Response Assessment In Neuro-Oncology Brain Metastases Research Articles

Radiotherapy combined with pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases: A single-arm, exploratory trial.

e13024 Background: Previous researches indicated the enhanced radiosensitivity in HER2-positive cancer cells by pyrotinib. For patients with treatment-naive brain metastases and central nervous system (CNS) symptoms, whether radiotherapy (current mainstay treatment) combined with pyrotinib-based systemic regimen is more beneficial remains unclear. This study explored radiotherapy combined with pyrotinib plus capecitabine in this population. Methods: In this exploratory trial (NCT04767828), patients aged 18-75 years who had HER2-positive metastatic breast cancer and untreated symptomatic brain metastases with an Eastern Cooperative Oncology Group performance status of 0-2 were included. Patients with meningeal metastases or without measurable CNS lesions were excluded. Eligible patients received whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRT). The irradiation sites, total radiation dose, and fractions were decided by investigator based on the number of CNS lesions and size. Pyrotinib (400 mg, once a day) and capecitabine (1000 mg/m2, twice a day, on days 1-14 of each 21-day cycle) were given since the start of radiotherapy until disease progression or intolerable toxicity. The primary endpoint was CNS progression-free survival (PFS), assessed by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Extracranial lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between May 5, 2020 and November 25, 2022, a total of 19 patients were enrolled. Thirteen (68%) patients had other visceral metastases, and 18 (95%) had prior trastuzumab treatment (5 for early breast cancer, 12 for advanced breast cancer, and 1 for both). Fifteen (79%) patients received WBRT and 4 (21%) received SRT. By the data cutoff date on January 16, 2023, the median follow-up duration was 15.0 months (range, 1.7-24.8). Median CNS PFS was 10.0 months (95% CI, 5.3-14.7). CNS objective response rate was 100%, including two (11%) patients with CNS complete response. Median overall PFS was 8.5 months (95% CI, 4.8-12.2). Median overall survival was 19.0 months (95% CI, 13.1-24.9). The most common grade 3 or 4 adverse events were vomiting (16%) and nausea (11%). For 11 patients with available results of Mini-Mental State Examination (MMSE), 10 (91%) had normal cognitive function during study period or recovered to normal level within 6 months after radiotherapy. Conclusions: Radiotherapy combined with pyrotinib plus capecitabine shows favorable CNS response and promising survival outcomes in patients with HER2-positive metastatic breast cancer and untreated symptomatic brain metastases, with an acceptable safety profile. This combination strategy warrants further validation in large samples. Clinical trial information: NCT04767828 .

Correlating volumetric and linear measurements of brain metastases on MRI scans using intelligent automation software: a preliminary study

The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group proposed a guide for treatment responses for BMs by utilizing the longest diameter; however, despite recognizing that many patients with BMs have sub-centimeter lesions, the group referred to these lesions as unmeasurable due to issues with repeatability and interpretation. In light of RANO-BM recommendations, we aimed to correlate linear and volumetric measurements in sub-centimeter BMs on contrast-enhanced MRI using intelligent automation software. In this retrospective study, patients with BMs scanned with MRI between January 1, 2018, and December 31, 2021, were screened. Inclusion criteria were: (1) at least one sub-centimeter BM with an integer millimeter-longest diameter was noted in the MRI report; (2) patients were a minimum of 18 years of age; (3) patients with available pre-treatment three-dimensional T1-weighted spoiled gradient-echo MRI scan. The screening was terminated when there were 20 lesions in each group. Lesion volumes were measured with the help of intelligent automation software Jazz (AI Medical, Zollikon, Switzerland) by two readers. The Kruskal-Wallis test was used to compare volumetric differences. Our study included 180 patients. The agreement for volumetric measurements was excellent between the two readers. The volumes of the following groups were not significantly different: 1-2mm, 1-3mm, 1-4mm, 2-3mm, 2-4mm, 3-4mm, 3-5mm, 4-5mm, 5-6mm, 5-7mm, 6-7mm, 6-8mm, 6-9mm, 7-8mm, 7-9mm, 8-9mm. Our findings indicate that the largest diameter of a lesion may not accurately represent its volume. Additional research is required to determine which method is superior for measuring radiologic response to therapy and which parameter correlates best with clinical improvement or deterioration.

