Intracranial Response Research Articles

Pressure-Volume Relationships in the Spinal Canal and Potential Neurological Complications After Epidural Fluid Injections.

High-volume fluid injections into the spinal canal may lead to severe neurological complications. But when anatomical or pathological conditions in the spinal canal are unfavorable, even small volume epidural injections can cause dangerously high epidural, subarachnoid, and intracranial pressures or pressure gradients. Data obtained from the scientific literature and direct clinical observation are used to derive a first-order approximation of epidural, subarachnoid, and intracranial pressure responses to epidural fluid injections. Maximum allowable fluid volumes for single or multiple divided fluid injections over time are calculated. In the presence of spinal pathology, 10 ml of fluids may increase epidural pressure to >100 mmHg. Injection speed >4 ml per second may also generate dangerously high intraspinal and intracranial pressures. Intermitted bolus injections provide limited protection, but intraspinal pressures may rise very fast when a critical total injected volume is reached. Potential complications of increased intracranial pressures or large pressure waves include nerve palsies, tinnitus, blindness, stroke, and death. Spinal injections or endoscopy should be performed in an awake responsive patient or with direct cerebrospinal fluid pressure monitoring. A set of guidelines for epidural fluid management is given.

Programmed cell death 1 pathway inhibitors improve the overall survival of small cell lung cancer patients with brain metastases

PurposeThe objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitors in small cell lung cancer patients with brain metastases.MethodsWe retrospectively reviewed the records of small cell lung cancer patients with brain metastases treated with chemotherapy and radiotherapy for brain metastases with or without immune checkpoint inhibitors at our institution from January 2019 to January 2021. Patients were divided into two groups. In Group A, patients received chemotherapy and radiotherapy for brain metastases. In Group B, patients received chemotherapy, radiotherapy for brain metastases and at least four cycles of immunotherapy. Overall survival and intracranial progression-free survival were assessed using Kaplan–Meier estimates and Cox regression models.ResultsA total of 282 patients were enrolled in our study. At the end of the study (May 12, 2021), the median overall survival was 13.3 months among 218 patients in Group A and 33.4 months among 64 patients in Group B (hazards ratio [HR] 0.320, 95% confidence interval [CI], 0.189–0.545, P < 0.001). Both univariate and multivariate analyses suggested that two factors were significantly correlated with overall survival: the inclusion of immunotherapy in the regimen and the presence of extracranial metastases. The median intracranial progression-free survival was 6.93 months in Group A and 10.73 months in Group B (HR = 0.540, 95% CI, 0.346–0.841, P = 0.006). The intracranial objective response rate of Group B was greater than that of Group A, but the intracranial disease control rate was similar between the groups.ConclusionImmunotherapy plus chemotherapy and radiotherapy for brain metastases showed promising efficacy for small cell lung cancer patients with brain metastases.

Symptomatic melanoma metastases in the brain: are we using all therapy options?

In recent years, significant advances have been made in systemic therapy for patients with metastatic melanoma of the skin, resulting in an increase in one-year overall survival (OS) from 25 to 85% and 5-year OS from less than 10 to 60% in certain patient subgroups. Approximately 50% of patients with metastatic skin melanoma are diagnosed with metastatic brain lesions in the course of the disease. Modern drug therapy for metastatic brain lesions is slowly but surely proving to be effective. Thus, in the presence of a mutation in the BRAF gene, BRAF inhibitor monotherapy provides an intracranial objective response rate (iORR) of 25 to 40%, whereas BRAFi + MEKi combined targeted therapy (CTT) achieves already 58% iORR, including in patients with symptomatic metastases to the brain. However, the duration of responses achieved on targeted therapy (TT) is shorter than for extracranial disease prevalence. On the other hand, regardless of the presence of a BRAF mutation, immunotherapy (PD-1 monotherapy) achieves a response in approximately 20-22% of patients, but these responses are more durable, although fewer than on TT. The combination of CTLA-4 + PD-1 checkpoint inhibitors produces long-lasting responses with a iORR of 51-54%. However, the achievement of these results and an overall increase in life expectancy with immunotherapy is mostly possible in symptom-free patients and in patients receiving low or no doses of glucocorticosteroids (10 mg or less on prednisolone). Therefore, for symptomatic patients, especially those whose tumors have been identified with a BRAF mutation, a combination of targeted therapy, which would quickly achieve an objective response in 58%, and anti-PD1/PDL1 immunotherapy, which is likely to increase the duration of the response achieved and give a chance for a sustained remission, looks promising. This article provides an overview of key studies and our own experience with the triple combination in metastatic brain lesions.

