Symptomatic Central Nervous System Research Articles

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.

Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients. In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1. Overall, 439 patients were randomized (zorifertinib n= 220; control n= 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p= 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3months with zorifertinib and 31.8months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib. Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC. This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.

Progression patterns, resistant mechanisms and subsequent therapy for ALK-positive NSCLC in the era of second-generation ALK-TKIs

BackgroundIn the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC).MethodsPatients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.ResultsThe incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15–0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18–1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.ConclusionsFirst-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient’s overall physical health and personal preferences.

The 31-GEP to identify patients with localized cutaneous melanoma at the highest risk of metastasis to the central nervous system.

9530 Background: Cutaneous melanoma (CM) metastasis to the central nervous system (CNS) has a poor prognosis; however, treatment of CNS metastasis while asymptomatic is associated with better outcomes. CNS imaging is not routinely recommended for patients with early-stage CM (i.e., AJCC stage I–II), yet ˜14% of patients with stage II melanoma will develop CNS metastases. The 31-gene expression profile test (31-GEP) identifies patients at a low (Class 1A), intermediate (Class 1B/2A), or high risk (Class 2B) of tumor recurrence and metastasis. We evaluated the association of CNS metastasis with the 31-GEP test result for the purpose of directing CNS-directed imaging to detect metastasis earlier and, thus, improve outcomes. Methods: A retrospective analysis of patients clinically tested with the 31-GEP from 2013-2017. Patients were included in the study if they had clinical or pathological AJCC stage I-II CM (n=1,662). Kaplan-Meier analysis was used to estimate 5-year recurrence-free survival (RFS), and the log-rank test was used to compare survival between groups. Patients with non-CNS metastasis were censored at the time of recurrence. Univariate analysis to identify predictors of CNS metastasis was performed for tumor location, mitotic rate, Breslow thickness, ulceration status, tumor-infiltrating lymphocytes, age, sex, regression, lymphovascular invasion, tumor subtype, and 31-GEP results. Only significant (p<0.01) factors in univariate analysis were included in Cox multivariable analysis. Results: Median follow-up time was 4.6 years (range: 0.02-14.5 years). Patients with a CNS metastasis tended to have thicker tumors (median 1.1 vs. 0.8, p=0.003), higher mitotic rate/mm2 (median 2.5 vs. 1.0, p<0.001) and a higher proportion of males (73% vs. 55%, p=0.03) than patients that did not develop CNS metastasis. Patients with a Class 2B result were significantly more likely to develop CNS metastasis (7.4% [15/202]) relative to patients with a Class 1B/2A (1.7% [5/291]) or Class 1A (0.9% [10/1,169], p<0.001) 31-GEP result. Patients with a Class 2B result had significantly lower 5-year RFS than patients with a Class 1B/2A or Class 1A result (91.6% vs. 98.2% vs. 99.1%, p<0.001) and had shorter times to CNS metastases (1.5 yrs. vs. 4.2 yrs. vs. 3.4 yrs. p<0.001). In multivariable analysis, only the 31-GEP Class 2B (HR=9.42, p<0.001) result was a significant predictor of CNS metastasis; mitotic rate, Breslow thickness, and ulceration were not significantly predictive. Conclusions: Under multivariable analysis, the 31-GEP was the only significant predictor of CNS metastasis, and CNS metastasis occurred early (1.5 yrs). Patients with early-stage I-II CM and a Class 2B result should be considered for CNS imaging to enable asymptomatic detection of CNS metastasis and, thus, improve survival relative to symptomatic CNS metastasis.

DCC-3116 in combination with ripretinib for patients with advanced gastrointestinal stromal tumor: A phase 1/2 study.