Adagrasib: A landmark in the KRASG12C-mutated NSCLC.

Adagrasib: A landmark in the KRASG12C-mutated NSCLC.

NCOG-04. RANO-BM RESPONSE CRITERIA VERIFICATION STUDY IN A SRS-TREATED COHORT

Abstract Brain metastases are frequently seen in neurosurgical practice. Standardised criteria are created to better classify these common pathologies in research studies. This study’s goal was to evaluate RANO-BM (Response Assessment in Neuro-Oncology - Brain Metastases) criteria’s current thresholds in a cohort of patients with brain metastases managed by stereotactic radiosurgery (SRS). We performed a retrospective metastasis-level analysis of patients treated with SRS for brain metastases. The data collected included cohort demographics, metastases characteristics, outcomes, and the rate of true positives, false negatives, true negatives and false positives as defined by RANO-BM criteria at last follow-up before second SRS. 251 metastases in 50 patients were included in the analysis. RANO-BM criteria using current thresholds yielded a sensitivity of 38%, a specificity of 95%, a positive predictive value of 71% and a negative predictive value of 84%. Modified RANO-BM criteria using absolute diameter differences of 2.5 mm yielded a sensitivity of 83%, a specificity of 87%, a positive predictive value of 67% and a negative predictive value of 94%. Pseudoprogression occurred significantly earlier than tumor progression, with a median time of onset of 6.9 months and 12.1 months respectively. Current RANO-BM criteria unreliably identifies clinically relevant tumor progression, but are useful in assessing diameter increases caused by tumor progression and pseudoprogression.

Efficacy and safety of immune checkpoint inhibitors plus anlotinib in small cell lung cancer with brain metastases: a retrospective, multicentre study.

Previous studies showed that both immune checkpoint inhibitors (ICIs) and anlotinib have central nervous system (CNS) efficacy. This study aimed to evaluate the efficacy and safety of ICIs combined with anlotinib in small cell lung cancer (SCLC) patients with brain metastases (BMs). We retrospectively reviewed SCLC patients with CNS metastases confirmed by brain magnetic resonance imaging (MRI). Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) were used to evaluate treatment response to ICIs plus anlotinib. Kaplan-Meier analysis and Cox regression analysis were performed to determine patient's prognosis. Sixty-six patients with baseline BMs were included. For patients with measurable intracranial lesions, the intracranial objective response rate (ORR) was 29.2% based on RECIST 1.1 criteria and was 27.1% based on RANO-BM criteria. The median intracranial progression-free survival (PFS) was 9.0months (95% confidence interval [CI], 6.5-11.5months). The median overall survival (OS) was 13.4months (95% CI, 10.7-20.5months). Multivariate Cox regression analysis showed that high disease burden (hazard ratio [HR] = 4.83, P < 0.001), multiple BMs (HR = 2.71, P = 0.036), and more than or equal to 3 prior lines of therapy (HR = 2.56, P = 0.023) were independent negative predictors of OS. The overall incidence of treatment-related adverse events (TRAEs) was 75.8%, and grade 3-4 TRAEs were reported in 19.7% of patients. Our results suggested that ICIs plus anlotinib had potent CNS efficacy with tolerable toxicity and could be a promising treatment option for SCLC patients with BMs.

O13-4 Efficacy and intracranial activity of tepotinib in Japanese patients with MET exon 14 skipping (METex14) NSCLC (VISION)