Abstract CT558: Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial

Abstract Background: MET dysregulation is a poor prognostic factor in advanced non-small cell lung cancer (NSCLC). MET exon 14 skipping (METex14) mutations occur in ~3% of patients with NSCLC. There is limited evidence of the efficacy of standard therapies, such as chemotherapy or immunotherapy, in patients with METex14-mutated advanced NSCLC. Capmatinib, a MET inhibitor (METi), is approved for the treatment of adult patients with metastatic METex14-mutated NSCLC, based on the results of the phase 2 GEOMETRY mono-1 study. Results (data cutoff: September 18, 2020) of this study in patients with METex14-mutated NSCLC treated with capmatinib showed an overall response rate (ORR) of 66.7% in first line (N=60), 51.6% in second line (N=31) and 40.6% in second- or third-line (2/3L; N=69). GeoMETry-III (NCT04427072) is a multicenter, open-label, randomized, controlled, global, phase 3 trial that is further evaluating the efficacy and safety of capmatinib vs docetaxel in the 2/3L setting in patients with METex14-mutated NSCLC. Methods: This study began enrollment in September 2020 and is currently recruiting adult patients with EGFR wild-type, ALK-negative, stage IIIB/IIIC/IV METex14-mutated NSCLC, who have progressed on 1 or 2 prior lines of systemic therapy for advanced/metastatic disease and are candidates for single-agent docetaxel. Other eligibility criteria include ≥1 measurable lesion per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), an Eastern Cooperative Oncology Group performance status of ≤1 and no prior treatment with any METi or hepatocyte growth factor-targeting therapies. Patients with neurologically unstable, symptomatic central nervous system (CNS) metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are excluded. Around 90 patients will be randomized 2:1 to receive either oral capmatinib 400 mg twice daily or intravenous docetaxel 75 mg/m2 every 21 days. Randomization is stratified by number of prior lines (1 or 2) of systemic therapy. Patients meeting protocol-specified eligibility criteria can cross over from the docetaxel to the capmatinib arm after blinded independent review committee (BIRC)-confirmed progressive disease as per RECIST 1.1.The primary endpoint is progression-free survival (PFS) by BIRC per RECIST 1.1. The key secondary endpoint is ORR by BIRC per RECIST 1.1. Other secondary endpoints include investigator-assessed ORR and PFS; duration of response, time to response and disease control rate (DCR) by BIRC and investigator; overall survival; safety; pharmacokinetics; patient-reported outcomes; overall intracranial response rate, intracranial DCR, duration of- and time to- intracranial response by BIRC per the Response Assessment in Neuro-Oncology Brain Metastases criteria in patients with baseline CNS lesions. Citation Format: Pierre Jean Souquet, Sang-We Kim, Johan F. Vansteenkiste, Anna Robeva, Aline Jary, Sabine Glaser, Alejandro Yovine, Juergen Wolf. Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial [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 CT558.

Abstract 4181: CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis

Abstract While immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancers, few of the 30% of cancer patients who develop brain metastases benefit from immunotherapy. Inhibition of CDK4/6 pathway - altered in &amp;gt;50% of brain metastatic patients - can reportedly increase tumor inflammation and sensitize extracranial tumors to ICI. To determine whether intracranial tumors can be similarly sensitized, we studied efficacy of combination CDK4/6 inhibitor Abemaciclib and ICI in immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial murine tumors that are ICI-resistant. 8-week-old female C57BL/6 mice received subcutaneous injections of 2x105 YUMM1.7 or B16-F10 melanoma cells 3 days prior to intracranial injections of 1x104 YUMM1.7-FmC (firefly luciferase-tagged) cells or 5x103 B16-F10 cells respectively. 8-week-old female BALB/C mice similarly received 2x105 4T1 mammary carcinoma cells in mammary fat pad 3 days prior to intracranial injections with 2x104 4T1-FmC cells. Mice were randomized into 4 treatment groups (n=5-7/group): Abemaciclib monotherapy (administered daily), anti-PD-1 monotherapy (every 3 days), Abemaciclib and anti-PD-1 (combination therapy), and treatment with vehicle and isotype-matched antibody as control. In all 3 tumor models, extracranial tumor growth was significantly reduced compared to control mice following combination therapy (P&amp;lt;0.05 for all), while Abemaciclib monotherapy only reduced growth of subcutaneous YUMM1.7 tumors (P&amp;lt;0.05). Intracranial tumor growth, calculated using bioluminescence imaging early-in-treatment and post-treatment, was significantly reduced compared to control-treated tumors following combination therapy in both YUMM1.7-FmC and 4T1-FmC models (P&amp;lt;0.05 for both). In mice bearing B16-F10 tumors, where overall survival was used as an indirect measure of intracranial tumor growth, combination therapy improved survival (p&amp;lt;0.05) compared to both control and Abemaciclib monotherapy arms. These results indicate CDK4/6 inhibition with Abemaciclib can improve both extracranial and intracranial responses to ICI and sensitize brain metastases to immunotherapy. Our pre-clinical findings warrant further investigation to determine whether this combination approach can improve patient outcomes. Citation Format: Naema Nayyar, Mohini Singh, Magali de Sauvage, Nazanin Ijad, Ashish Dahal, Jane Chuprin, Michael Brehm, Priscilla Brastianos. CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis [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 4181.

