Targeted Oncology最新文献

Background: The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix is the only oral androgen deprivation therapy (ADT) indicated for advanced prostate cancer (aPC). Combining ADT with androgen receptor signaling inhibitors (ARSIs) has shown improved clinical outcomes.

Objective: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of relugolix in combination with ARSIs in patients with aPC.

Methods: In this 52-week, open-label study, patients received relugolix (120 mg once daily) with abiraterone (1,000 mg once daily) and corticosteroid (Part 1) or relugolix (240 mg once daily) with apalutamide (240 mg once daily) (Part 2). Metastatic castration-sensitive patients were eligible for both parts, whereas castration-resistant patients were eligible for Part 1 if metastatic and Part 2 if non-metastatic. Adverse events and other safety data were evaluated over 52 weeks, while pharmacodynamic and pharmacokinetic (Part 2 only) data were assessed over 12 weeks. Medication adherence to relugolix was measured by pill count.

Results: Of 48 patients, 21 completed Part 1 and 20 completed Part 2. Most adverse events were grade 1 or 2, with hypertension (Part 1) and rash (Part 2) being most common. Mean testosterone concentrations remained below castrate level. Median prostate-specific antigen concentration was 0.04 ng/mL at week 12 in both parts. Concentrations of relugolix, apalutamide, and N-desmethyl-apalutamide were stable over 12 weeks similar to previous data. Relugolix adherence rates were > 97% in both parts.

Conclusions: The safety/tolerability profile of both combination therapies was consistent with those of the individual drugs. These findings support using relugolix in combination with abiraterone or apalutamide as treatment of aPC.

Clinical trial registration: ClinicalTrials.gov identifier NCT04666129.

Background: Chemotherapy plus epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, is standard therapy for KRAS wild-type (KRASwt) colorectal cancer (CRC); however, responses are infrequent. Magrolimab is a monoclonal antibody targeting CD47, an antiphagocytic signal overexpressed in solid tumors (STs).

Objective: This open-label, multicenter phase 1b/2 study (NCT02953782) aimed to determine the recommended phase 2 dose (RP2D) and evaluate the safety, tolerability, and efficacy of magrolimab + cetuximab in patients with advanced CRC or other STs.

Patients and methods: A total of 78 patients were enrolled at eight study sites in the USA. In phase 1b, patients with advanced STs received weekly maintenance doses of magrolimab at 10-45 mg/kg and cetuximab at 200-250 mg/m² following 3 + 3 dose-escalation. In phase 2, patients with anti-EGFR-refractory CRC received magrolimab + cetuximab at RP2Ds. Primary endpoints were dose-limiting toxicities, adverse events, and objective response rate (ORR; phase 2).

Results: The maximum tolerated dose was not reached in phase 1b. Two RP2Ds were explored in phase 2: magrolimab at 30 or 45 mg/kg plus cetuximab at 250 mg/m². Most common treatment-related adverse events (TRAEs) were dermatitis acneiform (35.9%), infusion-related reactions (33.3%), dry skin (32.1%), fatigue (32.1%), and headache (29.5%). Most common grade ≥ 3 TRAEs were anemia (11.5%), increased blood bilirubin (9.0%), and decreased lymphocyte count (9.0%). Discontinuation of any study treatment owing to TRAEs occurred in 3.8% of patients. No deaths occurred due to TRAEs. In phase 2, ORR was 6.3% and 0% in the KRASwt and KRASmt CRC cohorts, respectively; disease control rate was 50.0% and 38.1%, and median overall survival was 9.5 and 7.6 months, respectively.

Conclusions: These results indicate tolerability and potential antitumor activity when combining anti-CD47 therapy and cetuximab in heavily pretreated patients with CRC.

Inotuzumab ozogamicin (InO) was approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) on the basis of the phase 3 INO-VATE trial, which found that treatment-related mortality (TRM), primarily due to hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), was higher among patients who received InO versus standard therapy and proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Here, we use real-world data obtained from the Center for International Blood and Marrow Transplant Research database to evaluate post-HSCT outcomes in adult patients with ALL who received InO from 18 August2017 to 18 August 2022. Post-HSCT follow-up data were available for 244 patients with ALL (including 156 with R/R ALL) who received InO. VOD incidence within 100 days of HSCT was 14% among all patients and 18% among patients with R/R ALL. These data are consistent with a pooled analysis of the phase 1/2 study 1010 and the phase 3 INO-VATE trial that reported VOD in 19% of patients who received InO and proceeded to HSCT (n = 101). The current study demonstrates VOD incidence among patients receiving InO prior to HSCT in the real world is similar to that reported in clinical trials. Supplementary file1 (MP4 165809 KB).

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

Targeted therapies have revolutionized treatment of non-small-cell lung cancer (NSCLC); however, epidermal growth factor receptor (EGFR) exon20ins mutations are resistant to tyrosine kinase inhibitors. Amivantamab utilizes multiple mechanisms of action to bypass the altered binding site conformation and recruits immune cells for anti-cancer activity. Amivantamab is approved in the frontline setting of EGFR exon20ins-mutated NSCLC in combination with carboplatin plus pemetrexed. Single-agent amivantamab is approved in second line or later for EGFR exon20ins. Furthermore, amivantamab with lazertinib for first line as well as amivantamab in combination with carboplatin and pemetrexed for second line after osimertinib have both been approved in the treatment of NSCLC harboring EGFR-sensitizing mutations. Now with multiple indications, we must learn how to manage the unique side effects of amivantamab to maximize treatment benefit for the patients. Side effects of amivantamab can be associated with inhibition of the EGFR and/or mesenchymal epithelial transcription factor (MET) signaling pathways. This work reviews the mechanism of action, pharmacology, clinical trial data, and covers management of toxicities. This guide is designed as a practical reference tool for clinicians, pharmacists, and basic science researchers.

