Targeted Oncology最新文献

Background: The efficacy of immune checkpoint inhibitor (ICI) monotherapy on non-small-cell lung cancer (NSCLC) varies by epidermal growth factor receptor (EGFR) mutation subtypes. However, the impact of these subtypes on the clinical outcomes of chemoimmunotherapy (Chemo+ICI) or platinum-based chemotherapy (Chemo) in real-world practice remains unclear.

Objective: This study evaluated the impact of EGFR mutation subtypes on NSCLC treatment outcomes of Chemo and Chemo+ICI.

Patients and methods: We retrospectively analyzed patients with advanced or recurrent EGFR-mutant NSCLC from 20 institutions between January 2017 and July 2022. Patients received Chemo with or without ICI after failure of EGFR-tyrosine kinase inhibitors. Common EGFR mutations were categorized as exon 19 deletions and exon 21 L858R mutations.

Results: Among the 403 patients, 205 (50.9%) had exon 19 deletions, and 198 (49.1%) had L858R mutations. For patients with L858R mutations, Chemo+ICI significantly improved progression-free survival (PFS) compared with Chemo (7.0 vs 5.3 months; p = 0.04). However, no significant difference in PFS was observed between treatments for patients with exon 19 deletions (6.7 vs 6.0 months; p = 0.96). Multivariate analysis identified Chemo+ICI as an independent predictor of PFS in patients with L858R mutations (hazard ratio 0.63; 95% confidence interval 0.43-0.92; p = 0.02).

Conclusions: Among patients with common EGFR mutation subtypes, those with L858R mutations demonstrated significantly improved PFS with Chemo+ICI than with Chemo. These findings suggest that Chemo+ICI may offer a more effective treatment option for patients with L858R-mutant NSCLC, warranting further investigation in prospective studies.

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.

The treatment of renal cell carcinoma (RCC), a malignancy that is typically chemoresistant, has drastically evolved with the introduction of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs). The introduction of ICI-based regimens has significantly improved outcomes for patients with metastatic RCC. Currently, first-line therapy for patients with metastatic RCC involves multiple ICI-based regimens, either dual ICIs (with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA- 4) and anti-programmed cell death- 1 (PD- 1) therapies) or anti-PD- 1 therapy in combination with VEGFR TKIs. Despite improving patient outcomes with ICI-based regimens, durable responses remain uncommon, highlighting the need for innovative treatment strategies. In this review, we highlight the current standard of care ICI-based regimens followed by ongoing clinical trials with novel combinations of existing FDA-approved agents and targets. We also discuss novel immunotherapies currently in clinical trials, which aim to improve antitumor T cell immunity either by improving T cell activation or T cell navigation to the tumor microenvironment. The incorporation of these novel therapies offers the potential to improve RCC patient outcomes, particularly by enhancing the durability of treatment responses.

Background: Metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA1/2 mutations show significant responses to poly-ADP ribose polymerase inhibitors (PARPi), while the efficacy of these agents in patients with homologous recombination repair (HRR) gene alterations other than BRCA remains unclear.

Objective: This meta-analysis aimed at assessing the efficacy of PARPi in mCRPC harboring alterations in four rare HRR genes (i.e. CDK12, PALB2, ATM, and CHEK2).

Patients and methods: Five randomised phase III trials (PROfound, PROpel, MAGNITUDE, TALAPRO-2, TRITON3) were selected through searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction followed the PRISMA statement. The primary endpoints, radiographic progression-free survival (rPFS) and overall survival (OS) with the relative 95% CI, were calculated using fixed- or random-effects methods, depending on the studies' heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used.

Results: PARPi significantly improved rPFS in mCRPC patients with CDK12 alterations (hazard ratio (HR) = 0.65; p = 0.02) without OS benefit. In patients with ATM, CHEK2, or PALB2 alterations, no significant benefit was observed in rPFS or OS. Due to the low incidence of these rare mutations, we grouped them into gene panels, revealing a significant rPFS advantage when CDK12+PALB2 (HR = 0.63; p = 0.009) were combined, and a similar benefit when including CHEK2 in the gene panel (HR = 0.69; p = 0.01).

Conclusion: CDK12 alterations could be considered as a predictive biomarker of rPFS benefit with PARPi. A gene panel grouping CDK12 and PALB2 with or without CHEK2 mutations could also enable prediction of rPFS benefit with PARPi.

Soft-tissue sarcomas represent a diverse group of rare malignancies originating from mesenchymal tissue, accounting for less than 1% of adult cancers in the USA. With over 13,000 new cases and around 5350 deaths annually, patients with metastatic soft-tissue sarcomas face limited therapeutic options and an estimated median overall survival of 18 months. While immunotherapy has demonstrated effectiveness in several cancers, its application in soft-tissue sarcomas remains challenging owing to the tumors' largely "cold" immunological environment, characterized by low levels of tumor-infiltrating lymphocytes and a lack of soft-tissue sarcoma-specific biomarkers. This review examines potential mechanisms underlying immunotherapy resistance in soft-tissue sarcomas, including the complex interplay between innate and adaptive immunity, the tumor microenvironment, and the role of immune-related genes. Despite preliminary findings suggesting correlations between immune profiles and histological subtypes, consistent biomarkers for predicting immunotherapeutic responses across soft-tissue sarcoma types are absent. Emerging strategies focus on converting "cold" tumors to "hot" tumors, enhancing their susceptibility to immunologic activation. While research is ongoing, personalized treatment approaches may offer hope for overcoming the inherent heterogeneity and resistance seen in soft-tissue sarcomas, ultimately aiming to improve outcomes for affected patients.

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.