KRAS G12C mutations occur in approximately 11

The abscopal effect, first described in 1953, refers to the regression of distant, non-irradiated tumors following localized therapy. Historically considered rare, interest in this phenomenon has increased with the introduction of immunotherapy and local treatments for non-small cell lung cancer (NSCLC). This review summarizes the current evidence on the pathophysiology, clinical observations, and assessment of the abscopal effect in NSCLC following radiotherapy, lung ablation, and combined multimodality therapies. Preclinical and early clinical studies suggest that radiotherapy and ablative techniques such as cryoablation, microwave ablation, and pulsed electric field therapy may induce immunogenic cell death, leading to the release of tumor antigens and danger-associated molecular patterns that can activate systemic antitumor immune responses. When combined with immune checkpoint inhibitors, these local therapies may enhance immune activation, potentially improving both local and distant tumor control. However, recognition of abscopal effects remains inconsistent, largely due to limitations of conventional response assessment criteria. While iRECIST partly captures atypical response patterns, unequivocal out-of-field tumor regression is not systematically recorded in most clinical trials. The available evidence, primarily from preclinical models and early-phase studies, suggests that the true incidence of abscopal effects in NSCLC may be underrecognized. Accordingly, we propose a working definition of the abscopal effect in NSCLC: the regression (complete or partial response by iRECIST) of one or more non-irradiated lesions distant from the primary treatment site, occurring after localized therapy with or without systemic treatment, and confirmed by follow-up imaging within 4–8 weeks. Establishing standardized terminology and assessment criteria will be essential for accurately identifying and integrating potential abscopal responses in future NSCLC research and clinical practice.

Investigator response assessment of non-irradiated lesions, per modified itRECIST

Investigator response assessment of irradiated lesions, per modified itRECIST

Preclinical pharmacodynamic evaluation (groups)

PURPOSE:We present the preclinical rationale and clinical data from a phase 1b trial investigating the STING agonist dazostinag plus pembrolizumab following hypofractionated radiotherapy (RT) in patients with advanced non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous cell carcinoma of the head and neck (SCCHN) whose disease had progressed on prior checkpoint inhibitors (CPI; NCT04879849). PATIENTS AND METHODS:Eligible patients received radiation (8 Gy × 3 fractions) followed (≥40 hours) by pembrolizumab 200 mg every 3 weeks and dazostinag in escalating doses (0.2-5.0 mg). Primary endpoints were safety and tolerability. Secondary endpoints included preliminary antitumor activity in irradiated and nonirradiated lesions, pharmacokinetic analyses, and pharmacodynamic analyses. RESULTS:Preclinical studies demonstrated tumor control and enhanced intratumoral immune activation in mice treated with dazostinag plus radiation. Thirty-four patients (NSCLC: 15, SCCHN: 10, and TNBC: 9) with a median number of six prior treatments were enrolled. Thirty-three (97.1%) patients reported treatment-emergent adverse events (TEAE), none were dose-limiting toxicities; the most common were fatigue (52.9%), constipation (26.5%), and cough (20.6%). Dazostinag-related TEAEs occurred in 17 patients (50.0%); the most common were fatigue (26.5%), chills (8.8%), diarrhea, arthralgia, and myalgia (5.9% each). Antitumor activity, per RECIST v.1.1, was confirmed in two (7.1%) patients (one complete response and one partial response). Pharmacodynamic analyses indicated activation of STING and IFNγ pathways across multiple dose levels and induced immune responses, consistent with preclinical studies. CONCLUSIONS:Dazostinag, combined with pembrolizumab after RT, was well tolerated and demonstrated clinical activity in some patients with advanced/metastatic tumors whose disease had progressed on CPIs. SIGNIFICANCE:Dazostinag, an intravenous STING agonist, combined with radiation, demonstrated tumor control and enhanced intratumoral immune activation, preclinically. In phase 1b, dazostinag plus pembrolizumab following RT had a manageable safety profile and provided clinical benefit for some heavily pretreated patients with advanced/metastatic solid tumors whose disease had progressed on CPIs.