Abstract CT034: Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study)

Abstract Background: METex14 mutations was reported in 3~4% of NSCLC patients and became a new target in the treatment of NSCLC. SCC244 is a highly selective and potent oral MET inhibitor. This is the first report of data from an ongoing single-arm phase II study of SCC244 in NSCLC patients with METex14 mutations (GLORY study). Methods: GLORY study is an open label, international, multi-center, single-arm phase II study to evaluate the efficacy and safety of SCC244 in patients with locally advanced or metastatic NSCLC harboring METex14 mutations which was confirmed by central laboratory. The enrolled patients have either failed one or two prior lines of systemic therapies or been not eligible/refused chemotherapy after being well-informed. SCC244 was taken orally at a dose of 300 mg once daily in 21-day treatment cycles until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks for the first 8 treatment cycles and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) per RECIST 1.1, secondary endpoints include ORR by investigator assessment (INV), duration of response (DoR), time to response (TTR) and safety etc. Post-hoc analysis was done to explore the intracranial anti-tumor activity. Results: At data cut-off on May 6th, 2021, a total 73 patients screened from 163 patients in 42 sites were treated at 300 mg QD dose and had ≥2 post-baseline tumor assessments or discontinued for any reason. 69 of them were with METex14 mutation confirmed by central laboratory. In the 69 patients, ORR by BIRC was 60.9% (95% CI: 48.4%, 72.4%) overall, 66.7% (95% CI: 50.5, 80.4) and 51.9% (95% CI: 31.9, 71.3) in treatment naïve and previously treated patients respectively. Median DoR was 8.2 months (95% CI: 4.8, NE) and median PFS was 7.6 months (95% CI: 4.2, NE), tumor response from 30 of 42 responders was still ongoing. The response occurred fast with a median TTR of 1.4 months (range: 1.2, 4.2). Partial response was observed in 8 of 10 patients with brain metastasis. 5 patients who had brain metastasis selected as targeted lesion had intracranial response by INV with a median intracranial tumor shrinkage of 57% (range: 34%, 71%). The most common (≥20%) treatment-related adverse events (TRAEs) of any grade were peripheral edema, headache, nausea, loss of appetite, hypoalbuminemia, ALT increase and vomiting. The incidence of ≥ grade 3 TRAEs was 43.8%. TRAEs leading to treatment discontinuation occurred in 6.8% patients, among which peripheral edema was the most common (4.1%). Conclusions: The data shows high and robust efficacy of SCC244 in NSCLC patients with METex14 mutations across treatment lines and encouraging intracranial anti-tumor activity. The safety profile was favorable with manageable toxicity. The data supports SCC244 as a valuable targeted treatment option for METex14 NSCLC patients. Citation Format: Shun Lu, Yongfeng Yu, Jianya Zhou, Koichi Goto, Xingya Li, Jun Sakakibara-Konishi, Kazumi Nishino, Tanaka Kentaro, Lin Wu, Xuhong Min, Wei Zhang, Dingzhi Huang, Yongqian Shu, Chengzhi Zhou, Min Li, Xiaorong Dong, Chong Bai, Lu Li, Jiuwei Cui, Li Zhang, Lejie Cao, Xiaoling Li, AiMin Zang, Haruki Kobayashi, Yiping Zhang, Yan Yu, Xiuwen Wang, Terufumi Kato, Shoichiro Yamamoto, Yuki Shinno, Xiaoyan Lin, Yanqiu Zhao, Yanping Hu, Qitao Yu, Ziping Wang, Masahiro Kodani, Jian Fang, Jialei Wang, Meiqi Shi, Diansheng Zhong, Wen Dong, Hiroshi Tanaka, Yasuto Yoneshima, Minghui Sun, Jun Zhou, Qiuxia Wu, Meng Li. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study) [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 CT034.

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.

Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial.