TPS11587 Background: Advanced cancers driven by mutations at or downstream of receptor tyrosine kinases (RTKs), including KIT- and PDGFRA-mutant gastrointestinal stromal tumor (GIST), activate autophagy as an escape mechanism in response to RTK pathway inhibitors. ULK1/2 kinases are key regulators that initiate autophagy in response to stress, such as KIT/PDGFRA inhibition in KIT- and PDGFRA-mutant GIST. Therefore, ULK1/2 inhibition represents a potential targeted approach to selectively inhibit autophagy and is an attractive strategy for combination with RTK pathway inhibitors, including ripretinib. Ripretinib is a switch-control KIT/PDGFRA tyrosine kinase inhibitor approved as a ≥fourth-line therapy for advanced GIST. In the INTRIGUE trial, ripretinib demonstrated comparable efficacy and more favorable safety compared with sunitinib in second-line advanced GIST. DCC-3116 is an investigational, selective, potent, switch-control kinase inhibitor of ULK1/2 in development for combination with targeted therapies that activate autophagy, such as ripretinib. In a GIST xenograft model, animals treated with ripretinib demonstrated stable tumor burden while treatment with ripretinib + DCC-3116 resulted in complete regressions. Here, we describe the design of a phase 1/2, multicenter, open-label study evaluating the safety, recommended phase 2 dose (RP2D), and preliminary efficacy of DCC-3116 in combination with ripretinib in advanced GIST (NCT05957367). Methods: This phase 1/2 study includes safety/dose-finding (part 1) and expansion (part 2). In part 1, patients (pts) ≥18 years must have pathologically confirmed GIST with a KIT or PDGFRA mutation and disease progression on or intolerance to ≥1 systemic regimen. Escalating doses of DCC-3116 will be assessed with ripretinib 150 mg once daily. Part 1 will use safety, pharmacokinetics, pharmacodynamics, preliminary efficacy, and a Bayesian optimal interval design to identify the RP2D for part 2 and the maximum tolerated dose. In part 2, second-line pts with confirmed GIST with a KIT exon 11 mutation and disease progression on or intolerance to first-line imatinib will be enrolled. Part 2 will use a two-stage design with non-binding futility and efficacy analyses after stage 1 to explore efficacy of the combination dose selected in part 1. Exclusion criteria for both parts include use of other anticancer treatments, such as ripretinib, and any investigational therapies within 14 days, use of moderate or strong inhibitors or inducers of cytochrome P450 3A4 or P-glycoprotein, symptomatic central nervous system metastases or leptomeningeal disease, and active infections. Primary objectives in part 1 are to identify adverse events and the RP2D. The primary objective of part 2 is to determine the objective response rate per modified Response Evaluation Criteria in Solid Tumors version 1.1. The study is currently enrolling. Clinical trial information: NCT05957367 .

Abstract PO5-04-01: Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment

Abstract Objective: To explore the efficacy and safety of Inetetamab Combined with Sirolimus and Chemotherapy in the treatment of human epidermal factor receptor 2 (HER2) positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR (PAM) pathway after Trastuzumab treatment. Methods: This prospective multicenter clinical study enrolled HER2 positive metastatic breast cancer patients at the National Cancer Center in China from July 2021 to September 2022 with PAM pathway mutation confirmed by histology or peripheral blood genetic testing. The inclusion criteria included: 1) Recurrent and metastatic breast cancer patients with HER2 positive confirmed histologically; 2) ECOG PS score ≤ 2; 3) Patients who have progressed after previous treatment with Trastuzumab; 4) Patients with PAM pathway mutation confirmed by Genetic testing; 5) Patients' cardiac, pulmonary, liver and bone marrow functions are basically normal; 6) Patients voluntarily sign informed consent forms. The exclusion criteria included: 1) Patients previously treated with mTOR inhibitors or pyrotinib; 2) Patients who have used chronic Corticosteroid for more than 3 months or used Immunosuppressive drug within 4 weeks; 3) Patients with symptomatic central nervous system metastasis; 4) Patients with left ventricular Ejection fraction< 50% or clinical manifestations of obvious arrhythmia, myocardial ischemia, severe atrioventricular block, cardiac insufficiency, and severe valvular disease; 5)Diagnosed with other malignant tumors within five years. Patients were randomly divided into trial group and control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, and control group received pyrotinib and chemotherapy. RECISTv1.1 standard was used to evaluate the efficacy of patients. Descriptive statistics are used to summarize clinical pathological features. Kaplan Meier method was used to draw survival curves. Log-rank test was used to compare progression free survival (PFS) differences between groups. P< 0.05 was considered statistically significant. Results:A total of 59 HER2 positive metastatic breast cancer patients with abnormal activation of PAM pathway were included, of which 37 patients received the treatment of inetetamab group and 22 patients received the treatment of pyrotinib group. The median follow-up time was 5.33 months. In the intent-to-treat set, the median PFS of patients in the inetetamab group was 4.64 months, which was shorter than 5.69 months in the pyrotinib group. There was no statistically significant difference between the two groups (P=0.51; HR=0.41; 95% CI, 0.12-1.45). The objective response rate (ORR) of the inetetamab group and the pyrotinib group were 28.1% and 29.4%, respectively. In terms of safety, the incidence of adverse events (AE) in the experimental group was (33/37) 89.1%, while (16/21) 76.2% in the control group. The incidence of AE above level 3 in the inetetamab group and pyrotinib group were (13/37) 35.1% and (3/21) 14.3%, respectively. Conclusion:For the metastatic HER2 positive breast cancer patients with abnormal activation of PAM pathway treated with trastuzumab previously, the combination of inetetamab with sirolimus and chemotherapy regimen are equivalent to the combination of pyrotinib and chemotherapy regimen. It demonstrated that combination of inetetamab with sirolimus and chemotherapy could be one of the treatment options for the metastatic HER2 positive breast cancer patients. Citation Format: Qiao Li, Dan Lv, Xiaoying Sun, Mengyuan Wang, Li Cai, Feng Liu, Chenghui Li, Jiuda Zhao, Jing Sun, Yehui Shi, Fei Ma. Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-01.

