Fell, Geoffrey

Abstract INTRODUCTION Brigatinib is an oral ALK inhibitor that inhibits multiple tyrosine kinases. We previously published outcomes of patients with NF2-related schwannomatosis treated with brigatinib for a median of 10.4 months. We report updated results of these patients with extended follow-up. METHODS This multicenter, phase II, open-label study included participants ≥12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Patients were treated with brigatinib 180 mg daily. Patients discontinued treatment upon progression of target tumors but could continue treatment with isolated progression of non-target tumors if deemed clinically acceptable by the treating team and patient. One target and up to 5 non-target tumors were followed in each participant. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter with radiographic response (RR) defined as ≥20% decrease in volume compared to baseline. RESULTS Forty participants were treated for a median of 23 months (range, 3-40 months). Updated imaging data is available on 162 tumors (45 VS, 59 non-VS, 53 meningiomas, and 5 ependymomas). RR rate for all tumors was 28% and was 31% for non-VS, 28% for meningioma, 22% for VS, and 60% for ependymomas. The 12-month freedom from tumor progression was 77.1% for all tumors, 81.5% for non-VS, 78.1% for meningioma, 69.2% for VS, and 100.0% for ependymoma. The 24-month freedom from tumor progression was 73% for all tumors, 81.3% for non-VS, 72.4% for meningioma, 62.4% for VS, and 100.0% for ependymoma. There were no grade 4/5 treatment-related adverse events (AEs). The most common AEs were diarrhea (65%), nausea (40%), muscle cramps (40%), hypertension (35%), increased LDH (35%), increased AST (33%), and increased ALT (25%). CONCLUSION Brigatinib treatment was associated with high rates of tumor stability at 24 months across multiple tumor types in patients with NF2-related schwannomatosis.

Abstract BACKGROUND Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. METHODS INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects. RESULTS On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA. CONCLUSION In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.

Abstract INTRODUCTION NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases. METHODS This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2. RESULTS Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%). CONCLUSION Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.

PURPOSE The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid–dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS Patients with newly diagnosed O 6 -methylguanine–DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780 ). RESULTS Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05). CONCLUSION The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP), an emerging biomarker for personalized risk-directed interventions, is increased in cancer survivors. However, little is known about patient preferences for CHIP testing. We surveyed participants in a prospective cohort study of young women with breast cancer (BC). The emailed survey included an introduction to CHIP and a vignette eliciting participants’ preferences for CHIP testing, considering sequentially: population-based 10-year risk of BC recurrence, hematologic malignancy, and heart disease; increased CHIP-associated risks; current CHIP management; dedicated CHIP clinic; and hypothetical CHIP treatment. Preference changes were evaluated using the McNemar test. The survey response rate was 82.2% (528/642). Median age at time of survey was 46 years and median time from diagnosis was 108 months. Only 5.9% had prior knowledge of CHIP. After vignette presentation, most survivors (87.1%) recommended CHIP testing for the vignette patient. Presented next with CHIP-independent, population-based risks, 11.1% shifted their preference from testing to not testing. After receiving information about CHIP-associated risks, an additional 10.1% shifted their preference to testing. Preference for testing increased if vignette patient was offered a CHIP clinic or hypothetical CHIP treatment, with 7.2% and 14.1% switching preferences toward testing, respectively. Finally, 75.8% of participants desired CHIP testing for themselves. Among participants, 28.2% reported that learning about CHIP caused at least moderate anxiety. Most young survivors favored CHIP testing, with preferences influenced by risk presentation and potential management strategies. Our findings highlight the importance of risk communication and psychosocial support when considering biomarkers for future risk in cancer survivors. This trial has been registered at www.clinicaltrials.gov as #NCT01468246.

