Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-ß and PD-L1, in patients with advanced non-small cell lung cancer.

BACKGROUND: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-ß (TGF-ß) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort). METHODS: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity. RESULTS: Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-ß levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response. CONCLUSIONS: Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.

Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study.

INTRODUCTION: Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment. METHODS: This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. On the basis of the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary end point). RESULTS: A total of 153 patients were randomized to either BA (n = 75) or durvalumab groups (n = 78). The median progression-free survival was 12.8 months versus 14.6 months (stratified hazard ratio = 1.48 [95% confidence interval: 0.69-3.17]), in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% versus 32.1%) and disease control rate (66.7% versus 70.5%) were similar between the two groups. Any-grade treatment-emergent adverse events occurred in 94.6% versus 96.1% of patients in the BA versus durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). CONCLUSIONS: BA with cCRT followed by BA exhibited no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

EFFECTS OF REHABILITATION PROGRAM FOCUSED ON IMPROVING REAL-LIFE DAILY ACTIVITIES OF PATIENTS WITH MILD COGNITIVE IMPAIRMENTS OR DEMENTIA AND THEIR CAREGIVERS.

Objective: To evaluate the effectiveness of a dyadic outpatient rehabilitation program focused on improving the real-life daily activities of patients with mild cognitive impairments or dementia and their caregivers. Design: Retrospective study. Subjects: Eight patients with mild cognitive impairments or dementia and their caregivers. Methods: The rehabilitation program comprised eight 1-hour sessions by occupational therapists with patients and his/her caregivers. Patients were assessed for motor function, cognitive function, and quality of life, and their caregivers were assessed for depression and caregiver burden. Participants were assessed at pre-program and post-program, and 3-month follow-up. Results: The scores of caregiver-assessed Quality of life in Alzheimer's disease scale in patients significantly improved at post-program (median [interquartile range], 30.0 [7.0]) compared with pre-program (27.0 [2.8], effect size = 0.77, p = 0.029). In caregivers, the Zarit Caregiver Burden Interview scores decreased significantly at post-program (16.5 [13.0]) compared with pre-program (22.0 [17.5], effect size = 0.72, p = 0.042). There were no significant differences in other assessments. Conclusions: The rehabilitation program focused on real daily activities and demonstrated to improve patients' quality of life and caregivers' depression and caring burden through patient-caregiver interaction. Future enhanced follow-up systems are warranted.

Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting PD-L1 and TGF-ß, in Patients with Pretreated Colorectal Cancer: Results from a Phase I Trial.

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor ß (TGF-ß) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ß receptor II (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received bintrafusp alfa for a median duration of 7.1 weeks. The objective response rate was 3.1% and the disease control rate was 6.3% (1 partial response, 1 stable disease); 2 patients were not evaluable. The safety profile was consistent with previously reported data.

Stereotactic radiosurgery results for brain metastasis patients with renal cancer: A validity study of Renal Graded Prognostic Assessment and proposal of a new grading index (JLGK2101 Study).

BACKGROUND AND PURPOSE: The Renal Graded Prognostic Assessment (GPA) is relatively new and has not been sufficiently validated using a different dataset. We thus developed a new grading index, the Renal Brain Metastasis Score (Renal-BMS). MATERIALS AND METHODS: Using our dataset including 262 renal cancer patients with brain metastases (BMs) undergoing stereotactic radiosurgery (SRS) (test series), we validity tested the Renal-GPA. Next, we applied clinical factor-survival analysis to the test series and thereby developed the Renal-BMS. This system was then validated using another series of 352 patients independently undergoing SRS at nine gamma knife facilities in Japan (verification series). RESULTS: Using the test series, with the Renal-GPA, 95% confidence intervals (CIs) of the post-SRS median survival times (MSTs) overlapped between pairs of neighboring subgroups. Among various pre-SRS clinical factors of the test series, six were highly associated with overall survival. Therefore, we assigned scores for six factors, i.e., "KPS ≥ 80%/<80% (0/3)", "tumor numbers 1-4/≥5 (score; 0/2)", "controlled primary cancer/not (0/2)", "existing extra-cerebral metastases/not (0/3)", "blood hemoglobin ≥ 11.0/<11.0 g/dl (0/1)" and "interval from primary cancer to SRS ≥ 5/<5 years (0/1)". Patients were categorized into three subgroups according to the sum of scores, i.e., 0-4, 5-8 and 9-12. In the test and verification series, post-SRS MSTs differed significantly (p < 0.0001) with no overlaps of 95% CIs among the three subgroups. CONCLUSIONS: The Renal BMS has the potential to be very useful to physicians selecting among aggressive treatment modalities for renal cancer patients with BMs.

Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6.

We previously reported identifying SOX6 as a glioma antigen by serological screening using a testis cDNA library. Its preferential expression and frequent IgG responses in glioma patients indicate that SOX6 may be a useful target for immunotherapy. To examine whether cytotoxic T-lymphocyte (CTL) responses specific for SOX6 to destroy glioma can be generated in vivo, we treated glioma-bearing mice by vaccination with a plasmid DNA encoding murine full-length SOX6 protein. Following SOX6-DNA vaccination, CTLs specific for SOX6-expressing glioma cells were induced, while normal autologous-cells that had restrictedly expressed SOX6 during embryogenesis were not destroyed. Furthermore, DNA vaccination with SOX6 exerted protective and therapeutic antitumor responses in the glioma-bearing mice. This antitumor activity was abrogated by the depletion of CD4 positive T cells and/or CD8 positive T cells. These results suggest that the SOX6 protein has multiple CTL and helper epitopes to induce antitumor activity and the effectiveness of SOX6-DNA vaccine for the prevention and treatment of glioma.