Tepotinib is a highly selective MET inhibitor, approved in Japan for advanced METex14 skipping NSCLC, which occurs in 3-4% of NSCLC patients (pts). Brain metastases (BMs) are reported in 20-40% of pts, presenting a high unmet need with a poor prognosis. Tepotinib crosses the blood-brain barrier and has demonstrated intracranial activity in preclinical MET-driven lung cancer. In the phase II VISION study (NCT02864992), pts in Cohorts A+C with METex14 skipping NSCLC, detected by liquid or tissue biopsy, received 500 mg QD oral tepotinib. The primary endpoint was ORR per RECIST v1.1 by independent review committee (IRC). An ad hoc retrospective analysis of brain lesions was conducted by IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. By data cut-off (Feb 1, 2021), 275 pts with ≥3 months' follow-up from Cohorts A+C were evaluable for efficacy (49.1% male, median age 73 years [range: 41-94], 49.8% treatment-naÏve). ORR across treatment lines was 49.1% (95% CI: 43.0, 55.2), with mDOR of 13.8 months (95% CI: 9.9, 19.4), mPFS of 10.8 months (95% CI: 8.5, 12.4), and mOS of 19.7 months (95% CI: 15.6, 22.1). Per RECIST v1.1, 34 pts had BM at baseline; systemic ORR was 58.8% (95% CI: 40.7, 75.4). Of 38 pts from Japan, 68.4% were male, median age was 73 years [range: 62-87], and 47.3% were treatment-naÏve. ORR across treatment lines was 60.5% (95% CI: 43.4, 76.0), with mDOR of 18.5 months (95% CI: 8.3, ne), mPFS of 19.9 months (95% CI: 8.3, ne), and mOS of 20.4 months (95% CI: 16.3, ne). In Cohort A (data cut-off; Jul 1, 2020), 15 pts were evaluable by RANO-BM (12 received prior radiotherapy). Intracranial disease control was achieved in 5 of 7 pts with target lesions (all PRs), and 7 of 8 pts with non-target lesions. Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC including in Japanese pts, and showed intracranial activity in pts with BM.

Abstract CT559: Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification

Abstract Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ~5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment in the advanced NSCLC setting. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in, ~10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ~225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Citation Format: Yi-Long Wu, Ji-Youn Han, Terufumi Kato, Fabrice Barlesi, Edward B. Garon, Federico Cappuzzo, Yuji Shibata, Nathalie Smith, Sadhvi Khanna, Riccardo Belli, Alejandro Yovine, Daniel Tan. Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT559.

Capmatinib plus osimertinib versus platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIb/IIIc or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification.

TPS9153 Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ̃5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in about ten countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment for advanced NSCLC. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in,̃10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ̃225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Clinical trial information: NCT04816214.

Risk of tract recurrence with stereotactic biopsy of brain metastases: an 18-year cancer center experience.

Stereotactic biopsy is increasingly performed on brain metastases (BrMs) as improving cancer outcomes drive aggressive multimodality treatment, including laser interstitial thermal therapy (LITT). However, the tract recurrence (TR) risk is poorly defined in an era defined by focused-irradiation paradigms. As such, the authors aimed to define indications and adjuvant therapies for this procedure and evaluate the BrM-biopsy TR rate. In a single-center retrospective review, the authors identified stereotactic BrM biopsies performed from 2002 to 2020. Surgical indications, radiographic characteristics, stereotactic planning, dosimetry, pre- and postoperative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria. In total, 499 patients underwent stereotactic intracranial biopsy for any diagnosis, of whom 25 patients (5.0%) underwent biopsy for pathologically confirmed viable BrM, a proportion that increased over the time period studied. Twelve of the 25 BrM patients had ≥ 3 months of radiographic follow-up, of whom 6 patients (50%) developed new metastatic growth along the tract at a median of 5.0 months post-biopsy (range 2.3-17.1 months). All of the TR cases had undergone pre- or early post-biopsy stereotactic radiosurgery (SRS), and 3 had also undergone LITT at the time of initial biopsy. TRs were treated with resection, reirradiation, or observation/systemic therapy. In this study the authors identified a nontrivial, higher than previously described rate of BrM-biopsy tract recurrence, which often required additional surgery or radiation and justified close radiographic surveillance. As BrMs are commonly treated with SRS limited to enhancing tumor margins, consideration should be made, in cases lacking CNS-active systemic treatments, to include biopsy tracts in adjuvant radiation plans where feasible.