Outcomes of Operated Cases of Central Nervous System Metastases at a Tertiary Cancer Hospital – An Analysis

Abstract Background: Recent advances in the treatment have increased the survival of patients with common cancers. As a result, the incidence of symptomatic central nervous system (CNS) metastases has increased over time. Although systemic therapies remain the mainstay of metastatic cancers, surgical treatment is often required for progressive neurological deficits and to buy time for other modalities to be effective. The present retrospective study aimed to analyze various demographic, neurological, and short-term survival outcomes among operated cases of symptomatic CNS metastases. Materials and Methods: All surgically treated symptomatic brain and spine metastasis patients between August 2018 and March 2022 were included in the study. Patients who underwent procedures for primary tumors of the brain and spine were excluded. The details of demographic and clinical profile, neurological data, surgical treatment, and short-term survival data were retrieved from hospital medical records and analyzed. Patients with motor deficits (power grade 3/5 or less) were analyzed to look for improvement in motor deficits after surgery. Results: The first 100 operated cases of symptomatic CNS metastases were reviewed. The mean age of presentation was 46.42 years (females – 44.28, males – 49.13). Breast malignancy was the most common source of primary overall (29%) and lung malignancy (15%) was second most common. A total of 53 brain surgeries and 47 spine surgeries were performed. Preoperative motor deficits were seen more commonly among spine metastases (30/47) than brain metastases (17/53) patients. Around 64% of patients who presented with neurological deficits (motor deficits) had improvement postsurgery. Such improvement from deficits was observed more in patients with spine metastases (23/30; 76.7%) than brain metastases (7/17; 41.2%). Conclusion: Neurosurgery has an important role in the management of CNS metastases, and timely surgical intervention in a selected group of symptomatic CNS metastases can improve the quality of life of the patients.

A Phase I Study of Venetoclax in Combination with Inotuzumab Ozogamicin for Relapsed or Refractory ALL in Adults