LBA9009 Background: CNS metastases (mets) occur in 27–42% of NSCLC harboring KRASG12C mutations and are associated with poor prognosis. Adagrasib (ada), an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state, and is optimized for favorable PK properties, including a long half-life (̃24 h) and dose-dependent PK. Ada has demonstrated dose-dependent CNS penetration and intracranial (IC) tumor regression in preclinical models of CNS mets. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating ada as monotherapy or in combination with selected agents in patients (pts) with advanced solid tumors harboring a KRASG12C mutation. In a Phase 1b cohort, pts with KRASG12C-mutant NSCLC and active, untreated CNS mets were treated with ada 600 mg BID. The objectives for this Phase 1b cohort were to evaluate safety and clinical activity, including systemic and IC objective response rate (ORR) by blinded independent central review (BICR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Systemic responses were assessed by RECIST 1.1; IC responses were assessed by modified RANO criteria and IC RECIST. Cerebrospinal fluid (CSF) was collected when feasible and was used to measure ada concentrations for optional evaluation. Results: As of 31 December 2021, 25 pts with NSCLC were enrolled and treated. Median follow-up was 6.6 months at the cutoff date. Median age was 66 years, 52% were female, 28%/72% had ECOG PS 0/1, and median lines of prior systemic therapy was one (range 0–4+). IC ORR per modified RANO criteria by BICR was 31.6% (6/19; 3 CRs, 2 PRs, 1 unconfirmed PR); IC disease control rate (DCR) was 84.2% (16/19, including 10 SDs). Median IC DOR was not reached (95% CI 4.1–NE); median IC PFS was 4.2 months (95% CI 3.8–NE). CSF samples were obtained for two pts for whom regression of CNS mets was observed and ada CSF concentrations exceeded the CNS penetrance partition coefficients observed for other therapies with demonstrated CNS penetration and CNS antitumor activity (Kp,uu 0.47). Systemic ORR by BICR was 35.0% (7/20), DCR was 80.0% (16/20) and median DOR was 9.6 months (95% CI 2.7–9.6); median PFS was 5.6 months (95% CI 3.8–11.0). For all pts enrolled, OS was immature, and the median had not been reached at the time of analysis. Safety was consistent with that previously reported with ada; any grade TRAEs occurred in 96% of pts, grade 3 TRAEs in 36%, and there were no grade 4/5 TRAEs. Further data describing IC activity assessed by IC RECIST will be presented. Conclusions: Ada was well tolerated, and these preliminary data demonstrate CNS penetration and encouraging IC activity in pretreated pts with NSCLC harboring a KRASG12C mutation and active, untreated CNS mets. These are the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in this population. Clinical trial information: NCT03785249.

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib

IntroductionThe central nervous system (CNS) is a common site of progression among patients with ROS1-rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1-rearranged lung cancer who developed CNS-only progression on crizotinib. MethodsPatients with metastatic ROS1-rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability. ResultsA total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9–not reported) and 41.1 months (95% confidence interval: 17.6–not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed. ConclusionsLorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.

Phase I/II investigator-initiated study of olaparib and temozolomide in SCLC: Updated analysis and CNS outcomes.

8565 Background: Temozolomide has activity in small-cell lung cancer (SCLC), including patients (pts) with brain metastases (mets; Pietanza M, Clin Cancer Res 2012). Inhibition of Poly (ADP-ribose) polymerase (PARP) is another therapeutic strategy in SCLC. We hypothesized that olaparib plus temozolomide may be safe and effective for pts with relapsed SCLC and clinically active against CNS disease (Farago A, Cancer Discovery 2019). Here, we present an updated analysis of this combination in pts with relapsed SCLC, including a second cohort testing an alternative dosing strategy and an exploratory analysis of CNS-specific outcomes. Methods: In this phase I/II trial of olaparib plus temozolomide in pts with recurrent SCLC, pts were sequentially enrolled into two cohorts defined by dosing schedule. In cohort 1, olaparib was dosed on D1-7 of each 21d cycle. In cohort 2, olaparib was dosed on D1-21. Temozolomide was dosed on D1-7 in both cohorts. Each cohort had a phase I portion (conventional 3+3 dose-escalation) for determination of MTD and RP2D and a phase II portion with primary endpoint of ORR. Per protocol, eligible pts could have untreated asymptomatic brain mets &lt; 1cm and, after mandatory baseline imaging, CNS imaging was performed at investigator’s discretion. A post-hoc exploratory analysis of CNS-specific outcomes was performed using modified RECIST criteria (Long GV, Lancet Oncol 2012) in which brain mets ≥5mm were considered measurable, and intracranial response was independently assessed by an attending radiologist. Results: 66 pts with median of 2 prior lines of therapy (range, 1-7) were enrolled, 50 pts in cohort 1 and 16 pts in cohort 2. 33/66 (50%) pts had history of brain mets, 15/66 (23%) pts had untreated brain mets at enrollment. The confirmed ORR of cohort 2 was 7% (1/14 evaluable pts, 95% CI: 0.2-33.9%), and the updated confirmed ORR of the entire study population was 34% (21/62 evaluable pts, 95% CI: 22.3-47.0%). The most common adverse events were hematologic toxicities (thrombocytopenia, anemia, and neutropenia). 22/50 (44%) of cohort 1 pts and 4/16 (25%) of cohort 2 pts required dose reduction. Of 15 pts with untreated brain mets, best overall intracranial response (including both confirmed and unconfirmed responses) was CR in 6 pts, PR in 4 pts, SD in 3 pts and PD in 1 for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Of 10 pts with CR/PR as their best intracranial response, 4 responses were confirmed. With non-CNS progression as a competing risk, the probability of CNS progression among the entire study population was 17% (95% CI: 8.8-26.7%) at 6 months and 21% (95% CI: 12.1-32.0%) at 12 months. Conclusions: Olaparib and temozolomide may be an effective therapy for relapsed SCLC, especially for pts with CNS disease where we observed a high rate of intracranial disease control. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination. Clinical trial information: NCT02446704.

