Therapeutic Advances in Medical Oncology最新文献

Non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease that is frequently associated with a host of known oncogenic alterations. Advances in molecular diagnostics and drug development have facilitated the targeting of novel alterations such that the majority of NSCLC patients have driver mutations that are now clinically actionable. The goal of this review is to gain insights into clinical research and development principles by summary, analysis, and discussion of data on agents targeting known alterations in oncogene-driven, advanced NSCLC beyond those in the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK). A search of published and presented literature was conducted to identify prospective trials and integrated analyses reporting outcomes for agents targeting driver gene alterations (except those in EGFR and ALK) in molecularly selected, advanced NSCLC. Clinical efficacy data were extracted from eligible reports and summarized in text and tables. Findings show that research into alteration-directed therapies in oncogene-driven, advanced NSCLC is an extremely active research field. Ongoing research focuses on the expansion of new agents targeting both previously identified targets (particularly hepatocyte growth factor receptor (MET), human epidermal growth factor receptor 2 (HER2), and Kirsten rat sarcoma viral oncogene homolog (KRAS)) as well as novel, potentially actionable targets (such as neuregulin-1 (NRG1) and phosphatidylinositol 3-kinase (PI3K)). The refinement of biomarker selection criteria and the development of more selective and potent agents are allowing for increasingly specific and effective therapies and the expansion of clinically actionable alterations. Clinical advances in this field have resulted in a large number of regulatory approvals over the last 3 years. Future developments should focus on the continued application of alteration therapy matching principles and the exploration of novel ways to target oncogene-driven NSCLC.

Background: Lazertinib demonstrates efficacy similar to that of osimertinib in the first-line treatment of epidermal growth factor receptor (EGFR)-mutated advanced lung cancer. However, its cost-effectiveness has not yet been evaluated.

Objective: To study the cost-effectiveness of lazertinib as a first-line treatment for patients with EGFR-mutated advanced lung cancer.

Design: A partitioned survival model-based cost-effectiveness analysis.

Methods: We conducted the economic analysis from the perspective of the healthcare sector with a lifetime horizon. Simulated patients were entered into the models upon the diagnosis of EGFR-mutated advanced lung cancer. Lazertinib was compared with gefitinib. The model inputs were derived from the trials (survival outcomes, incidence of adverse events (AEs), and subsequent therapies), National Health Insurance payments (costs of drugs and AEs), and hospital cohorts (utility values). Deterministic and probabilistic analyses were also conducted.

Results: Applying the same daily price of osimertinib (US$110) to that of lazertinib, the incremental cost-effectiveness ratio of lazertinib versus gefitinib was US$93,792 per quality-adjusted life year (QALY). The cost of lazertinib was a major determinant. If the daily price of lazertinib could be reduced to US$75, lazertinib would become cost-effective at a willingness-to-pay (WTP) threshold of US$70,000 per QALY. Given the WTP threshold, the probability that lazertinib would be cost-effective was 0.7%.

Conclusion: Lazertinib is not a cost-effective first-line treatment for EGFR-mutated advanced lung cancer. Lowering prices enables cost-effectiveness.

Colorectal cancer (CRC) represents a major public health challenge globally, particularly in the Gulf Cooperation Council (GCC) countries, where it is identified as the second most prevalent form of cancer. Despite advancements in management strategies, tailored guidelines specific to the Gulf region are lacking. This paper presents consensus recommendations developed by a panel of experts from the GCC countries to address this gap. The guidelines cover epidemiology, screening, biomarkers, and treatment strategies for metastatic CRC. Treatment guidelines emphasize tailored approaches based on tumor characteristics, including sidedness and molecular profiles. Furthermore, the importance of maintenance therapy and emerging biomarkers are discussed. These guidelines aim to improve CRC management and outcomes in the Gulf region.

