ABSTRACT
BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSION: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.
ABSTRACT
BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.
ABSTRACT
Locally advanced rectal cancer has traditionally been treated with chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, a new strategy, total neoadjuvant therapy, involves the administration of CRT and neoadjuvant chemotherapy with the aim of eradicating micrometastases earlier and achieving greater control of the disease. The use of total neoadjuvant therapy has shown higher rates of pathological complete response and resectability compared with CRT, including improved survival. Nevertheless, distant relapse is the main cause of morbidity and mortality in locally advanced rectal cancer. To address this, new biomarkers are being developed to predict disease response.