A phase II study of alectinib in combination with bevacizumab as first-line treatment in advanced NSCLC with confirmed ALK fusion: ALEK-B trial.

9074 Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31st, 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no &gt; G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.

Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and to better predict intracranial tumor response in patients with non–small cell lung cancer with brain metastases: A prospective cohort study.

2023 Background: Cerebrospinal fluid (CSF) can be used as a type of liquid biopsy to detect brain tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor response and monitor mutational evolution during systemic treatment in non-small cell lung cancer (NSCLC) patients with brain metastases. Methods: We conducted aprospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and at disease progression. Primary extracranial tumor samples were available for 58 patients and all samples underwent targeted next generation sequencing of 425 cancer-related genes. Results: At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of heterogeneity was observed between paired CSF and plasma samples, while concordance in driver mutations was also observed. A higher number of unique copy number variations (CNVs) were detected in CSF ctDNA than in plasma. CtDNA-positivity in baseline CSF samples was associated with poor outcomes (HR = 2.565, P = 0.003). Moreover, patients with increased concentrations of ctDNA in CSF after 8 weeks of treatment had significantly shorter intracranial progression-free survivals (PFS) than patients with decreased concentrations of CSF ctDNA (6.13 months vs 13.27 months, HR = 3.92, P = 0.007). Increased concentrations of plasma ctDNA were associated with shorter extracranial PFS (6.13 months vs 11.57 months, HR = 2.626, P = 0.032). From clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of systemic treatment. The clonal mutations remained more than 80% in CSF after 8-weeks of treatment also predicted a shorter intracranial PFS (HR = 3.785, P = 0.039). Conclusions: CSF ctDNA revealed unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor response and track clonal evolution during treatment in NSCLC patients with brain metastases.

Gefitinib plus chemotherapy versus gefitinib alone in untreated patients with EGFR-mutated non–small cell lung cancer and brain metastases (GAP Brain): An open-label, randomized, multicenter, phase 3 study.

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P &lt; 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P &lt; 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

Updated analysis of the efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (NTRK-fp) solid tumors.

3099 Background: NTRK gene fusions, coding for chimeric TRK proteins, are oncogenic drivers in many solid tumors. In an integrated analysis of three phase 1/2 trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]), entrectinib, a potent CNS-active TRK inhibitor, showed durable systemic and intracranial responses in pts with NTRK-fp solid tumors. We report updated data from a larger cohort with longer follow-up (clinical cutoff 2 Aug 2021). Methods: Pts with locally advanced/metastatic NTRK-fp solid tumors and ≥12 months’ follow-up from first tumor assessment were efficacy evaluable. The safety cohort also included pts from TAPISTRY (NCT04589845). Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every 8 weeks thereafter. Primary endpoints: objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR and safety were also assessed. Results: The efficacy-evaluable cohort comprised 150 adults (vs 121 previously) with 17 different solid tumor types. Median age was 58.5 years; 91% of pts had ECOG PS 0–1 and 37% had received ≥2 prior lines of therapy. Median survival follow-up was 30.6 months. ORR was 61.3% (n = 92/150; 95% CI: 53.1–69.2), including 25 complete responses. Responses were observed in all tumor types with n&gt;1 (Table). Median DoR, PFS and OS were 20.0 months (95% CI 13.2–31.1), 13.8 months (95% CI 10.1–20.0), and 37.1 months (95% CI 27.2–not estimable [NE]), respectively. In pts with and without investigator-assessed baseline CNS metastases (n = 31 / n = 119), ORR was 61.3% (95% CI 42.2–78.2) and 61.3% (95% CI 52.0–70.1) respectively. IC-ORR was 69.2% (n = 9/13) in pts with BICR-assessed measurable CNS metastases; median IC-DoR was 17.2 months (7.4–NE). In the safety population (N = 235: all treated pts), most treatment-related adverse events (TRAEs) were grade 1/2 and not serious; the most frequent were dysgeusia (36.6%), diarrhea (29.8%) and weight increase (28.5%). TRAEs led to dose interruption, reduction and discontinuation in 32.8%, 24.3% and 7.2% of pts, respectively. Conclusions: In this updated analysis, entrectinib continued to demonstrate deep and durable responses and was well tolerated in pts with NTRK-fp solid tumors with or without baseline CNS metastases. Clinical trial information: STARTRK-2 [NCT02568267]. [Table: see text]

