Targeted Oncology最新文献

Importance

Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking.

Objective

This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time.

Evidence Review

On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint).

Findings

Expansion of clinical trial testing beyond lenvatinib’s initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3–5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11–69%), OS (6.2–32 months), and PFS (3.6–15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials.

Conclusion and relevance

Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib’s established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

This is a summary of the original article ‟Overall survival with osimertinib in resected EGFR-mutated NSCLC.ˮ Osimertinib blocks the activity of the epidermal growth factor receptor (EGFR) on cancer cells, causing cancer cell death and tumor shrinkage, and is an effective treatment for EGFR-mutated non-small cell lung cancer (NSCLC). The ADAURA study assessed the effects of osimertinib versus placebo in patients with EGFR-mutated (exon 19 deletion or L858R) early stage (IB–IIIA) NSCLC removed by surgery (resected). Previous results from ADAURA demonstrated that patients treated with osimertinib stayed alive and cancer-free (disease-free survival) significantly longer than patients who received placebo. Recent data showed the overall length of time patients were alive after starting treatment (overall survival). In both the primary stage II–IIIA and overall stage IB–IIIA populations, patients in the osimertinib group had a significant 51% reduction in the risk of death compared with the placebo group. The data demonstrated that osimertinib after surgery significantly improved overall survival in patients with resected, EGFR-mutated, stage IB–IIIA NSCLC.

Background: Despite improvement in progression-free survival (PFS) with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) as maintenance treatment for patients with epithelial ovarian cancer (EOC), a comparative analysis of clinical events of interest (CEIs) of different PARPi is scarce.

Objective: This study aimed to compare the safety of different PARPi in patients with EOC.

Patients and methods: Through analyzing the Korean National Health Insurance Service from January 2009 to January 2022, this study involved BRCA-mutated, platinum-sensitive patients with EOC treated with olaparib (tablet), niraparib, and olaparib (capsule) as first-line or second-line maintenance treatment. CEIs were identified using International Statistical Classification of Diseases (ICD) 9/10 codes, with additional outcomes being dose modification and persistence.

Results: In the first-line maintenance treatment [118 niraparib, 104 olaparib (tablet) patients], no significant differences were noted in CEIs, dose reduction, or 6-month discontinuation rate. For second-line maintenance treatment [303 niraparib, 126 olaparib (tablet), and 675 olaparib (capsule) patients], niraparib was associated with a higher risk of hematologic CEIs, particularly anemia, compared with olaparib (tablet) (0.51 [0.26-0.98] and 0.09 [0.01-0.74], respectively), and higher rate of discontinuation rate at 6 months. Of note, patients over 60 years old showed an increased risk of CEIs with niraparib, as indicated by the hazard ratio divergence in restricted cubic spline plots.

Conclusions: No differences were observed among the PARPi during first-line maintenance treatment. However, in the second-line maintenance treatment, significant differences were observed in the risk of experiencing CEIs, dose alteration possibilities, and discontinuation of PARPi between niraparib and olaparib (tablets). Moreover, our findings suggest that an age of 60 years may be a critical factor in selecting PARPi to reduce CEI incidence.

Background: DNA methylation profiles have emerged as potential predictors of therapeutic response in various solid tumors.

Objective: This study aimed to analyze the DNA methylation profiles of patients with stage IV metastatic melanoma undergoing first-line immune checkpoint inhibitor treatment and evaluate their correlation with a radiological response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST).

Methods: A total of 81 tissue samples from 71 patients with metastatic melanoma (27 female, 44 male) were included in this study. We utilized Illumina Methylation EPIC Beadchips to retrieve their genome-wide methylation profile by interrogating >850,000 CpG sites. Clustering based on the 500 most differentially methylated genes was conducted to identify distinct methylation patterns associated with immune checkpoint inhibitor response. Results were further aligned with an independent, previously published data set.

Results: The median progression-free survival was 8.5 months (range: 0-104.1 months), and the median overall survival was 30.6 months (range: 0-104.1 months). Objective responses were observed in 29 patients (40.8%). DNA methylation profiling revealed specific signatures that correlated with radiological response to immune checkpoint inhibitors. Three distinct clusters were identified based on the methylation patterns of the 500 most differentially methylated genes. Cluster 1 (12/12) and cluster 2 (12/24) exhibited a higher proportion of responders, while cluster 3 (39/45) predominantly consisted of non-responders. In the validation data set, responders also showed more frequent hypomethylation although differences in the data sets limit the interpretation.

Conclusions: These findings suggest that DNA methylation profiling of tumor tissues might serve as a predictive biomarker for immune checkpoint inhibitor response in patients with metastatic melanoma. Further validation studies are warranted to confirm the efficiency of DNA methylation profiling as a predictive tool in the context of immunotherapy for metastatic melanoma.

