Campian, Jian

Abstract Despite intensive research over the past two decades, all glioblastoma (GBM) Phase 3 drug trials have been negative. The utility of the preclinical studies used to inform development for 10 Phase 3 trials was evaluated by four criteria: 1) drug distribution to the brain, 2) tumor location (flank vs. intracranial), 3) GBM xenograft source (patient-derived (PD) vs. cell line-derived (CD)), and 4) magnitude of survival extension. For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%. B/P for imatinib was 1-3% and the other four drugs ranged from 25% to 51%. Except for enzastaurin, all drugs were studied in orthotopic tumor survival studies. The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide. However, only veliparib and sunitinib were studied in orthotopic PD models, and a single CD model (U87 or D54) was used exclusively for four drugs (enzastaurin, nimotuzumab, sunitinib, marizomib). In summary, 6 of 10 drugs had unknown or very poor brain distribution, 8 of 10 drugs were tested exclusively in CD models, which have questionable translational value, and 3 of 10 drugs had nominal activity (<50% survival prolongation) in preclinical survival studies. The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into advanced clinical testing.

Abstract BACKGROUND Cognitive symptoms are common among cancer patients treated with intracranial radiation but inadequately assessed and suboptimally treated, owing in part to the time-consuming and resource-intensive nature of formal neuropsychological testing. Through remote administration of brief cognitive assessments and symptom-directed interventions, decentralization uniquely addresses this problem. METHODS In this single-site phase 2 fully decentralized clinical trial (NCT06377696), patients treated with radiation therapy (RT) for primary or metastatic brain tumors undergo cognitive evaluations with the application, Mayo Test Drive, and the Short Test of Mental Status (STMS; via telehealth or in person), at baseline and every three months for one year. Participants are provided wearable devices for health promotion. Half the participants are randomized to metformin to evaluate this agent’s efficacy in treating RT-related cognitive symptoms. Target enrollment is 100 participants. RESULTS Seventy-three patients (median age 45.5, 46% female) with brain tumors who received RT were enrolled May 2024 to May 2025. In this unplanned interim analysis, we evaluated the impact of decentralization on study participation. Thirty-six participants (49%) reported a primary residence greater than 150 miles from our institution. Seven patients were consented remotely, the remainder in person. Of 380 study-related visits (201 STMS, 179 treatment toxicity checks) 216 (57%) were completed by telehealth. Thirty-two of 336 (9.5%) study-related lab draws were completed at locations outside our institution. Wearable device data was continuously collected, with median 3022 steps tracked per patient per day on study. 190/250 (76%) quality-of-life surveys sent digitally were completed to date. CONCLUSION Decentralization implemented as part of this clinical trial enabled participation despite significant distance from our institution and facilitated study-related assessments through digital solutions, eliminating the need for travel. Our findings demonstrate the feasibility of conducting a fully decentralized supportive care trial in neuro-oncology, which can increase participation and accelerate evaluation of novel therapeutics.

Abstract BACKGROUND Access to in-person evaluations is challenging for patients with glioma due to disease-related disability and distance from specialized neuro-oncology centers. Telehealth is an alternative to in-person evaluations, but acceptability of and therapy compliance with this model has not been prospectively evaluated. METHODS In this single-arm non-randomized pragmatic clinical trial, we compared patient satisfaction with telehealth and in-person assessments among patients with glioma undergoing chemotherapy with temozolomide. Participants acted as their own controls, alternating between telehealth and in-person visits. Patient satisfaction with care delivered was evaluated by Press-Ganey surveys with Likert response scales (1-5, 1=very poor, 5=very good). A digital pill diary (DPD) was implemented to track chemotherapy compliance. RESULTS We accrued 30 patients (median age 59, 38% female) between October 2024 and May 2025. Half of the patients (n=15) reported a primary residence greater than 150 miles from our institution. Surveys from 25 participants were reviewed, with 17/25 completing one or more surveys following an in-person visit, and 21/25 completing one or more surveys following a telehealth visit. Overall average Press-Ganey scores were similar between the two visit modalities with high scores (telehealth=4.8; in-person=4.7). Median scores for specific modalities were similarly highly rated: likelihood of recommending practice to others (telehealth=5.0; in-person=5.0), concern the care provider showed (telehealth=5.0, in-person=4.7), provider’s discussion of treatment options (telehealth=5.0, in-person=5.0), provider effort to include patients in decision-making (telehealth=5.0, in-person=5.0). DPDs used to monitor treatment compliance indicated adherence to all prescribed doses of temozolomide in 75/79 cycles; the other 4 (of 79) treatment cycles were halted per provider instructions. CONCLUSION This interim assessment demonstrates feasibility of treating patients with similar patient satisfaction of care delivered between telehealth and in-person visits. The DPD was effective in tracking chemotherapy administration. Additional results including visit type preference and acute care utilization data are maturing.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (>40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.