Standard treatment options for B cell malignancies include immunochemotherapies and/or targeted therapies, which often provide temporary disease remission. However, many patients do not achieve complete remission with these treatments, develop resistance, and eventually experience disease relapse. New immunomodulatory treatments, such as T cell-based therapies, show promise in treating various types of blood cancers, including B cell malignancies. However, their effectiveness is often limited by the immunosuppressive tumor microenvironment and altered function of patient-derived T cells. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been shown to restore immune balance and function in patients with chronic lymphocytic leukemia. Ibrutinib is being studied as adjuvant or combinatorial therapy with chimeric antigen receptor (CAR) T cells or T cell-engaging bispecific antibodies for the treatment of B cell malignancies. Current evidence suggests that ibrutinib could be beneficial when used before, during, or after CAR T cell administration, potentially providing higher complete response rates and reduced toxicity. In conclusion, existing evidence strongly supports the combined use of ibrutinib and T cell therapies. However, additional clinical trials are needed to further validate the effectiveness of this treatment strategy in patients with various B cell malignancies.

The ataxia-telangiectasia mutated (ATM) protein kinase plays a critical role in activating the cellular response to DNA double-strand breaks and promoting homology-directed repair. ATM is frequently mutated in cancer, contributing to an accumulation of DNA damage that drives genomic instability. To exploit cancer cells' inherent vulnerability to DNA damage, various small molecule inhibitors have been developed that target ATM. ATM inhibitors have shown great versatility in preclinical studies and increasing use in the clinic. Here, we review the development of ATM inhibitors and their role in cancer therapy. We describe their limitations and the advances that have led to increases in both the number and diversity of active clinical trials targeting ATM. We also discuss ATM's role in personalized medicine and the current challenges to more widespread use of ATM inhibitors in the clinic.

Background: Immune-checkpoint inhibitors (ICIs) enhance the immune response against cancer but can cause immune-related adverse events, with immune-mediated colitis (IMC) being among the most common.

Objective: We investigated variations in gastrointestinal disease behavior and outcomes among patients receiving different ICI regimens.

Methods: This retrospective chart review included patients who received ICIs and developed IMC. Groups were categorized by their last ICI regimen before IMC onset into either programmed cell death protein-1/ligand-1 monotherapy or cytotoxic T-lymphocyte antigen 4 (CTLA-4) monotherapy/combination immunotherapy. Demographic and IMC-related clinical information was collected.

Results: There were 414 patients included in this study: 169 treated with programmed cell death protein-1/ligand-1 monotherapy and 245 treated with CTLA-4 mono/combination therapy. Patients treated with CTLA-4 therapy had an earlier onset of IMC (median 46 days vs 123 days, p < 0.001). They were more likely to present with fever (p = 0.02), abdominal pain (p = 0.049), or hematochezia (p < 0.001). They also had more severe colitis with 47.3% of patients in the CTLA-4 group presenting with grade ≥3 colitis versus 20.2% in the programmed cell death protein-1/ligand-1 group (p < 0.05). On endoscopy, CTLA-4 mono/combination therapy was associated with increased ulcerative findings (24.4 vs 8.4%, p = 0.002). On histology, the programmed cell death protein-1/ligand-1 group was more likely to have microscopic colitis (13.9 vs 5.8%, p < 0.045).

Conclusions: This study provides insight into the effect of ICI type on IMC disease course. Cytotoxic T-lymphocyte antigen 4 inhibition leads to an earlier and more severe IMC onset with distinct endoscopic and histologic features. Further research is needed to refine treatment algorithms and identify the mechanisms underlying the variability in IMC presentation among different ICI regimens.

Background: Elranatamab is a BCMA-CD3 bispecific antibody approved for the treatment of relapsed or refractory multiple myeloma. Cytokine release syndrome is one of the most common adverse events associated with bispecific antibodies.

Objective: We aimed to determine the optimal elranatamab dosing regimen for mitigating cytokine release syndrome.

Patients and methods: Safety, pharmacokinetics, and exposure-response were analyzed across four clinical studies (MagnetisMM-1, MagnetisMM-2, MagnetisMM-3, and MagnetisMM-9). Different priming regimens evaluated across these studies included a one-step-up dose priming regimen of 44 mg with or without premedication, a two-step-up dose priming regimen of 12 mg on day 1 and 32 mg on day 4 with premedication, and a two-step-up dose priming regimen of 4 mg on day 1 and 20 mg on day 4 with premedication.

Results: The maximum elranatamab serum concentration on day 1 was positively associated with any-grade and grade ≥ 2 cytokine release syndrome. A slower time to maximum serum concentration and a lower dose-normalized maximum serum concentration were observed with subcutaneous versus intravenous administration, supporting subcutaneous dosing to help mitigate cytokine release syndrome.

Conclusions: Based on the incidence, severity, and predictable profile of cytokine release syndrome, the 12/32-mg priming-dose regimen with premedication was determined to be the optimal regimen before the first full dose of 76 mg on day 8.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT03269136, NCT04798586, NCT04649359, and NCT05014412.