Clinical Cancer Research最新文献

Purpose: ESR1 mutations mediate resistance to antiestrogen therapy in hormone receptor-positive metastatic breast cancer (MBC). Elacestrant, an oral selective estrogen receptor degrader, improves progression-free survival over standard endocrine therapy in ESR1-mutant MBC. We assessed real-world elacestrant use and clinical-genomic factors associated with outcomes.

Experimental design: This study used the GuardantINFORM database, linking >42,000 real-world breast cancer cases with sequencing and claims data. We included patients with activating ESR1 mutations detected <6 months before elacestrant initiation (January 2023-March 2024). Outcomes of time-to-treatment-discontinuation, time-to-next-treatment (TTNT), and overall survival were estimated with Kaplan-Meier and Cox regression analysis, adjusting for clinical variables.

Results: We identified 756 patients (76% with prior cyclin-dependent kinase-4/6 inhibitor and 38% with prior chemotherapy exposure), and 742 (98.2%) were evaluable for outcomes. The median TTNT was 6.4 months, and the time-to-treatment-discontinuation was 4.6 months. In those with ≤1 prior lines of metastatic therapy, the TTNT was 8.8 months, compared with 6.0 months in the third-line setting. Prior fulvestrant exposure trended toward shorter treatment duration (hazard ratio, 1.19; 95% confidence interval, 0.91-1.56). Higher ESR1 polyclonality (≥4 alterations; 11% of patients) correlated with a shorter TTNT of 5.2 months (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06), but efficacy was consistent across ESR1 alleles (e.g., Y537S and D538G). Disease with dual ESR1 and PI3K pathway mutations (PIK3CA, AKT1, and PTEN) had a median TTNT of 5.2 months.

Conclusions: In ESR1-mutant MBC, elacestrant treatment durations support the routine use of elacestrant monotherapy in appropriately selected patients. For patients with concurrent ESR1 and PI3K pathway mutations, single-agent activity was comparable with outcomes observed in phase III studies. See related article by Rugo et al., p. 179.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy though their use is limited by immune-related adverse events (irAEs) - off-target immune responses that can impact any organ, frequently lead to ICI discontinuation, and require immunosuppressive therapy. Barrier organs including the skin, gastrointestinal tract, and lung are among the tissues most frequently impacted by irAEs. As barrier organs, these tissues share important functions in maintaining separation from the external environment, participating in gas and nutrient exchange, and initiating localized immune responses that balance protection with tolerance. Here, we highlight common immunologic features of these barrier organs and how they contribute to the immunopathogenesis of tissue-specific irAEs. We specifically review the contribution of T lymphocytes, myeloid cells, interferons, interleukins, androgens, autoantibodies, oxygenation, and dysbiosis to irAE pathogenesis. Finally, we identify gaps in the understanding of shared immunologic mechanisms across barrier irAEs and highlight how an interdisciplinary approach to irAE treatment would improve the survival and quality of life of patients with cancer.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with a peak incidence coinciding with the pubertal growth spurt. Metastatic disease occurs in approximately 10 to 20% of newly-diagnosed patients, most commonly in the lung. While 5-year overall survival (OS) for patients with localized disease at diagnosis is approximately 70% after standard upfront treatment of multi-agent chemotherapy and surgical resection, patients with metastatic or recurrent disease have a 5-year OS of approximately 30% in the pediatric age group. Currently, there is no standard treatment or FDA-approved therapy for relapsed and refractory osteosarcoma. Progress in identifying promising new treatments has been limited by its complex disease biology and rarity, as well as unique challenges of clinical trial design including unreliability of objective response rate (ORR) as a predictor of drug activity. Given these challenges and the unmet need for new therapies, the FDA Oncology Center of Excellence hosted an educational symposium, "Current Challenges in Clinical Trial Design for Relapsed and Refractory Osteosarcoma," in May 2023. During this mini-symposium, patient advocates, regulators from the FDA, and academic thought leaders in the field of pediatric sarcoma discussed challenges in clinical trial design and implementation. Achieving progress in relapsed and refractory osteosarcoma will require intentional collaboration among all stakeholders to identify trial designs that are acceptable to patients and will provide sufficient evidence of efficacy and safety to support a marketing application. Herein, we summarize the key points and future directions discussed at this meeting.

Purpose: Angiosarcoma and epithelioid hemangioendothelioma (EHE) are two rare vascular sarcomas with limited therapeutic options. Prior reports have shown sensitivity to microtubule-targeting agents in these histologies. We report the efficacy and safety of eribulin in these two vascular sarcomas in a pooled analysis of two parallel phase 2 studies.

Patients and methods: Patients over age 18 years with metastatic or recurrent angiosarcoma or EHE were treated with eribulin (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was objective response rate by RECIST 1.1.

Results: 29 patients were accrued to the study, 25 (85%) having had prior taxane exposure. We observed an objective response rate (ORR) of 17% for angiosarcomas, with 6/23 (26%) patients achieving disease stability for greater than 6 months, and for EHE an ORR of 33% (2/6) with 2/6 continuing treatment for over 12 months. Five patients experienced a >1.3-fold time to progression ratio (TTP2/TTP1) on eribulin compared to the immediately prior therapy. Eribulin tolerability was consistent with published data.

Conclusions: Eribulin showed clinical activity in this largely taxane-pretreated population. Future studies will be needed to confirm activity.