%, respectively, and PFS was 60% and 45%, respectively. Limitations include a single-arm design and selected patient population. CONCLUSIONS: SABR and short-course pembrolizumab in oligometastatic ccRCC is well tolerated, with excellent local control. Durable responses and encouraging PFS were observed, warranting further investigation. PATIENT SUMMARY: The RAPPORT trial investigated the combination of high-dose precision radiotherapy and a short course of immunotherapy in patients with low-volume metastatic kidney cancer. We found that this treatment regimen was well tolerated, with excellent cancer control in sites of known disease. A proportion of patients were free from cancer relapse in the longer term, and these encouraging findings warrant further investigation.

Changing from telephone to videoconference for pre-treatment pharmacist consults in cancer services: Impacts to funding and time efficiency.

Introduction: This study examined the reimbursement opportunity and the time efficiency of a standard care model of unscheduled telephone consults compared to scheduled videoconference consults for obtaining pre-treatment medication histories for patients with cancer. Methods: Data related to (a) the available and the claimed activity-based funding for both models and (b) the number of contacts and the duration of each contact to complete the patient's medication history via either unscheduled telephone or scheduled videoconference consults were collected and compared. Results: Data was collected for 86 telephone and 56 videoconference consults. The actual activity-based funding claimed for telephone consults was $0, even though $86 of activity-based funding was available for each consult. This represented a $0 reimbursement for the staff time spent conducting the telephone consults, and a missed opportunity to claim $86 per consult. Activity-based funding was claimed for all but one videoconference consult with an average of $205 received per consult, when $221 per consult was available. Videoconference consults were an average of 2.3 min shorter than telephone consults. Discussion: When compared to unscheduled telephone consults, the scheduled videoconference consults represented increased reimbursement and equivalent time efficiency for the cancer pharmacist completing pre-treatment medication histories.

A phase I/II study of stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumours (RAPPORT): Clinical trial protocol.

BACKGROUND: The management of oligometastatic clear cell renal cell carcinoma (ccRCC) varies widely, ranging from observation to resection or systemic therapies. Prolonged survival has been observed following resection or stereotactic ablative body radiotherapy (SABR). Immunotherapy combinations have shown survival benefits, however, toxicity is higher than that for monotherapy and complete response rates remain less than 10%. The combination of effective local therapies in conjunction with immunotherapy may provide more durable control and pre-clinical models have suggested a synergistic immune-priming effect of SABR. OBJECTIVES: and Methods: RAPPORT is a prospective, single arm, phase I/II study assessing the safety, efficacy and biological effects of single fraction SABR followed by pembrolizumab for oligometastatic ccRCC. The study will include 30 patients with histological confirmed ccRCC and 1-5 oligometastases, one or more of which must be suitable for SABR. Patients can have received prior systemic therapy but not prior immunotherapy. A single 20Gy of SABR is followed 5 days later by 8 cycles of 200 mg pembrolizumab, every 3 weeks. Adverse events are recorded using CTCAE V4.03 and tumour response evaluated by Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Tumour tissue and peripheral blood samples will be collected pre-, during and post-treatment to assess longitudinal changes in immune subsets. OUTCOMES AND SIGNIFICANCE: The RAPPORT study will provide important safety and early efficacy data on the combination of SABR and pembrolizumab in oligometastatic ccRCC and will provide an insight into the underlying biological effects of combination therapy. TRIAL REGISTRATION: clinicaltrials.gov ID NCT02855203.

Implementing a nurse-enabled, integrated, shared-care model involving specialists and general practitioners in breast cancer post-treatment follow-up: a study protocol for a phase II randomised controlled trial (the EMINENT trial).

BACKGROUND: Due to advances in early detection and cancer treatment, 5-year relative survival rates for early breast cancer surpass 90% in developed nations. There is increasing focus on promotion of wellness in survivorship and active approaches to reducing morbidity related to treatment; however, current models of follow-up care are heavily reliant on hospital-based specialist-led care. This study aims to test the feasibility of the EMINENT intervention for implementing an integrated, shared-care model involving both cancer centre specialists and community-based general practitioners for early breast cancer post-treatment follow-up. METHODS: We describe a protocol for a phase II, randomised controlled trial with two parallel arms and 1:1 allocation. A total of 60 patients with early-stage breast cancer will be randomised to usual, specialist-led, follow-up care (as determined by the treating surgeons, medical oncologists, and radiation oncologists) or shared follow-up care intervention (i.e. EMINENT). EMINENT is a nurse-enabled, pre-specified shared-care pathway with follow-up responsibilities divided between cancer centre specialists (i.e. surgeons and oncologists) and general practitioners. The primary outcome is health-related quality of life as measured by the Functional Assessment of Cancer Therapy-Breast Cancer. Secondary outcomes include patient experience, acceptance, and satisfaction of care; dietary, physical activity, and sedentary behaviours; financial toxicity; adherence; health resource utilisation; and adverse events. DISCUSSION: The trial is designed to identify the barriers to implementing a shared-care model for breast cancer survivors following treatment. Results of this study will inform a definitive trial testing the effects of shared-care model on health-related quality of life of breast cancer survivors, as well as its ability to alleviate the growing demands on the healthcare system. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12619001594112 . Registered on 19 November 2019.

Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma.

BACKGROUND: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC. METHODS: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65-74 (n = 201) and ≥75 years (n = 63). RESULTS: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and 0.38 (95% CI: 0.18-0.79) for <65, 65-74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54-0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups. CONCLUSIONS: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.

SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines. Subsequent in silico connectivity screening demonstrated that the clinically approved antihistamine drug, chloropyramine, increased SASH1 mRNA levels. Chloropyramine has previously been shown to have anti-tumour activity in breast cancer in part through modulation of FAK signalling, a pathway also regulated by SASH1. This study demonstrated that chloropyramine increased SASH1 protein levels in breast cancer cells. Consistent with this the agent reduced cell confluency in 7/8 cell lines treated irrespective of their ER status but not apoptosis incompetent MCF7 cells. In contrast SASH1 siRNA-transfected breast cancer cells exhibited reduced chloropyramine sensitivity. The prognostic significance of SASH1 expression was also investigated in two breast cancer cohorts. Expression was associated with favourable outcome in ER-positive cases, but only those of low histological grade/proliferative status. Conversely, we found a very strong inverse association in HER2+ disease irrespective of ER status, and in triple-negative, basal-like cases. Overall, the data suggest that SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. Pharmacologic induction of SASH1 by chloropyramine treatment of breast cancer warrants further preclinical and clinical investigation.

Synchronous breast cancer and lymphoma: a case series and a review of the literature.

Four patients with synchronous breast cancer and lymphoma are described. In all cases, the lymphoma was an unexpected finding in the histopathology of the axillary lymph-node dissection. The diagnosis of synchronous malignancies poses challenges for both the diagnosing pathologist and the treating clinician.