Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.

BACKGROUND: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification. METHODS: This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing. FINDINGS: Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths. INTERPRETATION: These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies. FUNDING: Zymeworks.

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Management of toxicities associated with high-dose interleukin-2 and biochemotherapy.

High-dose interleukin-2, administered as a single agent or in combination with antineoplastic agents, known as biochemotherapy, holds the promise of durable remissions for patients with metastatic renal cell carcinoma and metastatic melanoma. The toxicities arising from high-dose interleukin-2-based therapies affect every organ system, causing significant acute morbidity. Administration of high-dose interleukin-2-based therapies requires specialized care and knowledge because of the severity and uniqueness of toxicities compared with the toxicities encountered with other forms of anticancer therapy. However, the toxicities of high-dose interleukin-2-based therapies are predictable and manageable by vigilant monitoring and appropriate supportive care protocols. To maximize outcomes, both acute and delayed toxicities require vigilant monitoring and adroit symptom management. This review details the pathophysiology, monitoring parameters, and management strategies for patients receiving high-dose interleukin-2-based therapy, with a focus on new and important management principles.

Syndrome of inappropriate antidiuretic hormone secretion caused by high-dose bolus interleukin-2 therapy for metastatic melanoma.

Melanoma is a relatively common cancer and is often associated with a dire prognosis once diagnosed as metastatic. Immunomodulatory therapy with high-dose bolus interleukin-2 may provide durable responses, albeit in a small subset of those afflicted with metastatic melanoma. High-dose interleukin-2 is well-known to cause substantial toxicities, both acute and delayed. We report on a single case of syndrome of inappropriate antidiuretic hormone secretion in a patient with metastatic melanoma with metastases to the lung and liver which was associated with high-dose bolus interleukin-2 therapy.

Optimising absorption of posaconazole.

Posaconazole, a triazole antifungal agent with proven efficacy for prophylaxis and treatment of fungal infections, is often limited by poor absorption. We report on five consecutive patients who received posaconazole along with a care bundle intended to increase absorption by addressing gastric pH, co-administration with food, dividing doses and avoiding drug interactions. Each patient yielded multiple robust posaconazole serum concentrations. No patient experienced breakthrough fungal infection while receiving posaconazole. The posaconazole care bundle administered to oncology patients is feasible and may optimise posaconazole absorption.

Burden of illness and treatment patterns among patients with peripheral T-cell lymphoma in the US healthcare setting.

OBJECTIVE: Limited real-world information exists on the characteristics or treatment patterns of patients with peripheral T-cell lymphoma (PTCL). We reported demographics, treatments and direct healthcare resource utilization (HRU) in a large cohort of US patients newly diagnosed with PTCL. METHODS: Patients aged ≥18 years with a PTCL diagnosis between January 2011 and December 2016 were identified from the Inovalon MORE2 Registry. Continuous medical/pharmacy enrollment 6-months prior to and ≥1-month after the first PTCL diagnosis was required. The main focus of this study was on newly diagnosed patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus other chemotherapy. RESULTS: A total 2971 patients with PTCL and chemotherapy information were included in the study; 1706 (57%) received CHOP and 1265 (43%) other chemotherapy. A majority of patients (51.7%) were female; mean (standard deviation) age at index was 61.0 (±16.0), Charlson score was 4.1 (±2.9), and follow-up time was 24.6 (±16.7) months. During the variable follow-up period, HRU was similar for the CHOP and other chemotherapy cohorts; 58.1% and 59.3% had ≥1 all-cause hospitalizations, respectively. The proportion of patients with ≥1 PTCL-related hospitalizations was higher in the CHOP than in the other chemotherapy cohort (40.3% vs. 9.7%, respectively) and mean length of stay was longer (4.6 vs. 3.7 days per patient per month, respectively). CONCLUSIONS: This retrospective analysis of patients with PTCL revealed high levels of comorbidity and HRU; novel interventions that improve patient outcomes and reduce the HRU burden of PTCL are needed.

Update on Aurora Kinase Targeted Therapeutics in Oncology.

INTRODUCTION: Mammalian cells contain three distinct serine/threonine protein kinases with highly conserved catalytic domains, including aurora A and B kinases that are essential regulators of mitotic entry and progression. Overexpression of aurora A and/or B kinase is associated with high proliferation rates and poor prognosis, making them ideal targets for anti-cancer therapy. Disruption of mitotic machinery is a proven anti-cancer strategy employed by multiple chemotherapeutic agents. Numerous small molecule inhibitors of the aurora kinases have been discovered and tested in vivo and in vitro, with a few currently in phase II testing. AREAS COVERED: This review provides the reader with updated results from both preclinical and human studies for each of the aurora kinase inhibitors (AKI) that are currently being investigated. The paper also covers in detail the late breaking and phase I data presented for AKIs thereby allowing the reader to compare and contrast individual and classrelated effects of AKIs. EXPERT OPINION: While the successful development and approval of an AKI for anti-cancer therapy remains unresolved, pre-clinical identification of resistant mechanisms would help design better early phase clinical trials where relevant combinations may be evaluated prior to phase II testing. The authors believe that aurora kinases are important anti-cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted and complimentary anti-cancer mechanism, expand the available armamentarium against cancer.