Updated analysis from the ATEZO-BRAIN trial: Atezolizumab plus carboplatin and pemetrexed in patients with advanced nonsquamous non–small cell lung cancer with untreated brain metastases.

9010 Background: Atezolizumab plus chemotherapy was safe and yielded promising clinical outcome as frontline therapy for patients (pts) with advanced NSCLC with untreated brain metastases (BM) in the ATEZO-BRAIN study (NCT03526900). Methods: A multicenter single-arm phase II trial with a Bayesian design for evaluating the safety and efficacy of atezolizumab plus carboplatin with pemetrexed every 3 weeks for 4-6 cycles, followed by maintenance with pemetrexed plus atezolizumab in pts with stage IV non-squamous NSCLC without EGFR or ALK genetic alterations and untreated BM. Pts not presented neurologic symptoms at baseline; but anticonvulsants and dexamethasone (DXM) ≤ 4mg qd were allowed. Co-primary endpoints were safety and investigator-assessed progression-free survival (PFS) at 12 weeks according to RANO-BM and RECIST v1.1 for brain and systemic disease, respectively. Here we present the final data and an exploratory analysis based on PD-L1 expression and corticosteroid treatment at baseline. Results: Out of 40 pts included in the study, 22 (55%) were receiving DXM at baseline and 20 (50%) had positive expression of PD-L1. Sixteen (40%) pts had confirmed intracranial response based on RANO-BM (12 PR, 4 CR) and 19 (47.5%) pts achieved systemic response (all PR). Only 4 pts had discordant responses between the body and the brain. No differences were observed in the overall systemic and intracranial response rate according to the PD-L1 expression or the use of corticosteroids at baseline. As of December 31, 2021 (median follow-up, 20 months), the updated median (95% CI) systemic PFS was 8.9 (6.7 to 13.8) and intracranial PFS was 6.9 (4.7 to 11.9). Median (95% CI) OS was 13.6 (9.72 to not reached) and estimated 2-year OS rate (95% CI) was 30.5% (18.4 to 50.4). Median (95%CI) OS was longer for PD-L1 positive pts (16.2; 10.3 to not reached) compared to PD-L1 negative pts (10.7; 7.6 to not reached) but differences were not statistically significant due to the limited statistical power (HR = 0.99; 95% CI 0.35 to 2.12). No significant differences in OS were observed between pts receiving or not baseline DXM treatment. Treatment was well tolerated and no grade 5 toxicities were observed. Conclusions: In this updated analysis, treatment with atezolizumab plus carboplatin and pemetrexed yields a promising 2-year OS rate and intracranial response rate in patients with untreated BM from NSCLC, regardless of treatment with corticosteroids at baseline and PD-L1 expression. Clinical trial information: NCT03526900.

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.

Brain metastases and immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.

