Targeted Oncology最新文献

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.

Background: Stem cell transplantation (SCT) and immune checkpoint inhibitors (ICIs) are both used in the treatment of hematological malignancies. There may be an overlap in patient exposure to both treatments. Theoretically, ICIs potentiate the graft-versus-tumor effect following SCT but may increase the risk of inflammatory adverse events (AEs). Conversely, immunosuppression following SCT may decrease the risk of immune-mediated AEs.

Objectives: We aimed to explore the effect of immunotherapy on the risk and severity of inflammatory AEs following SCT.

Patients and methods: We performed a single-center, retrospective chart review that included all patients with a hematological malignancy treated with immunotherapy and who received SCT. Patients who did not receive immunosuppressive regimens after their transplant (e.g., autologous transplants) were excluded. Patients were divided into two groups based on ICI timing: pre-SCT ICI (group 1) and post-SCT ICI (group 2).

Results: A total of 63 patients were included. Around 82% of patients in group 1 experienced a post-transplant AE compared with 50% in group 2 (p = 0.014). These AEs occurred earlier in group 1 patients (median 57 days in group 1 versus 195 in group 2; p = 0.007). Roughly 80% of the inflammatory conditions involved the gastrointestinal system. Severity and complication rates did not differ between groups, but gastrointestinal inflammation in group 1 was more likely to require immunosuppressive medication (75.7% and 37.8% requiring corticosteroids and selective immunosuppressive therapy, respectively, in group 1 patients versus 33.3% and 0% in group 2 patients; p < 0.05).

Conclusion: To our knowledge, our study is one of few exploring the impact of ICI timing in relation to SCT on the risk of post-SCT inflammatory AEs. Administration of immunotherapy prior to SCT may predispose patients to inflammatory AEs after SCT, which may occur earlier and last longer than if ICIs are started after SCT. Future studies are needed to further explore this phenomenon.

Multiple myeloma (MM) is a bone-marrow-based cancer of plasma cells. Over the last 2 decades, marked treatment advances have led to improvements in the overall survival (OS) of patients with this disease. Key developments include the use of chemotherapy, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. MM remains incurable, with outcomes influenced by many factors, including age, sex, genetics, and treatment response. This review summarizes recent studies regarding monitoring and treatment of MM, emphasizing the efficacy of new therapies, the impact of maintenance treatments, and approaches for managing relapsed or refractory MM. The role of specific drug classes used to treat MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and newer treatments such as chimeric antigen receptor T-cell therapies and bispecific antibodies are discussed. Combination therapies have significantly improved outcomes. Maintenance therapies, particularly with lenalidomide, have been effective in extending OS but lead to an increased risk of secondary cancers. Venetoclax, selinexor, and ruxolitinib have shown potential as new therapeutic options for patients with relapsed or refractory MM. Immune-based treatments, such as chimeric antigen receptor T-cell therapy and bispecific antibodies, mark a major advancement for heavily pretreated patients, although challenges remain related to cost, availability, and side effects. The treatment landscape for patients with MM has seen significant progress, with current therapies providing a longer OS and better quality of life. Future research should focus on optimizing these strategies, personalizing therapies, and exploring new therapeutic targets.

Background: The reported benefit of poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance in patients with newly diagnosed and platinum (Pt)-sensitive recurrent ovarian cancer (OC) included in randomized clinical trials needs to be corroborated in a less selected population.

Objective: The aim is to increase the evidence on niraparib in a real-world setting.

Methods: This is a retrospective observational study including women with platinum-sensitive relapsed high-grade serous OC who started niraparib maintenance between August 2019 (marketing data, Spain) and May 2022. Patients received ≥ 2 previous lines of therapy with complete or partial response to prior chemotherapy. Patient characteristics, niraparib dose, adequacy of dose individualization, effectiveness (progression-free survival [PFS] and overall survival), safety, and economic savings with an individualized starting dose (ISD) strategy were assessed.