Despite the availability of multiple treatment options for breast cancer, challenges such as adverse events, drug resistance, and disease progression persist for patients. The identification of human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers, alongside the development of HER2-targeted therapies, has significantly improved the prognosis of HER2-amplified breast cancers. However, therapeutic options remain limited for HER2-overexpressing or HER2-negative breast cancers. In response to this gap, antibody-drug conjugates (ADCs) have emerged as a promising approach. ADCs combine the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy, which allows for the targeted delivery of a cytotoxic payload to cancer cells. ADCs have been used as adjuvant chemotherapeutic treatments and salvage therapies across various breast cancer subtypes, which have greatly improved the prognosis of breast cancer patients. Numerous ongoing clinical trials seek to optimize dosing strategies and identify patient populations that would benefit most from ADCs. This review presents an updated and comprehensive overview of emerging investigational ADCs for treating breast cancer patients with various HER2 subtypes. These ADCs are spearheading a new era in targeted cancer therapy, promising to innovate treatment paradigms for both HER2-positive and HER2-low breast cancers.

Antibody-drug conjugates (ADCs) have emerged as a transformative approach in cancer therapy by enhancing tumor targeting and minimizing systemic toxicity compared to traditional chemotherapy. Initially developed with chemotherapy agents as payloads, ADCs have now incorporated alternative payloads, such as immune-stimulating agents, natural toxins, and radionuclides, to improve therapeutic efficacy and specificity. A significant advancement in ADC technology is the integration of Proteolysis Targeting Chimeras (PROTACs), which enable the precise degradation of cellular targets involved in tumorigenesis. This strategy enhances the specificity and precision of cancer therapies, addressing key mechanisms in cancer cell survival. Moreover, incorporating radioactive isotopes into ADCs is an emerging strategy aimed at further improving therapeutic outcomes. By delivering localized radiation, this approach offers the potential to enhance the efficacy of treatment and expand the therapeutic arsenal. Despite these innovations, challenges remain, including dysregulated immune activation, severe adverse effects, and intrinsic immunogenicity of some agents. These emerging issues highlight the ongoing need for optimization in ADC therapy. This review summarizes the latest developments in ADC technology, focusing on novel payloads, PROTAC integration, and the potential for combining ADCs with other therapeutic modalities to refine cancer treatment and improve patient outcomes.

Background: Selpercatinib is approved for the treatment of RET-fusion-positive non-small-cell lung cancer (NSCLC).

Objective: We present a final update on LIBRETTO-321 to enhance the understanding of long-term efficacy and safety in Chinese patients.

Design: This open-label, multicenter, phase II study included patients with advanced RET-altered solid tumors.

Methods: The primary endpoint was objective response rate (ORR), and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was assessed by the independent review committee. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), central nervous system (CNS) response, and safety.

Results: A total of 47 patients (treatment-naïve (n = 11); pre-treated (n = 36)) with NSCLC were enrolled. The ORR in overall NSCLC was 72.3% (95% CI: 57.4, 84.4), treatment-naïve was 100.0% (95% CI: 71.5, 100.0); and pre-treated was 63.9% (95% CI: 46.2, 79.2). Median DOR was not reached for overall NSCLC, with 53% of responses ongoing at the data cutoff (median follow-up: 34.2 months). With a median follow-up of 35.9 months, the median PFS for overall NSCLC was 27.6 months (95% CI: 22.3, not evaluable (NE)), treatment-naïve was 27.6 months (95% CI: 16.4, NE), and pre-treated was 27.8 months (95% CI: 19.29, NE). The 3-year OS rate for overall NSCLC was 62.0% (95% CI: 45.9, 74.6) with a median follow-up of 38.1 months. Among five patients with measurable CNS metastases, four achieved intracranial responses. The safety profile was consistent with previous reports.

Conclusion: With additional follow-up, selpercatinib showed durable responses, prolonged survival, and a consistent safety profile in Chinese patients with RET-fusion-positive NSCLC.

Trial registration: Clinical Trials.gov identifier (NCT04280081).

Background: Transarterial chemoembolization (TACE) is an effective and safe downstaging therapy for hepatocellular carcinoma (HCC). However, the selection of sequential therapeutic modalities is still controversial.

Objectives: This study compared the effectiveness and safety of surgical resection (SR) and thermal ablation (TA) after patients with HCC underwent TACE downstaging therapy.

Design: A retrospective, multi-institutional study.

Methods: From June 2008 to October 2022, a total of 4782 consecutive patients with HCC beyond the initial Milan criteria underwent TACE at 12 hospitals. Among them, 609 patients who received successful downstaging therapy were retrospectively reviewed. Among them, 209 patients underwent an SR, and 390 patients received TA after TACE. The propensity score matching (PSM) method was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test.