Introduction Adults with acute lymphoblastic leukemia (ALL), especially those who are older and/or have unfavorable disease biology frequently relapse. Inotuzumab ozogamicin (INO), an anti-CD22 monoclonal antibody covalently linked to calicheamicin, is approved for treatment of relapsed or refractory (R/R) CD22+ ALL. Although INO induces measurable residual disease negative (MRD-neg) complete remission (CR) in >75% of patients (pts), the duration of response (DOR) is limited (<6 months). Pre-clinical work demonstrates that malignant lymphoblasts are BCL2-dependent (Del Gaizo Moore Blood 2008). Initial results of the BCL2 inhibitor venetoclax (VEN) combination therapies for ALL are promising (Jain ASH 2019, Pullarkat Cancer Discov 2021). Due to distinct mechanisms of activity, non-overlapping toxicity, and possible synergy (Kirchhoff Blood 2021), we hypothesized that INO and VEN can be safely and effectively combined. Study Design and Eligibility This is an investigator-sponsored phase I study (NCT05016947) with a 3+3 dose escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of VEN plus INO at the FDA-approved doses in adults with R/R CD22+ ALL. Secondary objectives assess efficacy (hematologic response, MRD by multi-parametric flow cytometry [MFC] threshold <0.01%, and DOR). A 14 pt expansion cohort is planned. Dose-limiting toxicity (DLT) is defined as treatment-related CTCAE v5 non-heme toxicity grade 3+, sinusoidal obstructive syndrome (SOS) any grade, or liver toxicity during Induction (Ind) Cycle (C) 1 and/or failure of hematologic recovery (ANC ≥500, Plts ≥25 K/mL) by day 42 of Ind C1 in responding pts. Eligibility: ≥18 years (yrs); ALL (≥5% blasts) or LBL (marrow involvement not required); CD22 expression on ≥20% of blasts; R/R to one or more cycles of CC or in the case of Philadelphia-chromosome (Ph)-positive ALL, failed by two or more TKIs, or refractory to/ineligible for ponatinib; ≥60 days from bone marrow transplant (BMT), and off immune suppression ≥2 weeks; adequate liver and kidney function; no history of liver disease including SOS; blast count ≤25 K/mL prior to treatment; no symptomatic central nervous system (CNS) disease. Pts with prior INO or VEN treatment for R/R ALL are excluded. Regimen Pts are treated with a VEN Ramp-Up over 3 days (DL1: 100/200/200; DL2: 100/200/400) followed by Induction C1: IV INO days 1, 8, 15 (0.8/0.5/0.5 mg/m2) and VEN daily per DL days 1-21. DEX 10 mg/m2 IV/PO is administered during Ramp-Up and Ind C1 days 1-4 (7 days total). Pts with >5% blasts after C1 receive Ind C2 without DEX. Pts with <5% blasts after Ind (1 or 2 cycles) continue with up to four 28-day consolidation cycles (INO 0.5 mg/m2 days 1, 8, 15 plus VEN per DL days 1-21). Pts receive CNS prophylaxis with intrathecal chemotherapy. Results The 2-level dose-escalation phase has been completed; we enrolled 9 pts (5 female/4 male) with Ph-negative (n=7) or Ph-positive (n=2) ALL. The median age was 45 yrs (range 25 -74). Pts had received 1 (n=5) or 2 (n=4) prior lines of therapy. DL1 enrolled 3 pts without DLT. All DL1 pts achieved an MRD-neg CR and bridged to consolidation: 1 pt XRT to involved disease site (ankle) after 3 cycles and 2 pts to BMT after 2 cycles (Table). Three pts enrolled at DL2; no DLTs were observed. All achieved an MRD-neg CR. Two pts bridged to consolidation (donor lymphocyte infusion after 3 cycles, blinatumomab after 5 cycles) while 1 pt with KMT2A-r ALL experienced early relapse with lineage switch during second cycle. A confirmatory cohort of 3 pts enrolled at DL2 without DLT. All achieved a CR (n=2, MRD-neg; n=1, MRD-pos). The pt with MRD-pos CR as best response proceeded to blinatumomab as bridge to BMT after 2 cycles with 2 pts continuing treatment (currently cycle 2). Overall, CR was achieved in 100% (9/9) of pts with 7/8 (87%) achieving MRD-negativity. With median follow-up of 195 days (95% CI 80 - NR), 2 pts have relapsed 48 (on treatment) and 177 (after BMT) days from registration while other pts remain alive in CR. Non-heme grade 3-4 AEs include febrile neutropenia (2), DIC (1), tumor lysis syndrome (1), anxiety (1), hypertension (1), and hypotension (1). There have been no SOS. There were no delays in count recovery during C1, with median time from C1 to C2 being 30 days (range 27-42). Conclusion VEN 400mg x 21 days in combination with INO at standard doses was well tolerated and declared the recommended phase 2 dose (RP2D) with a CR rate of 100%.

Randomized phase 3 study of tarlatamab, a DLL3-targeting bispecific T-cell engager (BiTE),compared to standard of care in patients with relapsed small cell lung cancer (DeLLphi-304).

