Antibody drug conjugates for glioblastoma: current progress towards clinical use.

INTRODUCTION: Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors. AREAS COVERED: This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors. EXPERT OPINION: ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.

Treatment patterns and outcomes in older adults with castration-resistant prostate cancer: Analysis of an Australian real-world cohort.

INTRODUCTION: Prostate cancer (PC) is the second commonest malignancy and fifth leading cause of cancer death in men worldwide. Older men are more likely to develop PC but are underrepresented in pivotal clinical trials, leading to challenges in treatment selection in the real-world setting. We aimed to examine treatment patterns and outcomes in older Australians with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We identified 753 men with mCRPC within the electronic CRPC Australian Database (ePAD). Clinical data were analysed retrospectively to assess outcomes including time to treatment failure (TTF), overall survival (OS), PSA doubling time (PSADT), PSA50 response rate, and pre-defined adverse events of special interest (AESIs). Descriptive statistics were used to report baseline characteristics, stratified by age groups (<75y, 75-85y and >85y). Groups were compared using Kruskal-Wallis and Chi-square analyses. Time-to-event analyses were performed using Kaplan-Meier methods and compared through log-rank tests. Cox proportional hazards univariate and multivariate analyses were performed to evaluate the influence of variables on OS. RESULTS: Fifty-seven percent of men were aged <75y, 31% 75-85y, and 12% >85y. Patients ≥75y more frequently received only one line of systemic therapy (40% of <75y vs 66% 75-85y vs 68% >85y; P < 0.01). With increasing age, patients were more likely to receive androgen receptor signalling inhibitors (ARSIs) as initial therapy (42% of <75y vs 70% of 75-85y vs 84% of >85y; p < 0.01). PSA50 response rates or TTF did not significantly differ between age groups for chemotherapy or ARSIs. Patients >85y receiving enzalutamide had poorer OS but this was not an independent prognostic variable on multivariate analysis (hazard ratio [HR] 0.93(0.09-9.35); p = 0.95). PSADT >3 months was an independent positive prognostic factor for patients receiving any systemic therapy. Older patients who received docetaxel were more likely to experience AESIs (18% in <75y vs 37% 75-85y vs 33% >85y, p = 0.038) and to stop treatment as a result (21% in <75y vs 39% in 75-85y; p = 0.011). DISCUSSION: In our mCRPC cohort, older men received fewer lines of systemic therapy and were more likely to cease docetaxel due to adverse events. However, treatment outcomes were similar in most subgroups, highlighting the importance of individualised assessment regardless of age.

Taxane-induced neuropathy: How serious is this problem for patients with early breast cancer?

BACKGROUND: Taxanes form the mainstay of breast cancer therapy in the curative setting. Taxane-induced peripheral neuropathy (TIPN) is a common toxicity and confers significant morbidity with no validated therapies. Literature detailing TIPN is inconsistent in reporting its frequency, severity, risk factors, impact upon treatment course, and management practices. METHODS: A retrospective chart review was performed including 348 early-stage breast cancer patients undergoing weekly paclitaxel therapy between 2010 and 2020 in the adjuvant or neoadjuvant setting. The frequency, severity, and impact on treatment from TIPN were analyzed during treatment and at one year follow-up. Clinicopathological and patient factors were collected to identify potential risk factors. RESULTS: 279 out of 348 patients (80.2%) developed TIPN of any grade. One-year follow-up was available for 232 of the original 279 TIPN patients (83.2%). Of these, 52 patients (22.4%) exhibited persisting TIPN of any grade. The presence and severity of TIPN during treatment was significantly associated with a lower median dose intensity (100% versus 82.5% for non-TIPN and all-grade TIPN respectively, p < 0.001). Neoadjuvant treatment (p = 0.038) and body surface area (BSA, p = 0.035) were independently associated with TIPN during treatment. Increased age (p < .001) and pre-treatment diabetes (p = 0.009) were associated with TIPN at one-year follow-up. CONCLUSION: TIPN is common in breast cancer patients undergoing weekly paclitaxel therapy. TIPN results in patients receiving significantly lower dose intensity due to dose reductions and premature treatment cessation. Future prospective studies in similar cohorts are warranted, with a focus on long-term outcomes.

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.