Jyoti Mayadev

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty patients were randomized, 36 received treatment, and 25 were evaluable for the primary endpoint. After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (p = 0.0025) that remained higher at day 21, meeting the pre-specified endpoint on two-sample T-test (p = 0.052), but not on sensitivity analysis by Wilcoxon test (p = 0.13). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p = 0.28). There were no new safety signals. In conclusion, neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.

Open-access immunosequencing data | Zamarin, Dmitriy | Nature Communications | Adaptive Biotechnologies | Combination of immune checkpoint blockade (ICB) with chemoradiation (CRT) is now approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of differential sequencing of atezolizumab and CRT in patients with high-risk node-positive LACC. The primary objective was to evaluate the expansion of tumor-associated T-cell receptor (TCR) clones in peripheral blood as a surrogate measure of anti-tumor immune response. Secondary objectives included toxicity and 2-year disease-free survival (DFS). Forty patients were randomized and 36 received 3 doses of atezolizumab neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B). After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (median 0.39 vs. 0.06, p=0.0025) that remained numerically higher at the day 21 primary endpoint (p=0.052 by 2-sample t test). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p=0.28). There were no new safety signals. In conclusion, addition of neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.

PURPOSE: To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS: Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m² and G 50 mg/m² were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS: Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION: Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

There are more than 13,000 new cases of cervical cancer each year in the United States and approximately 245,000 survivors. External beam radiation and brachytherapy are the front-line treatment modalities, and 60% of patients develop vaginal damage and constriction, i.e., stenosis of the vaginal vault, greatly impeding sexual function. The incidence of vaginal stenosis (VS) following radiotherapy (RT) for anorectal cancer is 80%. VS causes serious quality of life (QoL) and psychological issues, and while standard treatment using self-administered plastic dilators is effective, acceptance and compliance are often insufficient. Based on published patient preferences, we have pursued the design of a soft inflatable dilator for treating radiotherapy-induced vaginal stenosis (VS). The critical component of the novel device is the dilator balloon wall material, which must be compliant yet able to exert therapeutic lateral force levels. We selected a commercially available silicone elastomer and characterized its stress–strain characteristics and hyperelastic properties. These parameters were quantified using uniaxial tensile testing and digital image correlation (DIC). Dilator inflation versus internal pressure was modeled and experimentally validated in order to characterize design parameters, particularly the dilator wall thickness. Our data suggest that an inflatable silicone elastomer-based vaginal dilator warrants further development in the context of a commercially available, well-tolerated, and effective device for the graded, controlled clinical management of radiotherapy-induced VS.