Beow Y. Yeap

Purpose: MTAP loss co-occurs with actionable genomic alterations in NSCLC and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established. Experimental Design: We assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring EGFR or KRAS mutations or ALK rearrangements. Results: Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 42 (17%) specimens, including 17 (13%) early-stage and 22 (20%) metastatic specimens. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty-one (64%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 inhibitor sensitivity. TKI + PRMT5 inhibitor combos had greater activity than monotherapy. Conclusions: MTAP loss occurs in 17% of NSCLC, including 24% of oncogene-driven tumors. PRMT5 inhibitor activity is independent of TKI exposure and SDMA expression and enhanced by TKI therapy. These findings support evaluation of PRMT5 inhibitor + TKIs in oncogene-driven NSCLC.

Purpose: Immune checkpoint inhibitors (ICI) have significantly altered the natural history of microsatellite instability (MSI)–high metastatic colorectal cancer (mCRC). For microsatellite-stable (MSS) refractory mCRC, ICIs recently demonstrated efficacy signals in patients without liver metastases. This study evaluated combined radiotherapy (RT) and ICI therapy in MSS mCRC. Patients and Methods: This multi-institution, open-label, single-arm phase II study enrolled patients with MSS mCRC previously treated with oxaliplatin, 5-fluorouracil, and irinotecan. Patients received combined RT and nivolumab/ipilimumab. The primary endpoint was the objective response rate (ORR) for unirradiated lesions. Secondary endpoints included the disease control rate (DCR) for unirradiated lesions, DCR and ORR of irradiated lesions, treatment-related adverse event (AE) rates, progression-free survival (PFS), and overall survival (OS). Results: Among 30 patients treated, the confirmed ORR was 10%. The DCR was 33.3% and the ORR was 10% in unirradiated lesions, whereas in irradiated lesions the ORR was 13.3% and the DCR was 83.3%. In eight patients without active liver metastases, the ORR was 25% [95% confidence interval (CI), 3.2%–65.1%], whereas in 22 patients with liver metastases the ORR was 4.6% (95% CI, 0.1%–22.8%). The median PFS was 2.4 months at a median follow-up of 19.8 months. The median OS of the cohort was 12.8 months (95% CI, 6.8–17.9 months). Treatment was tolerable, and only 10% of patients experienced grade 4 toxicity, which in all cases was lymphopenia. Conclusions: The combination of immunomodulating, nonablative doses of RT with ipilimumab and nivolumab has selective clinical activity in refractory MSS CRC, with responses concentrated primarily in patients without active liver metastases. Trial Registration: This trial is registered under the name “Nivolumab + Ipilimumab + RT in MSS mCRC” (ClinicalTrials.gov Identifier: NCT04575922).

Purpose: To evaluate long-term outcomes and determine whether longitudinal plasma profiling provides biological insight into disease progression after proton hypofractionated ablative radiation therapy (HART) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Patients and Methods: In this single-arm, multi-institutional phase II trial, 92 patients with localized unresectable HCC or ICC with Child-Pugh class A/B liver function received HART (up to 67.5 GyE in 15 fractions). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Plasma samples were collected at baseline, days 1, 8, 15, and 1-month after treatment for exploratory correlative analyses. Results: Among evaluable patients (44 HCC, 39 ICC), median OS was 29.2 months (HCC) and 20.8 months (ICC), with 5-year OS rates of 25.9% and 12.3%, respectively. Median PFS was 13.8 months (HCC) and 8.4 months (ICC). In-field local failure occurred in 2 HCC (4.5%) and 7 ICC (17.9%) patients, whereas out-of-field intrahepatic/distant progression remained the predominant pattern of failure. No grade >3 treatment-related toxicities were observed. Exploratory plasma profiling identified distinct biological signatures associated with progression: HCC was characterized by markers of hypoxia, inflammation, vascular remodeling, stromal activation, and hepatic regeneration, whereas associations in ICC predominantly involved signatures of hypoxia and vascular remodeling. Conclusions: HART provides durable long-term in-field local control with minimal toxicity, but disease progression remains predominantly out-of-field intrahepatic/distant. Exploratory correlative analyses suggest that biological signatures reflecting vascular remodeling, hypoxia, inflammation, stromal activation, and hepatic reserve are associated with progression despite successful local therapy, informing future translational studies and combination strategies.

Retinoblastoma is the most common primary intraocular neoplasm in children. Use of radiotherapy has decreased due to the incidence of second malignant neoplasms (SMNs). In our study, photon ( n = 42) and proton ( n = 66) radiotherapy cohorts had median follow‐up of 28.7 and 18.2 years, respectively. The majority of patients (74%) had bilateral disease at diagnosis. Proton radiotherapy is associated with significantly lower cumulative incidence of in‐field SMNs (0% vs. 11.1% at 15 years, p = 0.005), with three additional cases occurring > 20 years after photon radiotherapy. These findings suggest that when radiotherapy is indicated for patients with bilateral retinoblastoma, proton radiotherapy should be considered when feasible.

Study Representativeness Table.

Organs at risk dose constraints.

Purpose:Outcomes for grade 2 and 3 meningiomas are poor. A few studies suggest a benefit from radiotherapy dose escalation. This trial evaluates the safety and efficacy of dose escalation with intensity-modulated proton therapy (IMPT) for grade 2 and 3 meningiomas. Patients and Methods:This prospective single-arm phase I trial enrolled patients with grade 2 meningioma with residual disease or recurrence or patients with grade 3 meningioma after gross total resection. Patients underwent dose-escalated IMPT to 66 Gy relative biological effectiveness [Gy(RBE)] for grade 2 gross disease and 63 Gy(RBE) for grade 3 tumor beds. The primary endpoint was acute dose-limiting toxicity (DLT). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and late toxicity. Results:Twenty-one patients with 16 grade 2 and 5 grade 3 meningiomas were enrolled and treated between 2016 and 2023. The median clinical and radiographic follow-up periods were 3.4 and 3.2 years, respectively. No DLT was observed. Five new late grade 3 toxicities occurred in four patients. Three treatment failures were observed in two grade 2 and one grade 3 tumors. Two deaths occurred in patients with grade 2 meningiomas. The 1-, 2-, and 3-year PFS rates were 100%, 95%, and 88.2%, respectively. The corresponding OS rates were 100%, 95%, and 95%, respectively. Conclusions:This first prospective trial investigating dose-escalated IMPT for high-grade meningiomas demonstrated a favorable early safety profile and clinical outcomes. Phase II and III studies are warranted to confirm the superiority of dose escalation for high-grade meningiomas.

Overall survival. A: Complete cohort. B: Stratified by WHO grading. C: Stratified by treatment indication.

Local failure rates, progression-free survival, and overall survival.

Supplementary Figure S10 shows the fraction of DLL3 positive cells for subtype SCLC-A and SCLC-N.