Abstract BACKGROUND Pembrolizumab is FDA approved for solid tumors with high tumor mutation burden (TMB) and may thus have efficacy in hypermutant glioma. This study aimed to identify factors influencing efficacy of pembrolizumab in recurrent glioma. METHODS This retrospective study at Mayo Clinic included patients with adult-type diffuse gliomas who received pembrolizumab (≥2 cycles) for recurrent disease (01/01/2014–05/01/2025). The Mayo Clinic Solid Tumor Panel (MCSTP), which uses the Illumina TruSight Oncology 500 High-Throughput next-generation sequencing (NGS) assay, was also used to assess the molecular characteristics of the recurrent tumors. Responders to pembrolizumab were defined as patients who did not meet RANO 2.0 criteria for progressive disease on first radiographic response assessment. Progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox-Regression analyses. RESULTS Sixty-two patients were identified (median age: 46 years; 65% male; 94% white). All patients received pembrolizumab and had prior alkylating chemotherapy. The median PFS from pembrolizumab initiation was 2.3 months. Twenty-five (40%) patients were responders. Patients with IDH-mutant, 1p/19q co-deleted gliomas (OLIGO, n=13) had a longer PFS (4.3 months) than IDH wildtype gliomas (IDH-WT, n=33, 2.2 months, p=0.012) and IDH-mutant, 1p/19q non-co-deleted (IDH-MUT, n=16, 1.7 months, p=0.0006). The proportion of responders was significantly greater in OLIGO patients (IDH-WT, 33%; IDH-MUT, 19%; OLIGO, 85%, p=0.0008). Overall PFS was not impacted by patient age, sex, or extent of initial resection. Twenty-nine percent of patient tumors tested thus far (6/21) had a high TMB (≥10 mut/Mb). Two-thirds (4/6) of high TMB patients were responders, while only one-third (5/15) of low TMB patients were responders. CONCLUSIONS Patients with recurrent OLIGO may have a longer PFS with pembrolizumab therapy than IDH-WT and IDH-MUT. Furthermore, high TMB may be associated with longer PFS with pembrolizumab therapy in glioma. Additional patients are being assessed using MCSTP (total expected n=43); complete data will be presented.

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.

Abstract Glioblastoma is a highly lethal malignancy with dismal overall survival and near universal recurrence despite maximal multimodal therapy. Patients with unmethylated O6-methylguanine methyltransferase (MGMT) promoters do not derive survival benefit from adjuvant temozolomide. Immunotherapies have revolutionized cancer care; however, this modality has yet to translate into survival benefits in glioblastoma in part due to both local and systemic immunosuppressive states. Here, we report the results of a phase 1 clinical trial (NCT04015700) evaluating the safety and feasibility of GNOS-PV01, a personalized DNA vaccination platform that safely immunized against up to 40 patient-specific neoantigens in a clinically relevant timescale following surgical resection and radiation for MGMT-unmethylated glioblastoma patients. Multisector tumor sampling at time of resection enabled personalized and spatially representative neoantigen identification through an established pipeline. In the nine participants receiving vaccines, there were no unexpected toxicities or serious adverse events with a median vaccine delivery time of 10 weeks post-radiation. The vaccination was strongly immunogenic and induced activation and expansion of both local infiltrating CD8+ and CD4+ T-cells and circulating peripheral T-cells. T-cell receptor sequencing revealed both expanded pre-existing populations as well as novel neoantigen-specific populations, suggesting that vaccination both reinvigorates pre-existing immunity and generates novel immune reactivity. We developed a new technology to profile T-cells at single-nuclei resolution from frozen tissue revealing that vaccination altered gene expression signatures involved in inflammatory response and lymphocyte activation in the tumor microenvironment. Exposure to dexamethasone greatly suppressed immune reactivity, while PD-1 blockade enhanced local immune responses. With respect to efficacy, one third of patients survived longer than 24 months with one long-term survivor living >40 months from time of diagnosis, exceeding survival of recently published trials. Thus, our study demonstrates the safety, feasibility, and preliminary clinical efficacy of a personalized multivalent neoantigen vaccination platform in a devastating cancer.

Abstract BACKGROUND Pembrolizumab elicits durable responses in many solid tumors, yet activity in gliomas has been limited. Lymphopenia has been reported in association with reduced survival and a shorter time to progression on checkpoint inhibition in other solid tumors. We evaluated whether low absolute lymphocyte count (ALC) is related to worse outcomes in pembrolizumab-treated patients with gliomas. METHODS In this single-center retrospective study, we identified adults with gliomas who received ≥1 dose of pembrolizumab and had available lymphocyte counts at our center between 05/01/2018 and 1/31/2025. Patients’ demographics, dexamethasone use, baseline ALC (before initiation of pembrolizumab), and clinical outcomes were collected. Overall Survival (OS) was estimated using Kaplan–Meier analysis from the date of starting pembrolizumab to the date of death. RESULTS Ninety patients met eligibility criteria (glioblastoma [GBM] n = 44, astrocytoma n = 20, oligodendroglioma n = 13, meningioma n = 8, other n = 5); 62% were male and 31% (n = 28) harbored IDH-mutant tumors. Across all histological subtypes, baseline ALC<750 cells/mm³ was associated with significantly shorter OS compared to baseline ALC≥750 cells/mm³ (3.7 vs 7.7 months, P = 0.0063) with similar dexamethasone exposure (63% vs 52%). In the recurrent GBM subgroup (n = 43; MGMT-methylated 26%), ALC≥750 cells/mm³ correlated with longer OS (8.5 vs 3.4 months, P = 0.0065) with a slightly lower proportion of patients on dexamethasone in high ALC group (52% vs 75%). Conversely, among patients with IDH-mutant gliomas (n = 28), no significant difference in OS was observed based on ALC levels (7.8 vs. 7.3 months, P = 0.58) with similar dexamethasone use (57% and 43% in high and low ALC groups, respectively). CONCLUSION Baseline lymphopenia preceding pembrolizumab treatment is associated with shorter OS in patients with GBM, but not in IDH-mutant gliomas. These associations require further validation in additional patient cohorts.