Background: Checkpoint inhibitors have advanced treatment of many cancers. However, their efficacy in many rare tumor types remains unclear; hence, data in these cancers is an unmet need. Objective: This paper presents the results of combination therapy with both anti-CTLA and anti-PD-1 in the small bowel cohort of SWOG S1609 dual anti-CTLA-4 & anti-PD-1 blockade in Rare Tumors (DART). Design: DART is a prospective, open-label, multicenter (>1000 sites opened) phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors. DART was conducted through the SWOG Early Therapeutics and Rare Cancers Committee, supported by NCI, and opened at >1000 sites. Methods: The primary endpoints included overall response rate (ORR) (RECIST v1.1), complete response (CR) and partial response (PR). Progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity were secondary endpoints. Results: Twenty-six patients (evaluable, N = 23) were registered. The duodenum was the primary site in 48% ( N = 11). The ORR was 9% (CR, 4%, N = 1 (PFS 252 days); PR, 4%, N = 1 (1633+ days); clinical benefit rate (CBR; includes SD > 6 months/PR/CR), 13%. Six-month PFS was 17%; 6-month OS, 50%. Longest responder is ongoing at 1633+ days. The most common toxicities were fatigue and dyspnea (21.7% each), diarrhea and hypothyroidism (17.4% each), with diarrhea, increased bilirubin, colitis and elevated lipase as the most common grade 3–5 immune-related adverse events. Conclusion: Combination therapy with nivolumab plus low-dose ipilimumab in small bowel tumors resulted in a response rate of 9% in 23 treated patients (CBR 13%), including a CR lasting 8 months and a PR ongoing at >4.5+ years. However, the small sample size underpowers meaningful subgroup analysis. Translational studies are needed to identify biologic characteristics that predict response. Trial registration: ClinicalTrials.gov registry: NCT02834013.
Prostate cancer (PC) represents a heterogeneous disease with variable clinical outcomes. Despite most cases being diagnosed at localized stage, 20%–40% of patients experience disease recurrence, progressing to metastatic hormone-sensitive prostate cancer (mHSPC), and without effective intervention, lethal metastatic castration-resistant disease. Homologous recombination repair (HRR) gene mutations, particularly BRCA1/2 alterations, are identified in over 20% of metastatic PC patients and confer significantly worse prognosis, including shorter time to castration resistance and inferior overall survival. Following demonstrated efficacy in metastatic castration-resistant prostate cancer, poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are now being evaluated in earlier disease settings. The phase III trials AMPLITUDE and TALAPRO-3 are investigating PARPi combined with androgen receptor pathway inhibitors in HRR-mutated mHSPC, with preliminary results from AMPLITUDE demonstrating significant improvement in radiographic progression-free survival. Additional trials are exploring PARPi in HRR-proficient disease and neoadjuvant settings. However, there are critical questions regarding optimal treatment sequencing, long-term survival benefit, and gene-specific response patterns, particularly given minimal benefit in ATM/CHEK2-mutant populations. This review aims to investigate the role of PARPi and HRR mutations in patients with mHSPC, addressing this evolving therapeutic landscape.
