Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial.

PURPOSE: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm. METHODS AND MATERIALS: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival. RESULTS: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004). CONCLUSIONS: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis.

PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual. RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism. CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.

ctDNA-based detection of molecular residual disease in stage I-III non-small cell lung cancer patients treated with definitive radiotherapy.

Background: Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT. Methods: A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples. Results: Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001). Conclusion: Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification.

Measuring executive function skills in young children in Kenya.

Interest in measuring executive function skills in young children in low- and middle-income country contexts has been stymied by the lack of assessments that are both easy to deploy and scalable. This study reports on an initial effort to develop a tablet-based battery of executive function tasks, which were designed and extensively studied in the United States, for use in Kenya. Participants were 193 children, aged 3-6 years old, who attended early childhood development and education centers. The rates of individual task completion were high (65-100%), and 85% of children completed three or more tasks. Assessors indicated that 90% of all task administrations were of acceptable quality. An executive function composite score was approximately normally distributed, despite higher-than-expected floor and ceiling effects on inhibitory control tasks. Children's simple reaction time (ß = -0.20, p = .004), attention-related behaviors during testing (ß = 0.24, p = .0005), and age (ß = -0.24, p = .0009) were all uniquely related to performance on the executive function composite. Results are discussed as they inform efforts to develop valid and reliable measures of executive function skills among young children in developing country contexts.