Sacituzumab govitecan (TRODELVY^®) is a first-in-class trophoblast cell-surface antigen 2 (Trop-2)-directed antibody and topoisomerase I inhibitor conjugate that is approved globally as monotherapy for the treatment of adults with unresectable locally advanced or metastatic, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-; defined as immunohistochemistry 0, 1+ or 2+ and in situ hybridization-negative) breast cancer who have received endocrine-based therapy and ≥ 2 additional systemic therapies in the advanced setting. In the phase III TROPiCS-02 trial, intravenous sacituzumab govitecan demonstrated statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared with physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in adults with metastatic HR+/HER2- breast cancer. Sacituzumab govitecan had a generally manageable tolerability profile in these patients; the most common treatment-related grade ≥ 3 adverse events included neutropenia, diarrhoea, leukopenia, anaemia, fatigue and febrile neutropenia. Sacituzumab govitecan carries regulatory warnings for severe neutropenia and severe diarrhoea. Sacituzumab govitecan demonstrated an overall benefit in terms of health-related quality of life. Current evidence indicates that sacituzumab govitecan is an effective treatment option, with a generally manageable tolerability profile, for patients with pre-treated, unresectable locally advanced or metastatic HR+/HER2- breast cancer.

Background: Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT.

Objective: The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy.

Patients and methods: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity.

Results: Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce.

Conclusions: Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunothe

Background: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma.

Objective: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes.

Methods: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis.

Results: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188).

Conclusions: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Background: Data from studies looking at both EGFR and ERBB2 exon 20 insertion mutations (-20ins) in the same cohort of patients with non-small cell lung cancer (NSCLC) are limited.

Objective: The purpose of this study was to analyze EGFR/ERBB2-20ins in all-stage NSCLC patients to reveal their histological and molecular features, and to retrospectively evaluate the results of first-line real-world systemic treatments in patients with advanced-stage disease.

Patients and methods: We collected 13,920 formalin-fixed paraffin-embedded NSCLC specimens. Clinicopathological features were recorded and DNA-based next-generation sequencing was performed. First-line systemic treatment data were obtained via chart review.

Results: In total, 414 (2.97%) EGFR-20ins cases and 666 (4.78%) ERBB2-20ins cases were identified. Both were more common in women, non-smokers, and patients with adenocarcinoma. The incidence of EGFR/ERBB2-20ins in adenocarcinoma is inversely proportional to the degree of invasion; 77 and 26 variants were detected in EGFR-20ins and ERBB2-20ins cases, respectively. The most common concurrently mutated genes were TP53 and RB1. In invasive adenocarcinoma, lepidic components were more common in EGFR/ERBB2-20ins-alone cases than in those with other concurrent mutated genes. In EGFR-/ERBB2-20ins patients, there was no significant difference in progression-free survival (PFS) or treatment response to first-line systemic treatments in this study. There was no significant difference in PFS or treatment response among patients with different EGFR/ERBB2-20ins variants and those with or without concurrent mutated genes.

Conclusions: EGFR/ERBB2-20ins is more common in early lung adenocarcinoma. EGFR-20ins had more variants. In both cohorts, the results for first-line systemic treatments showed no significant difference.

Background: The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial.

Objective: We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer.

Methods: In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer.

Results: In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed.

Conclusions: The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.

Background: Patients with non-small cell lung cancer harbouring mesenchymal-epithelial transition exon 14 (METex14) skipping typically demonstrate poorer prognosis than overall non-small cell lung cancer. Until recently, no targeted treatments were available for patients with non-small cell lung cancer harbouring METex14 skipping in the UK, with limited treatments available.

Objective: This study estimates the long-term survival and quality-adjusted life-year benefit of MET inhibitor tepotinib versus current standard of care from a UK perspective.

Methods: A partitioned-survival model assessed the survival and quality-adjusted life-year benefits of tepotinib versus immunotherapy ± chemotherapy and chemotherapy for untreated and previously treated patients, respectively, using evidence from the single-arm VISION trial (NCT02864992). Two approaches were used to inform an indirect treatment comparison: (1) published clinical trials in overall non-small cell lung cancer and (2) real-world evidence in the METex14 skipping population. Results are presented as median and total quality-adjusted life-year gain and survival for progression-free survival and overall survival. Survival curves were validated against the external literature and uncertainty assessed using a probabilistic sensitivity analysis.

Results: Using the indirect treatment comparison against the published literature, tepotinib is estimated to have a median progression-free survival gain versus pembrolizumab ± chemotherapy (11.0 and 9.2 months) in untreated patients, and docetaxel ± nintedanib (5.1 and 6.4 months) in previously treated patients. Across the populations, tepotinib is estimated to have a median survival gain of 15.4 and 9.2 months versus pembrolizumab ± chemotherapy in untreated patients and 12.8 and 5.1 months versus docetaxel ± nintedanib in previously treated patients. The total quality-adjusted life-year gain ranges between 0.56 and 1.17 across the untreated and previously treated populations. Results from the real-world evidence of indirect treatment comparisons are consistent with these findings.

Conclusions: Despite the limitations of the evidence base, the numerous analyses conducted have consistently indicated positive outcomes for tepotinib versus the current standard of care.