Purpose:The goal of this study is to report the feasibility and outcomes of hypofractionated proton reirradiation in patients with recurrent thoracic tumors. Materials and Methods:Data were retrospectively collected for patients who received hypofractionated proton therapy for recurrent lung cancer at a single facility. Proton reirradiation was delivered using a total of 15 fractions. Patient and tumor characteristics, adverse events, and dose-volume histogram parameters were collected and analyzed descriptively. Tumor control and patient survival were analyzed using Kaplan-Meier statistics. Univariate logistic regression was performed to analyze the relationship between dose-volume histogram parameters and acute and late toxicity. Results:Thirty-one patients who received thoracic proton reirradiation were included. The median patient age was 71.4. Most patients (77.4%) were treated to a total of 60 Gy (RBE) in 15 fractions and had tumors smaller than 50 cc (64.5%). The median interval between the 2 radiation courses was 21.3 months (2.9-227.1). Twenty-one out of 31 plans (67.7%) successfully reached a target PTV coverage with V95% > 95%. Complete prior plan dosimetric information was available for 19 out of 31 plans. The median value of the equivalent dose in 2 Gy (RBE) fractions (EQD2) from the plan sum for the lung V20 Gy (RBE) was 24.9%, and for the V5 Gy (RBE) was 44.8%. The median follow-up was 9.0 months. One-year local, regional, and distant control were 92.3% (95% CI 78.9-100), 71.1% (95% CI 52.1-97.0), and 80.6% (95% CI 64.6-100), respectively. Only two patients experienced grade 3 or higher acute or late toxicities. Acute esophagitis was associated with the esophagus Dmax (P = .031) and Dmean (P = .041). Conclusion:This study demonstrates the feasibility and efficacy of a hypofractionated course of proton reirradiation for recurrent thoracic tumors. Data availability:The data that support the findings of this study are available on request from the corresponding author.

Leptomeningeal metastases (LM) can cause debilitating neurologic symptoms and are associated with a poor prognosis. Compared to involved-field radiation therapy, craniospinal irradiation (CSI) improves progression free survival and overall survival. Recent studies have shown that inhibiting the receptor for advanced glycation end-products (RAGE) may mitigate tumorigenesis, neuroinflammation, and potentiate response to radiation. This trial assesses the safety of concurrent Azeliragon, an oral RAGE inhibitor, with CSI. We designed a single institution, open-label, phase IB trial assessing the safety of concurrent Azeliragon with CSI in patients with LM (NCT06724926). Patients with KPS ≥60 and progressive radiographic and/or CSF cytologic diagnosis of LM from a solid tumor or primary CNS high-grade glioma are eligible. In the dose finding phase, a 3 + 3 design is used to determine the recommended dose of Azeliragon. In this phase, 6-18 patients will be enrolled and given a loading dose of Azeliragon 7 days prior to starting 14 days of concurrent Azeliragon and CSI, followed by 7 days of adjuvant Azeliragon. Once the recommended dose is identified, an additional 14 patients will be enrolled in the dose expansion phase. CSI will be delivered with protons or VMAT photons to a dose of 30 Gy in 10 fractions per investigator’s choice. The primary objective is to determine the safety profile of concurrent Azeliragon and CSI. The secondary objective is to estimate CNS progression free survival and overall survival. Time-to event outcomes will be analyzed with Kaplan-Meier curves. Patient and disease characteristics will be analyzed descriptively. This study was activated on 2/19/2025 with 6 patients (2 patients with metastatic solid tumors and 4 patients with high grade gliomas) enrolled at time of submission.

Preclinical efficacy study (groups)

Most common AEs (all-cause) ≥10% overall patients (safety population).

