Search

BackgroundThere 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.MethodsNUTMEG 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.ResultsA 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.ConclusionsDue 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.

Key Clinical Message: We describe the first case in literature of malignant mesothelioma of the tunica vaginalis that has shown partial response to systemic immunotherapy (ipilimumab‐nivolumab) post orchiectomy, warranting further investigation in a trial setting. We present a case report of an 80‐year‐old ex‐smoker with a rare diagnosis of metastatic mesothelioma of the tunica vaginalis, managed with immunotherapy. The patient, with no known history of asbestos exposure, presented with a left scrotal mass and pain. Scrotal ultrasound confirmed a large paratesticular mass, and computed tomography (CT) of the chest, abdomen, and pelvis revealed a bilobed mass in the left scrotal compartment without associated inguinal or abdominopelvic lymphadenopathy, and an indeterminate, subcentimeter, bi‐basal subpleural nodules. He underwent a left orchiectomy, and histopathology confirmed the diagnosis of a paratesticular mesothelioma. Postoperatively, the patient had a positron emission tomography (PET) scan showing a new right pleural effusion as well as increasing size of the lobar and pleural nodules bilaterally, all metabolically active and suggestive of progressive metastatic disease. The patient was commenced on ipilimumab and nivolumab immunotherapy, a regimen indicated for malignant pleural mesothelioma; however, the efficacy on paratesticular mesothelioma is not known. After 6 months of treatment, the patient demonstrated a partial response to immunotherapy, with a reduction in the size of known pleural nodules and effusion. Literature review suggests that diagnosis requires a high index of suspicion and patients commonly have metastatic disease at the time of diagnosis. Orchiectomy is a common management modality. However, the role, regimen, and benefits of systemic therapy are unclear, warranting further studies investigating management strategies. [ABSTRACT FROM AUTHOR]

Aim Autologous hematopoietic stem cell transplantation (auto-HSCT) remains an experimental therapy for metastatic breast cancer (MBC) and there is no established protocol for cluster of differentiation 34+ (CD34+) hematopoietic progenitor cell (HPC) mobilization with historic studies using growth factors with or without chemotherapy. This study describes the feasibility and kinetics of CD34+ HPC mobilization following a single administration of docetaxel and the pegylated form of recombinant human granulocyte colony-stimulating factor analogue filgrastim (pegfilgrastim). Methods The study design was serial measurement of peripheral blood CD34+ HPC in patients with MBC following a single administration of intravenous (IV) docetaxel 100 mg/m2 on day 1 and subcutaneous (SC) pegfilgrastim 6 mg on day 2. Results Eight patients with MBC were enrolled. The median age was 56 years (range 51-75 years). All patients had human epidermal growth factor receptor 2 (HER2) negative disease and either hormone refractory or negative disease. Three patients had bone only disease, four had visceral organ disease with or without bone involvement and one had locally unresectable disease only. All patients had prior therapy for early-advanced stage disease and prior therapy for MBC included seven patients receiving at least one line of hormone therapy and three having palliative chemotherapy. Six patients recorded a rise in the CD34+ count greater than 20 cells/μL. The median peak level was 40.2 cells/μL (standard deviation = 28.7) occurring on day 9 and with an average duration of 4 days. Overall, treatment was well tolerated with manageable side-effects. Conclusion The single administration of docetaxel and pegfilgrastim was effective in mobilization of CD34+ HPC and peak levels followed a predictable course. This approach needs validation in prospective studies by preparation of auto-HSCT by leukapheresis and quantification of total CD34+ HPC yields. [ABSTRACT FROM AUTHOR]

Background: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors., Methods: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1., Results: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer., Conclusions: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted., Trial Registration Number: NCT04047290., Competing Interests: Competing interests: WW, ZMW, BL, and YX are all employees of Akeso Biopharma, Zhongshan, China. JIGC provided consultancy work for Akeso since 2022. The other authors declare no potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Autologous hematopoietic stem cell transplantation (auto-HSCT) remains an experimental therapy for metastatic breast cancer (MBC) and there is no established protocol for cluster of differentiation 34 + (CD34 + ) hematopoietic progenitor cell (HPC) mobilization with historic studies using growth factors with or without chemotherapy. This study describes the feasibility and kinetics of CD34 + HPC mobilization following a single administration of docetaxel and the pegylated form of recombinant human granulocyte colony-stimulating factor analogue filgrastim (pegfilgrastim)., Methods: The study design was serial measurement of peripheral blood CD34 + HPC in patients with MBC following a single administration of intravenous (IV) docetaxel 100 mg/m 2 on day 1 and subcutaneous (SC) pegfilgrastim 6 mg on day 2., Results: Eight patients with MBC were enrolled. The median age was 56 years (range 51-75 years). All patients had human epidermal growth factor receptor 2 (HER2) negative disease and either hormone refractory or negative disease. Three patients had bone only disease, four had visceral organ disease with or without bone involvement and one had locally unresectable disease only. All patients had prior therapy for early-advanced stage disease and prior therapy for MBC included seven patients receiving at least one line of hormone therapy and three having palliative chemotherapy. Six patients recorded a rise in the CD34 + count greater than 20 cells/μL. The median peak level was 40.2 cells/μL (standard deviation = 28.7) occurring on day 9 and with an average duration of 4 days. Overall, treatment was well tolerated with manageable side-effects., Conclusion: The single administration of docetaxel and pegfilgrastim was effective in mobilization of CD34 + HPC and peak levels followed a predictable course. This approach needs validation in prospective studies by preparation of auto-HSCT by leukapheresis and quantification of total CD34 + HPC yields., (© 2016 John Wiley & Sons Australia, Ltd.)