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Purpose Immune checkpoint inhibitors (ICIs) are integral to first-line treatment of metastatic non–small cell lung cancer (NSCLC). Circadian biology may influence antitumor immunity, raising the hypothesis that time-of-day of ICI administration could affect outcomes. We evaluated the association between initial and cumulative ICI administration time-of-day and clinical outcomes in metastatic NSCLC. Materials and Methods We conducted a retrospective cohort study of 778 patients with metastatic NSCLC treated with first-line ICI-containing therapy across Mayo Clinic sites between January 2021 and March 2024. Patients were stratified by time-of-day of first ICI administration: early (0700-1200) versus late (1201-2400). Primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end point was immune-related toxicity. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates. Exploratory analyses evaluated cumulative infusion time-of-day and alternative administration-time thresholds using spline and cut-point analyses. Results Of 778 patients, 277 received early and 501 received late initial ICI administration. Median OS was 1.33 versus 1.48 versus years and median PFS was 0.65 versus 0.67 years in the late and early groups, respectively. Time-of-day of initial ICI administration was not associated with OS (HR, 1.01 [95% CI, 0.85 to 1.20]) or PFS (HR, 1.03 [95% CI, 0.88 to 1.21]). Findings were unchanged after multivariable adjustment. Immune-related toxicity occurred in 26.9% and 24.2% of patients in the late and early groups, respectively ( P = .40). Cumulative infusion time-of-day was not associated with OS or PFS, and spline analyses identified no significant administration-time threshold associated with outcomes. Conclusion In this large real-world cohort of patients with metastatic NSCLC, neither initial nor cumulative ICI administration time-of-day was associated with survival or immune-related toxicity. Prospective studies incorporating chronotype and circadian biomarkers are warranted to further define the role of chronotherapy in immuno-oncology.

Abstract Purpose Bevacizumab is an effective treatment for radiation necrosis; dose dependent radiographic and edema response data are lacking. Methods Multicenter, retrospective cohort study of adult patients with primary central nervous system tumors or brain metastases who received bevacizumab for radiation necrosis between June 2021 and July 2024. Patients were grouped by bevacizumab dose (7.5 mg/kg vs 10 mg/kg administered every three weeks). Primary outcome was edema response, assessed by a blinded neuro-oncologist. Secondary outcomes included contrast enhancing disease response, clinical response, adverse events, treatment discontinuation, and re-dosing for recurrent radiation necrosis. Analyses were performed with and without adjustment for tumor type. Results 104 patients were included (7.5 mg/kg, n = 53; 10 mg/kg, n = 51). Edema response differed between dosing groups in unadjusted analyses (p = 0.032), favoring the 7.5 mg/kg cohort; however, this association was attenuated after adjustment for tumor type. Contrast enhancing disease response did not differ between groups in either unadjusted or adjusted analyses (p = 0.43). Clinical response was higher in the 7.5 mg/kg group (65.2% vs 37.8%, p = 0.013). Tumor type differed significantly between cohorts (p < 0.001), with more primary CNS tumors in the 10 mg/kg group. Rates of adverse events, treatment discontinuation, and re-dosing were similar. Conclusions While lower-dose bevacizumab was associated with greater edema reduction in unadjusted analyses, this effect was attenuated after accounting for tumor type. Importantly, 7.5 mg/kg dosing appeared sufficient for achieving edema control and contrast enhancing disease response. These findings support an individualized approach to bevacizumab dosing in radiation necrosis and highlight the need for prospective, tumor-stratified studies.

Abstract Background Bevacizumab is a treatment for radiation necrosis; the optimal dosing remains inadequately studied. Methods Retrospective review of adult patients with primary central nervous system (CNS) tumors or brain metastasis treated with bevacizumab for radiation necrosis from 6/29/2021 to 7/31/2024. Primary outcome was to compare edema response with two different bevacizumab doses: 7.5 mg/kg and 10 mg/kg. Edema response was classified according to the following groups: (1) increase of edema, &gt;105% of baseline; (2) constant edema, 75%-105% of baseline; (3) slight decrease of edema, 25%-75% of baseline; (4) large decrease of edema, &lt;25% of baseline. Results 104 patients were evaluated (median age 59 years, 56% male); 53 patients in the 7.5 mg/kg group and 51 patients in the 10 mg/kg group. Tumor type varied significantly across dosing groups (p &lt; 0.001). In the 7.5 mg/kg group, tumor type was primary CNS (n = 23, 43%), lung (n = 14, 26%), breast (n = 8, 15%), melanoma (n = 4, 8%) and other (n = 4, 8%). In the 10 mg/kg group, tumor type was primary CNS (n = 43, 84%), lung (n = 2, 4%), melanoma (n = 2, 4%) and other (n = 4, 8%). Median number of bevacizumab doses administered was 4. There was a statistically significant difference in distribution of edema response across all response levels favoring bevacizumab 10 mg/kg (p = 0.032). When edema response was dichotomized (large decrease vs other), the difference remained statistically significant (p = 0.015). Conclusion Bevacizumab 10 mg/kg was more efficacious in terms of edema response; this result is impacted by the significantly higher incidence of primary CNS tumors in the 10 mg/kg dosing group.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.