Results: After PSM 1:1 (n = 185 in both groups), the cumulative 1-, 3-, 5-, and 10-year OS rates were 98.8%, 89.3%, 82.9%, and 64.4%, respectively, in the SR group and 99.5%, 88.4%, 75.3%, and 53.9%, respectively, in the TA group; these two groups were not significantly different (HR: 1.22; 95% CI: 0.78-1.89; p = 0.381). The cumulative 1-, 3-, 5-, and 10-year PFS rates were 88.5%, 69.2%, 58.8%, and 32.2%, respectively, in the SR group and 90.6%, 71.4%, 53.1%, and 32.0%, respectively, in the TA group, revealing no significant difference between the two groups (HR: 0.97; 95% CI: 0.71-1.32; p = 0.855).

Conclusion: For HCC patients beyond the Milan criteria who received TACE downstaging therapy, TA might be acceptable as an alternative to SR in the first-line sequential treatment scheme.

Background: For non-small-cell lung cancer (NSCLC) patients who progressed after first-line chemotherapy, immunotherapy targeting programmed cell death (ligand) 1 has shown promising activity. However, the activity is relatively limited in patients harboring epidermal growth factor receptor (EGFR) mutations.

Objectives: This study aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in previously treated patients with locally advanced and metastatic NSCLC.

Design: A single-center, single-arm, phase II study.

Methods: Previously treated patients with locally advanced and metastatic NSCLC were enrolled to receive camrelizumab (200 mg, administered intravenously every 3 weeks) and famitinib (20 mg, administered orally once daily). Patients harboring EGFR mutation genes had received at least one EGFR tyrosine kinase inhibitor and no more than two lines of chemotherapy regimen before the enrollment. The other patients had progressed on first-line chemotherapy with or without immunotherapy before the enrollment. The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by the investigator.

Results: Our study encompassed 23 NSCLC patients between October 2019 and October 2022. For all patients, the confirmed ORR was 30.4%, and the disease control rate was 95.7%. The median progression-free survival (PFS) was 6.9 months (95% CI: 4.9 months-not reached). The median overall survival (OS) was not reached. 1- and 2-year OS rates were 85.6% (95% CI: 71.8%-100.0%) and 56.8% (95% CI: 37.7%-85.7%). Especially, for the 6 patients with EGFR genetic aberrations, the confirmed ORR was 33.3%, the median PFS was 10.3 months (95% CI: 1.8-18.8 months), and the median OS was 20.3 months (95% CI: 0.8-39.8 months). The most common grade 3 and above treatment-related adverse events were platelet count decreased, white blood cell count decreased, and hypertension. No unexpected adverse events were reported.

Conclusion: Camrelizumab plus famitinib demonstrated encouraging clinical activity with a manageable safety profile in previously treated patients with locally advanced and metastatic NSCLC. The results warranted further validation.

Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026641.

Background: Given advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial.

Objectives: This study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations.

Methods: This retrospective single-center study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 (ERBB2), ALK, ROS1, B-Raf proto-oncogene (BRAF) V600E, mesenchymal-epithelial transition factor (MET) exon14 skipping, and rearranged during transfection (RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons.

Results: Among 225 patients, mutations included the following: KRASG12C (n = 101, 45%), MET exon 14 skipping (n = 26, 12%), EGFR Exon 20 (n = 25, 11%), ERBB2 (n = 25, 11%), ALK fusion (n = 16, 7%), ROS1 fusion (n = 14, 6%), BRAF V600E mutation (n = 13, 6%), and RET fusion (n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008).

Conclusion: While RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations.

Chimeric antigen receptor T (CAR T) cells have shown their potential in hematological malignancies and the treatment of solid tumors, especially in metastases. However, CAR T-cell therapy may carry risks of inducing severe adverse effects, which are recognized as immune-related adverse events. Here, we report two cases of severe colitis presented with refractory bloody diarrhea, which were induced by carcinoembryonic antigen (CEA)-directed CAR T therapy in the treatment of metastatic colorectal adenocarcinoma. These patients were treated as part of a clinical trial. The clinical trial was registered at ClinicalTrials.gov (NCT05396300), submitted, and started on May 25, 2022. Glucocorticoids combined with vedolizumab were used to control their gastrointestinal symptoms but the outcomes were unsatisfactory. This report highlights the potentially serious risks of anti-CEA CAR T therapy and provides management options.