The use of immune checkpoint inhibitors (ICIs) for brain metastases (BMs) from non-small cell lung cancer (NSCLC) remains debatable. This study aimed to explore the efficacy of ICIs for NSCLC with BMs. We also evaluated the effect of BMs on outcomes of ICIs. A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted to identify studies where the efficacy of ICIs against BMs from NSCLC, or the association between BMs and outcomes of ICIs were evaluated. Outcomes included intracranial objective response rate (icORR), intracranial disease control rate (icDCR), systemic ORR and DCR. Overall, 33 studies were included in this meta-analysis. The pooled icORR was 13% (95%CI 6-23%) and icDCR was 50% (95%CI 40-63%) for programmed cell death-ligand 1 (PD-L1) unselected patients with any BMs. For active BMs, pooled icORR was 15% (95%CI 6-28%) and icDCR was 47% (95% CI 36-57%). For PD-L1 ≥ 50% patients with any BMs, pooled icORR and icDCR were 68% (95%CI 57-80%) and 82% (95%CI 73-92%), respectively. Additionally, pooled systemic ORR and DCR for any BMs were 22% (95%CI 15-30%) and 41% (95%CI 18-67%), respectively. Patients with BMs had inferior progression-free survival (HR 1.19, 95%CI 1.07-1.33, P = 0.0016) and overall survival (HR 1.14, 95%CI 1.03-1.25, P = 0.011) when applying ICIs compared to those without BMs. However, no significant difference in systemic ORR between patients with and without BMs was observed (OR 0.94, 95%CI 0.72-1.20, P = 0.629). ICIs may be clinically active in NSCLC patients with BMs. More effective treatments for BMs from NSCLC are needed.

Bevacizumab for radiation necrosis of the brain or steroid-refractory edema in patients with melanoma receiving immune checkpoint inhibitors.

e14008 Background: For patients with melanoma brain metastasis (MBM) treated with stereotactic radiosurgery (SRS), 5-6.5% develop radiation necrosis of the brain (RNB), which is commonly treated with corticosteroids (CS). Nonetheless, high-dose CS may reduce efficacy of immunotherapy (IO). Bevacizumab (BV) has been shown to reduce symptoms and peritumoral edema associated with RNB. However, data on the efficacy and toxicity of BV in patients with MBM who also receive IO is limited. We aimed to describe clinical features and outcomes of patients with MBM who received BV and were also treated with IO. Methods: Under an IRB-approved protocol, patients with MBM who developed RNB or steroid-refractory edema (SRE) and were treated with BV were identified. The selection criteria were as follows: (1) one or more MBM; (2) prior SRS for MBM; (3) development of RNB or SRE detected radiographically or based on expert opinion; (4) treatment with one or more cycles of BV; (5) treatment with IO for metastatic melanoma. Results: In this single-center retrospective series, 8 patients received IO and BV: 4 concurrently and 4 patients received IO immediately prior to or after BV. IO therapy included ipilimumab-nivolumab, nivolumab alone or pembrolizumab. Median number of MBM was 3.6 (range, 1-8) and median number of RNB/SRE foci were 1.125 (range, 1-2). Median time from diagnosis of RNB/SRE to initiation of BV was 1.4 months (range, 0.5-3 months). BV dosing regimen was 5 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. 71% (5 of 7) patients who required CS for RNB/peritumoral edema symptoms at the time of starting BV were able to taper CS after receiving BV or stop CS completely. This allowed for 4 of these patients to subsequently start or resume IO. 28% (2 of 7) patients had increasing neurological symptoms during CS taper and required an increase in CS dosing. Only 1 patient was not on CS at the time of BV initiation. 75% (6 of 8) cases attained intracranial radiologic response, with documented decreased edema or tumor size, or resolution of enhancement on MRI; 1 patient had stable disease after BV; and 1 patient had continued clinical deterioration despite BV. 62.5% (5 of 8) patients had no adverse events from BV, but 37.5% (3 of 8) had DVT/PE, 1 requiring a thrombectomy, and 1 additionally had perforated diverticulitis. Median follow-up time from BV administration was 17.94 months (range, 1-58 months), with 75% (6 of 8) patients with survival &gt; 10 months. Conclusions: Treatment of RNB/SRE with BV in patients with MBM receiving IO appears to be effective and relatively well tolerated, though with occasional serious adverse events. BV led to improvement of symptoms and allowed for CS taper in a substantial proportion of patients. By reducing CS requirement, BV may permit continuation of IO, which leads to durable survival in a large proportion of patients.

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study.