Abstract OT2-09-01: Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases

Abstract Background: Breast cancer patients with brain metastases have a high unmet clinical need and improved management strategies are needed. There has been interest in studying CDK 4/6 inhibitors in the management of breast cancer brain metastases. A phase II study has shown abemaciclib to have activity in the management of hormone receptor (HR)+/HER2- brain metastases. Pre-clinical data suggests a potential synergy with CDK inhibitors and radiation therapy. Stereotactic radiosurgery (SRS) is a cornerstone in the management of limited brain metastases. We hypothesize treatment with abemaciclib and SRS will be safe and improve intracranial progression free survival (PFS) compared to abemaciclib alone. Trial Design: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of abemaciclib and endocrine therapy with SRS among patients with HR+/HER2- metastatic breast cancer brain metastases. Treatment will be initiated with one week of abemaciclib followed by stereotactic radiation to sites of brain metastases or post-operative cavities with continued abemaciclib. Safety will be monitored initially by a 3+3 design. If unexpected neurologic toxicities are noted, the dose of radiation therapy will be reduced. This will be followed by a phase II study to evaluate intracranial PFS. Eligibility: Eligible patients include those that are HR+/HER2-, ≥18, ECOG ≤2 with ≤15 breast cancer brain metastases with measurable disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Specific Aims: The primary objective of the phase I study is to evaluate the safety and feasibility of abemaciclib and SRS to sites of brain metastases in the management of HR+/HER2- metastatic breast cancer with brain metastases. The primary objective of the phase II portion is to determine PFS intracranially. Secondary objectives include evaluation of extracranial PFS, local and distant intracranial control, and overall survival. Statistical Methods: Safety and feasibility will be monitored in the phase I study using a 3 + 3 design followed by a phase II study to assess intracranial PFS. The phase II study is designed as a single-arm, two-stage trial using the Restricted-Kwak-and-Jung’s method. In the first stage, a total of 21 patients will be enrolled. If pre-specified endpoints are met, an additional 10 patients will be enrolled in the second stage. Patient Accrual: A total of up to 31 patients will be enrolled inclusive of patients in the phase I portion treated at the recommended phase II dose. Clinical trial information: NCT04923542. Citation Format: Kamran A. Ahmed, Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, Rashmi K. Murthy, Jing Li, Avan J. Armaghani, John A. Arrington, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Daniel E. Oliver, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Michael A. Vogelbaum, Michael Yu, Hyo S. Han. Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-09-01.

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases.

BackgroundImproved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases.MethodsA multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by “planned LITT+SRT” versus “LITT alone” versus “repeat SRT alone.” Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.ResultsFifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0–30.5), age of 60 years (range: 37–86), Karnofsky Performance Status (KPS) of 80 (range: 60–100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7–19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004).ConclusionsThese data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

Deep Learning-Based Computer-Aided Detection System for Automated Treatment Response Assessment of Brain Metastases on 3D MRI.

BackgroundAlthough accurate treatment response assessment for brain metastases (BMs) is crucial, it is highly labor intensive. This retrospective study aimed to develop a computer-aided detection (CAD) system for automated BM detection and treatment response evaluation using deep learning.MethodsWe included 214 consecutive MRI examinations of 147 patients with BM obtained between January 2015 and August 2016. These were divided into the training (174 MR images from 127 patients) and test datasets according to temporal separation (temporal test set #1; 40 MR images from 20 patients). For external validation, 24 patients with BM and 11 patients without BM from other institutions were included (geographic test set). In addition, we included 12 MRIs from BM patients obtained between August 2017 and March 2020 (temporal test set #2). Detection sensitivity, dice similarity coefficient (DSC) for segmentation, and agreements in one-dimensional and volumetric Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria between CAD and radiologists were assessed.ResultsIn the temporal test set #1, the sensitivity was 75.1% (95% confidence interval [CI]: 69.6%, 79.9%), mean DSC was 0.69 ± 0.22, and false-positive (FP) rate per scan was 0.8 for BM ≥ 5 mm. Agreements in the RANO-BM criteria were moderate (κ, 0.52) and substantial (κ, 0.68) for one-dimensional and volumetric, respectively. In the geographic test set, sensitivity was 87.7% (95% CI: 77.2%, 94.5%), mean DSC was 0.68 ± 0.20, and FP rate per scan was 1.9 for BM ≥ 5 mm. In the temporal test set #2, sensitivity was 94.7% (95% CI: 74.0%, 99.9%), mean DSC was 0.82 ± 0.20, and FP per scan was 0.5 (6/12) for BM ≥ 5 mm.ConclusionsOur CAD showed potential for automated treatment response assessment of BM ≥ 5 mm.

