Navigating restriction from interstitial lung disease (ILD) with stereotactic ablative radiotherapy (SABR) in early-stage non-small cell lung cancer: soaring beyond the current treatment paradigm

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte–macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan–Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0–58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1–not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0–NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4–26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7–NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

Introduction: Immune checkpoint inhibitors (ICI) effectively treat advanced cutaneous squamous cell carcinoma (cSCC), yet some patients continue to have disease progression. Combining radiation therapy (RT) with ICI represents a potential therapeutic option, yet limited data exist regarding oncologic outcomes and safety profile. Methods: This retrospective cohort study examined patients treated with concurrent ICI and RT between April 2019 and November 2022 and stratified by locally advanced or metastatic status. Outcomes included locoregional control (LRC), freedom from distant metastases (FFDM), progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analysis was performed using Kaplan-Meier or Fine-Gray competing risk survival analyses. Results: Thirteen patients (median age 77 years) with locally advanced (53.8%) or metastatic (46.2%) cSCC on cemiplimab (84.6%) or pembrolizumab (15.4%) received concomitant RT using intensity-modulated radiotherapy (69.2%) or stereotactic body radiotherapy (30.8%). With median follow-up of 15.4 months, overall 1-year and 2-year outcomes were OS: 75.2% and 62.7%; PFS: 59.8% and 25.6%; FFDM: 83.8% and 62.4%; LRC 100% and 84.3%, respectively. Locally advanced patients had significantly greater LRC than metastatic patients (100% vs . 56.3%; p<0.001), but no significant difference in PFS, FFDM, or OS. Only one patient experienced grade 3 radiation dermatitis, with no grade 4+ toxicities. Conclusion: Radioimmunotherapy demonstrated favorable oncologic outcomes with minimal toxicity. Addition of consolidative RT to ICI therapy may represent a safe and effective approach for this challenging patient population, warranting further prospective investigation.

Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAF^V600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAF^V600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAF^V600E and TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAF^V600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients.

Lung cancer is one of the most common malignancies and causes the most cancer deaths in the United States. Targeted therapies have improved the survival of patients with advanced disease. Neurotrophic tropomyosin receptor kinase (NTRK) fusions are a rare oncogenic driver that has been targeted with the tumor-agnostic drug, larotrectinib. There are limited data on the treatment of non-small-cell lung cancer (NSCLC) with larotrectinib because of the rarity of this fusion in this population. We present the case of a patient who was diagnosed with SQSTM1-NTRK1 fused NSCLC with polymetastatic disease involving the brain and subsequently treated with a multidisciplinary approach via neurosurgical resection, radiotherapy, and larotrectinib. The combination of aggressive local treatments and systemic therapy is a relatively new treatment paradigm and represents a new area of research to optimize local control of metastatic lesions and potentially improve progression-free survival compared to the trials that show the efficacy of systemic monotherapies. The patient has experienced a sustained complete response to treatment almost 3 years later, and he has tolerated the drug without any significant adverse effects. The combination of systemic therapy with larotrectinib and aggressive local treatments could benefit patients with targetable fusions even with multiple metastatic lesions.