Results: The study included 217 patients with a median of 8.9 months of niraparib duration: breast cancer gene (BRCA) wild-type OC, 70%; two prior treatment lines, 49%; Research on Adverse Drug Events and Reports (RADAR) criteria, 82% (receiving mainly 200 mg of niraparib, 79%). Median PFS was 10.8 months (95% confidence interval [CI], 8.4-14.8) without statistically significant differences based on starting dose strategy, contrary to what was observed on the basis of prior lines, response to prior chemotherapy, BRCA mutational status, and International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis. The last three variables also showed a statistically significant predictive prognostic value for effectiveness. Dose interruptions due to toxicity were required in 7% of patients, and dose adjustments in 56% were mainly due to hematologic toxicities. The actual dose of niraparib reveals economic savings versus the theoretical cost.

Conclusion: This large real-world analysis corroborates the tolerability and activity of niraparib maintenance for platinum-sensitive recurrent OC and economic savings.

Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) approved for use in patients with newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase (CP) chronic myeloid leukemia (CML), as well as Ph-positive CP, accelerated phase, or blast phase (with chemotherapy) CML resistant or intolerant to prior therapy. Clinical trials have shown bosutinib is effective as first-line therapy for patients with CML as well as in later lines of therapy after prior TKI failure. Bosutinib has an established safety profile; however, as with all TKIs approved for the treatment of CML, there are adverse events (AEs) that require management. The safety profile of bosutinib is characterized by gastrointestinal, hematological, hepatic, and skin toxicities. Many of these AEs can be managed with dose adjustment strategies. In this podcast, the authors summarize data from some recent bosutinib publications and discuss implications for optimizing bosutinib treatment of patients with CML. Podcast Video (MP4 210846 KB).

Background: BERIL-1 was a randomized phase 2 study that studied paclitaxel with either buparlisib, a pan-class I PIK3 inhibitor, or placebo in patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Considering the therapeutic paradigm shift with immune checkpoint inhibitors (ICIs) now approved in the first-line setting, we present an updated immunogenomic analysis of patients enrolled in BERIL-1, including patients with immune-infiltrated tumors.

Objective: The objective of this study was to identify biomarkers predictive of treatment efficacy in the context of the post-ICI therapeutic landscape.

Patients and methods: Genomic analyses were performed at baseline on tumor and/or plasma circulating DNA (ctDNA) samples, and immunohistochemistry (IHC) studies, including immune infiltration [tumor-infiltrating lymphocytes (TILs) and CD8 expression], were performed on tumor samples. Immunogenomic biomarkers were correlated to overall survival (OS).

Results: Among 158 patients enrolled in BERIL-1, either tumor (53.2%; n = 84) or ctDNA samples (70.8%; n = 112) were available in 85.4% (n = 135). The most commonly mutated genes were TP53 (57.0%), NOTCH1 (23.7%), and PIK3CA (22.2%). In the IHC studies, 98.6% (n = 68/69) of patients were TILs positive in the buparlisib arm versus 94.4% (n = 68/72) in the placebo arm. In patients with TILs-positive tumors, enrichment for clinical benefit on the buparlisib arm was seen in those with PIK3 pathway activation [25.0% (n = 17/68)] with a hazard ratio (HR) for death of 0.43 [95% confidence interval (CI) 0.21-0.87, p = 0.016]. Similarly, improved OS was seen in patients on the buparlisib arm and NOTCH pathway activation [20.5% (n = 14/68)] with a HR for death of 0.40 (95% CI 0.18-0.90, p = 0.022). Both associations were absent in the placebo group. TP53 and tumor mutational burden (TMB) did not correlate with OS in the buparlisib or placebo arms.

Conclusions: In this immunogenomic analysis of BERIL-1, improved HRs for OS were seen in patients with tumor immune infiltration and selected oncogenic alterations, including PIK3 and NOTCH pathway activation (NCT01852292).

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.

Background: Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off is uncertain. It is also uncertain whether there is a sharp TMB threshold or a more graduated change in clinical outcomes as TMB increases.