SYST-06. PHASE II TRIAL OF PAXALISIB (GDC-0084) IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

Abstract BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha &amp;lt;10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.

TRLS-03. Intracranial activity of tepotinib in patients with MET exon 14 (METex14) skipping NSCLC enrolled in VISION

BackgroundBrain metastases (BMs) are reported in 20–40% patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, has demonstrated an objective response rate (ORR) of 45% and median duration of response (mDOR) of 11.1 months, in METex14 skipping NSCLC patients in Cohort A of the Phase II VISION study. Here, we report the intracranial activity of tepotinib in Cohort A.MethodsPatients received oral tepotinib 500 mg QD. Study eligibility allowed for patients with BM (asymptomatic and symptomatic/stable). Primary endpoint: systemic objective response (RECIST v1.1); subgroup analysis in patients with BM (RECIST v1.1) was predefined.An ad hoc retrospective analysis of brain lesions (by CT/MRI) was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For non-measurable lesions (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020.ResultsTwenty-three patients had baseline BM. Systemic efficacy in patients with BM (ORR 47.8% [95% CI: 26.8, 69.4]; mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population.Fifteen patients were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and progressive disease (PD; n=3).Of seven patients with measurable CNS disease (all of whom received prior radiotherapy), intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL.ConclusionsTepotinib demonstrated intracranial activity in patients with METex14 skipping NSCLC with BM. Prospective evaluation of intracranial activity in VISION Cohort C is ongoing.

Intracranial activity of tepotinib in patients (pts) with MET exon 14 (METex14) skipping NSCLC enrolled in VISION.

9084 Background: Brain metastases (BMs) are reported in 20–40% of pts with METex14 skipping NSCLC and present a high unmet need with poor prognosis. Tepotinib is a highly selective MET inhibitor that has demonstrated intracranial activity in preclinical MET-driven lung cancer orthotopic BM models, and has high binding in brain tissue with 25% of free tepotinib levels in brain, relative to plasma. In VISION Cohort A (N = 152), tepotinib had robust and durable clinical activity in pts with METex14 skipping NSCLC, with an objective response rate (ORR) of 45% and a median duration of response (mDOR) of 11.1 months. Here, we report the intracranial activity of tepotinib. Methods: In the Phase II VISION study, pts with METex14 skipping NSCLC received 500 mg QD (450 mg active moiety) oral tepotinib. Study eligibility allowed for pts with BM (neurologically stable on symptomatic therapy with stable steroids, and pts with asymptomatic BM). Primary endpoint: systemic OR per RECIST v1.1; subgroup analysis in pts with BM (determined by RECIST v1.1) was predefined. An ad hoc retrospective analysis of brain lesions determined by CT/MRI was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, which accounts for pts’ clinical status and steroid use. Responses were determined in pts with ≥1 evaluable post-baseline tumor assessment (due to the retrospective nature and resulting incomplete data, confirmation was not required). For pts with non-measurable lesions per RANO-BM (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020. Results: Based on RECIST v1.1, 23 pts in Cohort A had BM at baseline. Systemic efficacy in pts with BM (ORR 47.8% [95% CI: 26.8, 69.4], mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population. 15 pts were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before tepotinib initiation [range 2.6–44]). Systemic best objective responses (BORs) were partial response (PR, n = 9), stable disease (SD, n = 3), and progressive disease (PD; n = 3). Of 7 pts with measurable CNS disease per RANO-BM (all of whom received prior radiotherapy), intracranial BORs were PR (n = 5; including 3 with complete disappearance of target lesions), SD (n = 1) and PD (n = 1). Of 8 pts with NTL only, 7 achieved intracranial disease control and 1 had PD. Of the 7 pts with disease control, 3 had CR of the enhancing NTL. Conclusions: Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC with BM; this is complemented by intracranial activity in an ad hoc analysis using RANO-BM. Small pt numbers, a large proportion of pts with prior radiotherapy for BM, and the retrospective nature of analysis should be considered. Prospective evaluation of intracranial activity data from VISION Cohort C is ongoing. Clinical trial information: NCT02864992.

Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: A non-randomized, open-label phase Ib study.

e14010 Background: There may be a potential synergy intracranially between stereotactic radiation and immune checkpoint inhibition in brain metastases management. We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone in the management of breast cancer brain metastases. Methods: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≤ 10 brain metastases. The primary objective was to evaluate the safety and feasibility of study therapy. Secondary objectives included evaluation of local brain metastasis control, distant brain metastasis control, progression free survival (PFS), and overall survival following study therapy. Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria were used to assess intracranial and extracranial disease, respectively. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. Results: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. Median follow-up from start of protocol therapy is currently 9.6 months (range: 2.8-18.7 months). No dose limiting toxicities (DLTs) were noted in our patient population. The most common neurologic adverse events included grade 1-2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% CI 3.0 -14) with 6 and 12 month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic PFS has not been reached with 6 and 12 month rates of 63% and 51%, respectively. Conclusions: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary studies reveal activity in certain breast cancer patients to study therapy. Clinical trial information: NCT03807765.

Abstract OT-09-10: A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer

Abstract Background: Endocrine therapy has been the primary treatment modality for HR+, HER2- metastatic breast cancer (MBC). Endocrine agents are administered sequentially, either in combination with targeted therapy or as monotherapy. The majority of patients with HR+, HER2- MBC will develop endocrine resistant disease. More effective and less toxic therapies are needed for the treatment of endocrine resistant disease. OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates Estrogen Receptor (ER), blocks ER-driven transcriptional activity, inhibits ER-driven breast cancer cell growth, and induces degradation of ER. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against metastases in the brain and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic profile supportive of once-daily dosing. OP-1250 is hypothesized to completely antagonize ER resulting in superior efficacy compared to agents that only have partial antagonism of ER. Its favorable pharmacologic profile makes it an attractive agent for chronic use in patients with MBC. Trial design: This is a Phase I/II open-label, first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D), to characterize the safety and pharmacokinetic (PK) profile, and to determine the preliminary efficacy of OP-1250 in adult subjects with HR+, HER2- MBC. Treatment will consist of oral, once a day dosing and subject evaluation will be performed in 28-day cycles. This study comprises 2 parts. Part 1 (Dose Escalation) will evaluate the safety and pharmacology of a range of doses of OP-1250 administered orally to subjects and to determine the maximum tolerated dose (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during the first cycle of study treatment. Part 2 (Dose Expansion) will evaluate the preliminary activity of OP-1250. Patients with and without central nervous system (CNS) disease will be enrolled at the RP2D. This is designed using a Simon 2 Stage Design. Total accrual will be determined by the number of dose levels needed to identify the RP2D. Eligibility criteria:Males and females, age 18 or older, with ER+, HER2− advanced or MBCPrior treatment with endocrine therapyECOG performance status of 0 or 1For dose expansion the subject must have measurable disease according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 ObjectivesPart 1 (Dose Escalation)To identify the DLT, MTD and/or RP2D of OP-1250To assess the safety and tolerability of OP-1250To assess the pharmacokinetics of OP-1250 Part 2 (Phase II: Monotherapy Expansion)Objective response rate (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases.To conduct a preliminary assessment of the antitumor activity (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have CNS disease. Assessment of response will be determined according to RECIST 1.1 and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria Correlative ScienceTo determine biomarker expression, such as, ER, PR, Ki67 and others in the most recently obtained archival tumor tissue sampleTo evaluate whether ESR1 in circulating tumor DNA (ctDNA) can be correlated with response and/or activity of OP-1250To examine ctDNA pre- and post-therapy for mutESR1 and PIK3CA variants, and other relevant markers For more information, please contact clinical@olemapharma.com Citation Format: Erika Hamilton, Carlos Alemany, Nancy U Lin, Pamela M Klein, Trinh Le, Peter J Kushner, Cyrus Harmon, Jo Anne Zujewski, Manish Patel. A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-10.