Investigator response assessment of best overall response, per modified itRECIST

Radiation recall dermatitis is a known but rare adverse effect that is characterized by the development of dermatitis in the region of prior irradiated tissue triggered by exposure to a systemic agent. Capivasertib is a small-molecule inhibitor targeting the phosphatidylinositol 3-kinase/protein kinase B pathway recently approved in locally advanced and metastatic breast cancer; however, the safety of its use in the setting of palliative radiation is currently unclear. Here, we report a case of radiation recall dermatitis in a patient with metastatic breast cancer on capivasertib with history of radiation to the right lower extremity managed with corticosteroids, antibiotics, and switching to alpelisib.

Overview of AEs (safety population).

Best overall response, per RECIST v.1.1 criteria (response-evaluable population).

PurposeRadiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex.Methods and MaterialsWe conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity.ResultsOf 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P = .04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P = .03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events.ConclusionsThis report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal.

A strong understanding of radiation techniques, including CRT and SBRT, and the expected posttherapy imaging manifestations enables more confident and accurate interpretations of surveillance CT imaging studies in patients with prior RT. Knowledge of common complications and corresponding CT imaging appearances, particularly tumor recurrence and infection, leads to more accurate diagnoses, timely treatment, and avoidance of pitfalls in interpretation.

BACKGROUND AND OBJECTIVES:Stereotactic radiosurgery (SRS) is effective for patients with medically refractory trigeminal neuralgia with a 75%-90% response rate. Consideration of the integral dose (ID) to the target nerve within the 50% isodose line was reported to help select prescription doses to maximize effectiveness and minimize bothersome numbness. The objective of this study was to externally validate the ID as a predictor of outcomes after SRS. METHODS:We reviewed the outcomes and parameters of 94 consecutive patients of type 1 trigeminal neuralgia who had SRS for the first time where nerve ID was calculated. 70% of the prescription doses were 80 Gy, with 28% at 85 Gy, and 2% at 70 Gy. RESULTS:The median follow-up time was 14.4 months. A total of 85 (90%) patients reported significant pain relief (Barrow Neurological Institute I-III) after initial SRS. The median pain recurrence-free survival was 82 months (95% CI 41.1-NA), and estimates at 1, 3, and 5 years were 80.5%, 65.5%, and 55.9%, respectively. The ID was not significantly associated with initial pain relief, or affect the risk of pain recurrence or sensory dysfunction after SRS using the Cox proportional hazards model. A nerve mean dose ≥65 Gy was associated with a reduced risk of pain recurrence on multivariate analysis (hazard ratio 0.408, P = .039). Twenty (21%) patients experienced sensory dysfunction after SRS with 3 (3%) requiring further medications, which was not correlated with the prescription dose or brainstem maximum dose. CONCLUSION:The ID did not predict recurrence-free survival or sensory dysfunction. Our observations suggest improved nerve coverage by the most powerful area of the isocenter, for instance, by targeting a narrower segment if feasible, could result in more durable pain relief. Further studies to validate these findings are needed.

A 64-year-old male smoker (0.25 packs per day for 40 years) with known chronic obstructive pulmonary disease (COPD) (forced expiratory volume < 1 L) undergoing surveillance imaging for multiple indeterminate lung nodules since 2019 was found to have a growing fludeoxyglucose-18 avid right posteromedial upper lobe spiculated nodule on imaging in 2022. He underwent computed tomography (CT)-guided biopsy demonstrating adenocarcinoma, epidermal growth factor receptor equivocal, anaplastic lymphoma kinase negative, programmed death ligand 1 of 5%, and next-generation sequencing negative for actionable mutations. Positron emission tomography CT showed 2 additional fludeoxyglucose-18 avid suspicious nodules: left anterior upper lobe and right posterolateral upper lobe. After multidisciplinary discussion, it was decided to treat the largest right posteromedial nodule first, assess response and adverse effects, and treat additional lesions as tolerated.