Objective: We aimed to determine the relationship between TMB and ICI treatment outcomes using alternative statistical approaches in patients with non-small cell lung cancer.

Methods: Tumour mutational burden was evaluated as a prognostic and predictive biomarker in advanced non-small cell lung cancer utilising data from two real-world cohorts of ICI use (n = 968) and three randomised controlled trials evaluating ICIs (n = 1588). The non-linear relationship between continuous TMB and response/survival/efficacy outcomes was evaluated using statistical methods that do not require specifying a TMB cut-off.

Results: Median TMB for all cohorts was seven mutations/megabase, excluding MYSTIC, where the median was 13 mutations/megabase. Progressively higher TMB was significantly associated with a progressively higher objective response rate and progression-free survival in ICI-treated patients in Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] (objective response rate: p < 0.001, progression-free survival: p < 0.001), Strata Clinical Molecular Database [SCMD] (progression-free survival: p = 0.023) and OAK/POPLAR (objective response rate: p = 0.017, progression-free survival: p < 0.001) This relationship was not apparent for patients treated with chemotherapy. There was no obvious TMB threshold for ICI response. The relationship between TMB and overall survival was more complex and heterogeneous.

Conclusions: Using a single cut-off to analyse a continuous biomarker may hide important information. Methods that provide more nuance to the underlying relationship between TMB and outcomes enable readers to judge for themselves the value and limitations of TMB cut-offs proposed for clinical practice.

Fibroblast growth factor receptor (FGFR) 2/3 alterations have been implicated in tumorigenesis in several malignancies, including urothelial carcinoma. Several FGFR inhibitors have been studied or are in development, and erdafitinib is the sole inhibitor to achieve regulatory approval. Given the rapidly evolving treatment landscape for advanced urothelial carcinoma, including regulatory approvals and withdrawals, determining the most appropriate treatment strategies and sequencing for FGFR-altered urothelial carcinoma is becoming increasing critical. However, the clinical efficacy of FGFR inhibitors is limited by acquired resistance similar to that seen with other tyrosine kinase inhibitors. Additional challenges to the clinical use of FGFR inhibitors include treatment-related adverse events and the financial costs associated with treatment. In this review, we describe known mechanisms of FGFR inhibitor resistance, including gatekeeper mutations, domain mutations, and the development of new mutations. In addition, we discuss management strategies, including ongoing clinical trials evaluating FGFR inhibitors, antibody-drug conjugates, and combination therapies with immune checkpoint inhibitors that may provide additional treatment options for localized and metastatic urothelial carcinoma.

Background: Although anaplastic lymphoma kinase inhibitors (ALKis) are the effective initial treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), most patients experience resistance to ALKis, leading to the need for alternative therapies. Immune checkpoint inhibitors (ICIs) are a standard NSCLC treatment. On the other hand, their efficacy remains unclear for ALK-positive NSCLC.

Objective: We aim to describe the treatment patterns and treatment outcomes for patients with ALK-positive NSCLC receiving later-line ICI treatment.

Methods: This retrospective cohort study used claims data from Japanese acute care hospitals and included patients with lung cancer (International Classification of Diseases, 10th version (ICD-10), code: C34) diagnosed between 1 December 2015 and 31 January 2023. We extracted patients who received ALKis as first-line therapy and subsequent lines of treatment. Patient characteristics and treatment patterns and durations were descriptively summarized. Time to treatment discontinuation (TTD) for ICIs was examined using Kaplan-Meier estimates.

Results: Of 478 patients who received ALKi as first-line treatment, 30 received ICIs, 249 ALKis, and 154 non-ICI/ALKi therapy as second-line treatment. Most patient characteristics showed no differences among the groups. ICIs were more likely to be administered to patients who underwent shorter durations of ALKi treatment. The median TTD for ICIs was 66 days, with a 1 year TTD rate of 13%.

Conclusions: Given the rarity of ALK-positive NSCLC, this study contributes to add evidence through an expanded database and increased sample size, supporting previous suggestions that ICIs have limited effectiveness in patients positive for ALK.