2012 Background: Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. We report on the feasibility and conduct of this approach. Methods: Tumor genotyping was performed prior to treatment assignment on eligible participants with newly diagnosed MGMT-unmethylated glioblastoma to identify biomarker signatures. Initial randomization was 1:1:1:1 between control (temozolomide) and 3 experimental arms (abemaciclib, CC-115, and neratinib). Subsequent randomization was adapted based on Bayesian estimation of biomarker-naïve and biomarker-specific probabilities of treatment impact on progression-free survival (PFS). Ineffective or toxic arms were discontinued by protocol amendment. The primary endpoint was overall survival (OS). Results: INSIGhT randomized 71 patients to the control arm, 73 patients to the abemaciclib arm, 12 patients to the CC-115 arm, and 81 patients to the neratinib arm between 2/9/2017 and 5/14/2021. Following the initial equal randomization period, early data were repeatedly analyzed during the study to capture early signals of treatment effects across the enrolled population or in specific biomarker subgroups. The results of these interim analyses influenced the randomization probability for future enrolled patients. In total, 77% of the participants were randomized before assessing their biomarker profile and 23% were biomarker randomized. The CC-115 arm opened and closed three times during the safety lead-in. The randomization probability to the CC-115 arm decreased based on poor early PFS results and the arm eventually closed after 12 patients due to toxicity. The randomization probability to the abemacicilb arm increased based on promising early PFS results. After the completion of accrual into the abemaciclib arm, the trial switched to block randomization to finish enrolling into the remaining neratinib and control arms. A total of 28 interim analyses and 32 randomization tables were created throughout the course of the trial with 4 adjustments (3 due to CC-115 closures and 1 due to completion of the abemaciclib arm). Biomarker association trends for neratinib and abemaciclib were similar to those seen in preclinical modeling of the trial. Conclusions: Relative to a standard randomization design, the adaptive platform design facilitated more efficient and economical testing of experimental arms by sharing a control arm, decreasing the probability of enrollment to potentially ineffective arms, and increasing the probability of enrollment to potentially effective arms. Additional future arms are planned on INSIGhT. Clinical trial information: NCT02977780.

e24108 Background: Clonal hematopoiesis of Indeterminate Potential (CHIP) is associated with adverse clinical outcomes including increased risk of hematologic malignancies and heart disease. Limited data suggest an increased prevalence of CHIP in patients treated for solid tumors, particularly after exposure to radiation and chemotherapy. CHIP testing may inform risk-reduction strategies for cancer survivors. Little is known about patient knowledge, attitudes, and preferences regarding CHIP testing. Methods: We surveyed survivors without history of recurrence participating in an ongoing prospective cohort study of young women with breast cancer (BC). The survey was sent by email and included an introduction to CHIP including risk factors and clinical associations. Respondents then reviewed a vignette and were asked about CHIP testing preferences (definitely/probably test vs. definitely/probably not test) considering sequentially: 1) population-based 10-year risk of BC recurrence, hematological malignancy and heart disease; 2) estimated increase in these risks with CHIP; 3) current CHIP management; 4) a dedicated CHIP clinic; and 5) a theoretical CHIP treatment. Changes in preferences from the prior scenario were evaluated with the McNemar's test using a type I error rate of 5%. Results: 528/642 (82.2%) eligible women responded to the survey, at a median age of 46 (range: 31-54) years (median time from diagnosis: 108 months (range: 60-168)), and 88% were white. Most had stage 1/2 BC (78.8%) and had received chemotherapy (73.1%) and/or radiation (61.9%). 93.6% had never heard of CHIP prior to survey. After initial patient vignette presentation, most women (87.1%,) recommended CHIP testing if offered. Preferences for testing decreased (p<0.05) when considering population-based risks, with 11.1% shifting their preference from CHIP testing to not testing. After considering increased risks associated with CHIP, interest in testing increased (p<0.05), with 10.1% shifting their preference to testing. Interest significantly (p<0.05) increased with the possibility of managing CHIP through a clinic or a hypothetical CHIP treatment, with 7.2% and 14.1% switching their preferences towards testing, respectively. Finally, 75.8% responded that they themselves, after learning about CHIP and reviewing the vignette, would want to have CHIP testing; 28.2% reported that learning about CHIP and the associated risks caused them at least moderate anxiety. Conclusion: Few young BC survivors were aware of CHIP yet most indicated an interest in testing after learning about it. Testing preferences were influenced by risks presented and potential management strategies. Findings highlight the importance of effective risk communication and the need for adequate psychosocial support when considering testing for CHIP and other potential clinical biomarkers predictive of cancer and other medical risks in cancer survivors.

2014 Background: The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for HR+/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. Methods: Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150-200 mg orally BID). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS which was assessed using the log-rank test estimated via the Kaplan Meier method using a type I error of 5%. The hazard ratio (HR) was estimated using a cox proportional hazards model. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. Results: There were 142 patients (69 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (HR 0.67; p = 0.03, logrank test) with abemaciclib (median 6.54 months) compared to the control arm (median 5.88 months). For patients with activation of the CDK4 pathway the PFS HR was 0.64 (p-value = 0.04). However, there was no significant improvement in overall survival (HR 0.9; p-value > 0.05) between abemaciclib (median 15.5) compared to the control arm (median 15.5). Conclusions: Abemaciclib was well-tolerated and prolonged PFS but there is no evidence of an overall survival improvement compared to standard radiochemotherapy. Clinical trial information: NCT02977780.