Abstract Background Isocitrate dehydrogenase-1 (IDH-1) inhibitor ivosidenib and dual-IDH1/2 inhibitor vorasidenib have demonstrated clinical activity in the treatment of IDH-mutant gliomas. We evaluated the efficacy of vorasidenib in patients with prior exposure to ivosidenib. Methods Retrospective review of patients with IDH-mutant glioma treated with vorasidenib who had prior treatment with ivosidenib. Previous treatments, radiographic response, and adverse events were collected and analyzed descriptively. Results Twenty-nine patients (median age 42, 34% female) were evaluated. Tumor types included IDH-mutant astrocytoma (grade 2 n = 9, 31%; grade 3 n = 3, 10%; grade 4 n = 3, 10%) and oligodendroglioma (grade 2 n = 10, 34%; grade 3 n = 4, 14%). Treatments received prior to ivosidenib included surgical resection (n = 23, 79%), radiation (n = 16, 55%), temozolomide (n = 15, 52%), procarbazine, lomustine, vincristine (PCV, n = 2, 7%), bevacizumab (n = 3, 10%), lomustine (n = 2, 7%), and pembrolizumab (n = 1, 3%). Four patients received additional treatment in between ivosidenib and vorasidenib treatment. Ten of 16 (63%) patients who experienced disease progression on ivosidenib achieved stable disease and remain on vorasidenib, while 6 (37%) had continued progression. Eleven patients with stable disease on ivosidenib transitioned to vorasidenib following FDA approval and remained without progression. Two patients who transitioned to vorasidenib due to ivosidenib-related adverse effects (diarrhea and fatigue) experienced symptom resolution and maintained disease stability. Conclusions Vorasidenib demonstrated clinical efficacy in patients with IDH-mutant gliomas previously treated with ivosidenib. Notably, stable patients who transitioned maintained disease stability, while some of those with progressive disease achieved stabilization with vorasidenib. These findings support vorasidenib as a viable therapeutic option following ivosidenib exposure.

Abstract Background Vorasidenib is Food and Drug Administration‐approved for treatment of grade 2 isocitrate dehydrogenase (IDH)–mutant gliomas and has demonstrated a benefit in progression‐free survival compared to a placebo. This study assessed the cost‐effectiveness of this treatment strategy compared to standard treatment: observation or chemoradiation (CRT). Methods The authors used an integrated Markov model to compare quality‐adjusted life‐years (QALY) gained and cost‐effectiveness of patients with IDH‐mutated low‐grade glioma (LGG) treated with vorasidenib, observation, or CRT. Outcomes were expressed as incremental cost‐effectiveness ratios (ICERs) per QALY gained. Treatment is considered cost‐effective if it meets the commonly accepted willingness‐to‐pay threshold of $100,000 per QALY gained. Results Based on model parameters, vorasidenib demonstrated an ICER of $356,756 per QALY when compared to CRT. When compared to observation, vorasidenib demonstrated an improved ICER of $215,191 per QALY. On one‐way sensitivity analysis compared to observation, median cost of vorasidenib and median overall survival were most likely to affect ICER with only marginal changes on analysis of other model factors. For ICER to become ≤$100,000 compared to observation, the cost of vorasidenib would need to drop to below $14,072 monthly or have a median survival gain of at least 11.9 years. The probabilistic sensitivity analysis demonstrated that vorasidenib was favored in none of 5000 Monte Carlo iterations. Conclusion Using the best available data, the current price of vorasidenib does not meet commonly accepted cost‐effectiveness thresholds in treatment of IDH‐mutated LGGs.