9515 Retraction The abstract by Dummer et al entitled, “Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study,” ( Journal of Clinical Oncology 40, no. 16, suppl 9515) published on June 2, 2022, has been retracted due to corrected data that has led to a change in the conclusions of the abstract. The updated results have been published online by Lancet Oncology in July 2023. See Dummer R, Queirolo P, Gerard Duhard P, et al: Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol doi: 10.1016/S1470-2045(23)00334-0. This abstract was retracted on August 7, 2023. Background: Despite recent advances in the treatment of melanoma, there remains an urgent need to improve outcomes in pts with CNS mets. To date, studies evaluating intracranial activity of immunotherapies and targeted therapies have included limited numbers of pts with symptomatic CNS mets. Cohort 2 of the phase 2 Tricotel study evaluated the safety and efficacy of A + C + V in BRAFV600-mutated melanoma with CNS mets, including symptomatic pts receiving corticosteroids. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Primary outcome was intracranial objective response rate (ORR; confirmed by assessments ≥4 wk apart per independent review committee [IRC]). Secondary end points were investigator-assessed intracranial ORR, extracranial ORR, overall ORR, duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Prespecified subgroup analyses were performed in pts receiving corticosteroids (&gt;2 mg/d dexamethasone) and/or with CNS-related symptoms at baseline vs asymptomatic pts. Results: This study enrolled 65 pts (median age, 55 y; 63% male). At baseline, 37% were on corticosteroids and/or were symptomatic; 49% had elevated lactate dehydrogenase. Median follow-up was 9.7 mo for all pts, 10.0 mo for pts on corticosteroids and/or symptomatic at baseline (n = 24), and 9.7 mo for asymptomatic pts (n = 41). Intracranial ORR was 42% by IRC and 51% by investigator (BOR concordance: 68%). Intracranial DOR and PFS are listed in the Table. In pts on corticosteroids and/or symptomatic at baseline, ORR was 58%, DOR was 10.2 mo, and PFS was 7.2 mo by investigator; in asymptomatic pts, ORR was 46%, DOR was 5.7 mo, and PFS was 5.5 mo. Additional secondary efficacy end points will be presented. In 60 pts who received A + C + V, grade 3/4 adverse events (AEs) occurred in 70% of pts; most commonly lipase increased (27%) and blood CPK increased (17%). Serious AEs occurred in 30% of pts. AEs led to discontinuation of any study treatment in 27% of pts. Conclusions: Addition of A to C + V provides promising intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets, particularly in those receiving corticosteroids and/or in symptomatic pts. The safety profile of A + C + V is consistent with that observed in the IMspire150 study. Clinical trial information: NCT03625141. [Table: see text]

Real-world assessment of clinical outcomes in NSCLC patients with MET exon 14 skipping mutation and brain metastases (BM) treated with capmatinib.

e21171 Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 NSCLC in the US in 2020 based on the GEOMETRY mono-1 trial data. Subgroup analyses from that study showed intracranial (IC) efficacy in pts with BM. However, there were no data on the effectiveness of capmatinib in pts with BM in the real-world setting; IC effectiveness is particularly challenging to study as many pts are also treated with radiation therapy (RT) to the brain. The current study examined real-world clinical outcomes of pts with NSCLC with MET exon 14 skipping mutation and BM who were treated with capmatinib, including those who were RT-naïve. Methods: A retrospective medical record review was performed by panel-based oncologists recruited nationwide in the US. Eligible pts were aged ≥ 18 years, had confirmed BM diagnosis and MET exon 14 skipping mutated NSCLC, started capmatinib therapy in any line following BM diagnosis (with ≥ 1 IC lesion ≥ 10 mm), and had a follow up of ≥ 6 months after starting capmatinib (except death). Modified (pseudo) RECIST and RANO-BM criteria were used for response assessments. Key outcomes were IC and systemic real-world best overall response rate (rwORR), disease control rate (rwDCR), progression-free survival (rwPFS), and time-to-treatment discontinuation (TTD) assessed separately for first-line (1L) capmatinib and immunotherapy (IO)-containing regimens alone or in combination with chemotherapy (CT). The analyses are descriptive in nature. Outcomes were also analyzed in RT-naïve pts (no prior/concurrent BM RT). Results: A total of 68 eligible pt charts were abstracted (median age at BM diagnosis, 64.3 years; 60.3% male; 72.1% treated in academic setting; 83.8% de novo metastatic). For the 1L therapy after BM diagnosis, 80.9% (n = 55) received capmatinib, 16.2% (n = 11) received IO-containing regimens, and 2.9% received CT alone; 29 pts were RT-naive. The IC rwORR in RT-naïve pts was 85.0% for capmatinib 1L and 11.1% for IO 1L (Table). In the overall cohort, the IC rwORR was 87.3% (rwDCR 96.4%) for capmatinib 1L and 27.3% (rwDCR 45.5%) for IO 1L. Median systemic rwPFS was 14.1 months for capmatinib 1L and 5.1 months for IO 1L. The 1-year systemic rwPFS rate was 70.8% for capmatinib 1L and 18.2% for IO 1L. TTD was 13.2 months for capmatinib 1L and 5.1 months IO 1L. Conclusions: This study shows a substantial systemic and IC effectiveness associated with capmatinib 1L use in pts with NSCLC with MET exon 14 and BM in the real-world setting. These findings remain true in RT-naïve pts.[Table: see text]