Abstract OT1-08-05: Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM)

Abstract Background: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. Methods: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha &amp;lt;10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983. Citation Format: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin. Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-05.

Abstract P1-18-03: Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA study

Abstract Background: There is an unmet need for evidence-based systemic therapies for pts with HER2-positive MBC and progressive brain metastases. Despite assumptions that monoclonal antibodies do not cross the blood-brain barrier, molecular imaging in pts shows localization of 89Zr-trastuzumab to brain metastases. Furthermore, preclinical data support dose-dependent activity of H in intracranial tumor models. The PATRICIA study (NCT02536339) evaluated safety and efficacy of P plus high-dose H in pts with HER2-positive MBC with CNS metastases and CNS progression after RT. Herein, we present results from the primary efficacy analysis of PATRICIA. Methods: PATRICIA was a US-based, phase II, open-label, single arm study. Eligible pts had measurable (≥10 mm) CNS disease that had progressed after CNS-directed RT, in the setting of stable extracranial disease. CNS-directed RT included whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) and must have been completed ≥60 days before study entry. Pts received P (840 mg loading dose, then 420 mg every 3 weeks) and high-dose H (6 mg/kg weekly), which continued until progression (CNS or systemic) or unacceptable toxicity. Pts could continue their existing systemic anti-cancer therapy during the study, with the exception of trastuzumab emtansine (T-DM1) or lapatinib. Switch of other anti-cancer therapy was not permitted during the study. Restaging evaluations including brain MRI were completed every 2 cycles. The primary efficacy endpoint was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR) in the CNS, and safety. Samples were collected for exploratory pharmacokinetic analyses on Day 1 of weeks 1, 4, 10, and 16. Results: From 15 Dec 2015 to 18 May 2017, 40 pts were enrolled across 16 sites. Median age was 48 (range 34–69) years, with 33% and 67% of pts having an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, respectively. 41% of pts had received prior WBRT only, 28% had received prior SRS only, and 31% had received both. At the data cut off (1 May 2019), of 39 treated pts, 2 remained on study treatment and 37 discontinued treatment, most commonly due to CNS progression (n=27). Median treatment duration was 4.5 (range 0.3–37.3) months. Four pts in the efficacy population (N=37) experienced a confirmed partial response (Table), leading to an ORR of 11% (95% confidence interval [CI], 3–25%). Response durations were 3.2, 3.3, 4.6, and 5.6 months (median DOR 4.6 months). The CBR (complete response + partial response + stable disease [SD] of ≥4 or ≥6 months) was 68% (SD ≥4 months) and 51% (SD ≥6 months). Results from exploratory pharmacokinetic analyses confirmed greater H exposure with the high-dose schedule. The adverse event profile was similar to that previously reported for P and H, with no new safety signals. One pt discontinued treatment due to an adverse event (grade 3 left ventricular dysfunction, considered related to study treatment). No Grade 5 adverse events were reported. Conclusions: The CNS ORR of 11%, ≥6-month CBR of 51%, and lack of any new safety signals suggest that P plus high-dose H may have clinical utility in some pts with HER2-positive MBC with progressive CNS metastases. Table. Efficacy within the CNS per RANO-BM criteriaEfficacy population (N=37)n (%)95% CIORR*4 (11)3, 25CBR (CR + PR + stable disease [SD] ≥4 months)25 (68)50, 82CBR (CR + PR + SD ≥6 months)19 (51)34, 68Confirmed best response (SD ≥4 months)CR0—PR4 (11)—SD ≥4 months21 (57)—Pts without clinical benefit12 (32)—Confirmed best response (SD ≥6 months)CR0—PR4 (11)—SD ≥6 months15 (41)—Pts without clinical benefit18 (49)—*Confirmed complete response (CR) or confirmed partial response (PR). Citation Format: Nancy U Lin, Priya Kumthekar, Solmaz Sahebjam, Nuhad Ibrahim, Anita Fung, Anna Cheng, Alan Nicholas, Bei Wang, Mark Pegram. Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-03.

TRLS-03. PHASE II TRIAL OF GDC-0084 IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha < 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.