Abstract Background Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative tumors with limited treatment options at recurrence. Early studies suggest IDH inhibition has therapeutic activity. We evaluated clinical outcomes associated with IDH-1 inhibitor ivosidenib in recurrent IDH-1-mutant gliomas and molecular predictors of response. Methods We retrospectively analyzed adults treated with ivosidenib from January 2021 to August 2025 with predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted. Prior anticancer treatments, toxicities, enhancement status at ivosidenib initiation, and genomic alterations were collected. The primary endpoint was progression-free survival (PFS); secondary analyses evaluated associations between PFS, genomic complexity, and CDKN2A/B homozygous deletion. Results Ninety-two adults, median age 43, were included: 61 astrocytomas and 31 oligodendrogliomas, mostly grade 2. Before ivosidenib, 69 had surgery, 64 chemotherapy, and 64 radiation. Median time from diagnosis to ivosidenib was 4.8 years, with median of two prior progressions. Median treatment duration was 5.8 months. Median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, 14.0 and 6.9 months for oligodendroglioma grades 2-3. Increasing genomic complexity was associated with shorter PFS in univariate analysis. Patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months. Two patients with homozygous deletion had median PFS of 0.6 months. Conclusions In this retrospective analysis of predominantly recurrent IDH-1-mutant glioma, ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles. These findings support a context-dependent benefit of IDH inhibition in recurrent disease.

PURPOSE The difference in time to serum calcium normalization and rates of subsequent refractory hypocalcemia between bisphosphonates requires further investigation. Our primary objective was to assess the difference in normalization of serum calcium between pamidronate and zoledronic acid during treatment of hypercalcemia of malignancy (HCM) and rates of subsequent, refractory hypocalcemia following therapy. METHODS A retrospective review of patients with cancer who received pamidronate or zoledronic acid inpatient at Mayo Clinic for treatment of HCM between January 2018 and January 2024 was conducted. Logistic regression evaluated the association between treatment groups and outcomes. Multivariable modeling was adjusted for baseline differences, including severity of hypercalcemia. RESULTS We evaluated 856 patients. The median age was 68 (IQR, 59-75) years, and 476 (55.6%) were male. The most common cancer diagnoses were lymphoma (n = 158, 18.5%), followed by multiple myeloma (n = 145, 16.9%) and lung cancer (n = 111, 13%). Overall, 292 (46.8%) patients and 154 (32.8%) patients achieved serum calcium normalization by hospital day 4 and day 7, respectively. The rate of normalization was similar between all bisphosphonates, regardless of pamidronate dose. Significantly higher rates of hypocalcemia were observed on day 4 for patients who received zoledronic acid 4 mg once compared with either dose (60 mg once and 90 mg once) of pamidronate (40.7% v 27.6% v 26.8%, P = .049, respectively). No significant difference in rates of hypocalcemia were observed on day 7 (56.8% v 50% v 42.9%, P = .26, respectively) and day 30 (39.1% v 39.0% v 37.5%, P = .50, respectively). CONCLUSION Bisphosphonates were equally efficacious in normalizing serum calcium in patients with HCM. Pamidronate 90 mg was not more efficacious than 60 mg. Rates of refractory hypocalcemia were similar.

Abstract BACKGROUND The IDH inhibitor vorasidenib was FDA-approved for treatment of IDH-mutant grade 2 gliomas in August 2024. We evaluated vorasidenib in patients with grade 3 and 4 IDH-mutant gliomas who would not have been eligible for the INDIGO trial. METHODS Retrospective review of patients with grade 3 or 4 IDH-mutant gliomas treated with vorasidenib between 9/1/24 and 5/31/25. Prior treatments, radiographic response, adverse events and seizure control were collected for each patient. RESULTS Thirty-two patients (median age 39.5, 46.9% female) met inclusion criteria. Tumor types included grade 3 oligodendroglioma (11, 34.4%), grade 3 astrocytoma (13, 40.6%) and grade 4 astrocytoma (8, 25%). Thirty patients had contrast-enhancement; 2 patients had non-enhancing tumor. Prior treatments included surgical resection (30, 93.8%), radiation (27, 84.4%), cytotoxic chemotherapy (25, 78.1%), bevacizumab (5, 15.6%), pembrolizumab (3, 9.4%), and ivosidenib (8, 25%). Four patients (12.5%) were naïve to systemic treatment at the time of vorasidenib initiation. Median duration of vorasidenib was 101.5 days (range 18-255) with 19 patients still on vorasidenib at the time of last follow-up. Seventeen patients (53.1%) had stable disease, 11 (34.4%) had progressive disease, 2 (6.3%) did not yet have response assessment, and 2 (6.3%) died. Grade 1 transaminitis occurred in 12 patients with no high grade transaminitis. Two patients developed lymphopenia; both were heavily pre-treated with multiple alkylating agents; no other hematologic toxicity was noted. One patient developed myalgias leading to vorasidenib discontinuation. Nine patients had fatigue, 4 headaches, 2 nausea, 2 decreased appetite. In patients with a history of epilepsy, there were no reported seizures. CONCLUSIONS Vorasidenib was well-tolerated in this heavily pre-treated cohort of grade 3–4 IDH-mutant gliomas, with low-grade transaminitis and fatigue being the most common toxicities. Preliminary results show disease stability in 53.1% of patients after a median of 3.5 months. Conclusions are limited by short-interval follow-up.