Background Although neoadjuvant immunochemotherapy (NCIT) has shown promising prospects in the treatment of locally advanced esophageal squamous cell carcinoma (LA-ESCC), the role of adjuvant radiotherapy in these patients remains unclear. Objectives This study aimed to investigate the impact of postoperative adjuvant radiotherapy on treatment outcomes in patients with LA-ESCC who underwent NCIT and surgery. Design This retrospective cohort study used propensity score matching (PSM) to balance baseline characteristics. Methods This study included patients with LA-ESCC who underwent NCIT and achieved R0 resection between January 2020 and December 2023, and divided them into a postoperative adjuvant radiotherapy group (PORT) and a non-adjuvant radiotherapy group (non-PORT). PSM was used to balance the two groups on covariates. The primary endpoints were to compare disease-free survival (DFS) and overall survival (OS), and to evaluate treatment-related adverse events (AEs). Results A total of 318 patients were included in the study. The 2-year DFS and OS rates in the overall population were 68.1% and 81.1%, respectively. After PSM, median DFS was 17.96 months in the non-PORT group, whereas it was not reached (NR) in the PORT group (HR=0.527, 95%CI: 0.329-0.843, p=0.007). The median OS was NR in either group, with 2-year OS rates of 83.5% and 62.0%, respectively (p=0.005). The PORT group had a higher incidence of Grade 3 and Grade 4 hematologic toxicity (25.32% vs. 18.37%), while no significant differences were observed for other Grade 3 and Grade 4 non-hematologic toxicities. Conclusions For patients with LA-ESCC who undergo NCIT and R0 resection, PORT is associated with improved DFS and shows preliminary evidence of a beneficial effect on OS, while toxicity remains within an acceptable and manageable range.
Background Obesity is a serious public health challenge known to adversely affect cancer outcomes, but its relationship with radiation-induced interstitial lung disease (RILD) in lung cancer patients is poorly investigated. Objectives This study aims to investigate the impact of obesity on RILD and identify key mediating factors. Design A multi-cohort clinical and mechanistic study. Methods A retrospective cohort (N=169) and a prospective cohort (N=87) of lung cancer patients treated between November 2018 and June 2025 were analyzed. Kaplan-Meier curves were used to estimate time to ≥ grade 2 RILD, overall survival (OS), and progression-free survival (PFS). A two-step Mendelian randomization (MR) analysis explored the mechanism by which obesity influences ILD through renin, further validated by enzyme-linked immunosorbent assay (ELISA). Results In the retrospective training cohort, overweight and obesity were associated with a higher risk of ≥ grade 2 RILD versus normal weight ( P = 0.002), with a similar trend in the prospective validation cohort ( P = 0.017). Furthermore, renin levels were higher in obesity than normal weight ( P < 0.001) and correlated with RILD grade (R = 0.670, P < 0.001). Finally, the two-step MR supported a causal effect of higher BMI on ILD (OR = 1.483, P < 0.001), partially mediated by renin (mediated proportion = 9.9%, P = 0.040). Conclusion Obesity is associated with ≥ grade 2 RILD in lung cancer patients through renin-mediated mechanisms in this study. These findings underscore the importance of risk stratification for patients with obesity and highlight renin as a potential therapeutic target for preventing and treating RILD.
Background Long-term clinical benefit from drugs targeting the programmed cell death protein 1/ligand 1 axis (anti-PD-1/PD-L1s) remains limited. Thus, identifying biomarkers of their durable efficacy is crucial. Objectives We assessed whether a serum kynurenine-to-tryptophan ratio (KYN/TRP), a surrogate of systemic indoleamine-2,3-dioxygenase 1 (IDO1) function, predicts long-term benefits of anti-PD-1/PD-L1 therapy in non-small cell lung cancer. Design Prospective observational cohort study reported in accordance with the STROBE guidelines. Methods A total of 103 patients were evaluated. Blood was collected at baseline and at the end of cycles 1, 2, 3, and 4. The concentrations of TRP, KYN, and other metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) and correlated with treatment outcomes. Results In the pembrolizumab cohort, the on-treatment KYN/TRP ratios were lower in patients with durable benefits. A low KYN/TRP ratio (≤0.0619) at the end of the fourth cycle has been associated with ≥12-month benefits (OR=20.43, p=0.008), later progression (HR=0.300, p=0.006), and death (HR=0.299, p=0.013) in multivariable analyses. No such observations were noted in the atezolizumab group. Conclusions A low KYN/TRP ratio around the third month of treatment has been identified as an exploratory biomarker candidate of long-term benefits of immunotherapy, but not in all patients. Given between-cohort differences (e.g., in smoking status), further studies are warranted to explore the determinants of the observed discrepancies.