TPS8611 Background: Small cell lung cancer (SCLC) is an aggressive malignancy for which very few patients achieve long term disease control; response to most treatments is transient and second line treatment options are limited. Delta-like ligand 3 (DLL3) is a Notch ligand aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it an attractive therapeutic target. Tarlatamab is a bispecific T cell engager (BiTE) molecule designed to bind DLL3 on target cancer cells and CD3 on T cells, thereby driving T cell-dependent killing of tumor cells. Results from the first-in-human study in patients with relapsed/refractory SCLC (DeLLphi-300; NCT03319940) demonstrate tarlatamab efficacy in pretreated patients with confirmed responses in 23% of patients and median duration of response > 12 months.1 Median overall survival (OS) was 13.2 months. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 31% of patients and TRAEs resulted in discontinuation in 4% of patients. This promising efficacy/safety profile is being evaluated further in a phase 2, open-label study in patients with relapsed/refractory SCLC after ≥2 lines of prior treatment (DeLLphi-301; NCT05060016). Methods: NCT05740566 is a randomized, open-label, phase 3 study of tarlatamab compared with standard of care (SOC) in ~700 patients with relapsed SCLC after platinum-based first-line chemotherapy. Patients will be randomized 1:1 to receive tarlatamab or SOC therapy (lurbinectedin or topotecan in US, Canada, Australia, Singapore, Korea; amrubicin in Japan; topotecan in all countries except Japan), stratified by prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) exposure, chemotherapy-free interval, presence of brain metastases, and SOC (topotecan/amrubicin vs lurbinectedin). The primary objective is to compare the efficacy of tarlatamab with SOC on prolonging OS. Key secondary endpoints include comparison of progression free survival (PFS) based on investigator assessment per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and patient-reported outcomes (PRO) including disease-related symptoms, physical function, and global health status of quality of life. Key eligibility criteria include adults with histologically or cytologically confirmed relapsed SCLC who progressed following 1 platinum-based regimen. Patients must have measurable lesions as defined per RECIST 1.1 within the 21-day screening period and must have adequate organ function. Exclusions include untreated or symptomatic central nervous system metastases, history of immune checkpoint inhibitor use resulting in severe immune-mediated adverse event, and previous history of NSCLC. Enrollment is ongoing.

Dramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge

Poorly differentiated pancreatic neuroendocrine tumors (PDNEC), are a subtype of pancreatic cancer encompassing both small cell and large cell neuroendocrine carcinoma subtypes, and are characterized as distinct in terms of biology and prognosis compared to the more common pancreatic adenocarcinoma. Until recently, there has been a paucity of data on the genomic features of this cancer type. We describe a male patient diagnosed with PDNEC and extensive metastatic disease in the liver at diagnosis. Genomic analysis demonstrated a germline pathogenic variant in BRCA2 with somatic loss-of-heterozygosity of the BRCA2 wild-type allele. Following a favorable response to platinum-based chemotherapy (and the addition of immunotherapy), the patient received maintenance therapy with olaparib, which resulted in a further reduction on follow-up imaging (Fig. 1). After seventeen months of systemic control with olaparib, the patient developed symptomatic central nervous system metastases, which harboured a BRCA2 reversion mutation. No other sites of disease progression were observed. Herein, we report an exceptional outcome through the incorporation of a personalized management approach for a patient with a pancreatic PDNEC, guided by comprehensive genomic sequencing.

Abstract OT2-16-02: Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12

Abstract Background: Patients (pts) with human epidermal growth factor receptor 2–positive breast cancer (HER2+ BC) have a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in pts with HER2+ BC with BM, an unmet medical need remains. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM (n=24), with a confirmed objective response rate (ORR) of 61.4%, an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, and median progression-free survival (PFS) of 19.4 and 18.1 months, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). T-DXd also demonstrated preliminary efficacy in a subgroup of pts with BM in the DESTINY-Breast03 trial, with an extracranial ORR of 67.4%, intracranial ORR of 63.9%, and median PFS of 15.0 months (Hurvitz S et al. SABCS 2021. Abst GS3-01). However, both trials excluded pts with active/progressive BM. Here we describe a trial evaluating T-DXd in a real-world setting in pts with stable or active BM and pts without BM with previously treated advanced/metastatic HER2+ BC. The data generated by this study will complement previous and ongoing studies, providing a more robust understanding of T-DXd treatment in patients with and without BM. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (91 sites in the US, Europe, Australia, Canada, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg every 3 weeks in pts with HER2+ BC ± BM. As part of prescreening, all pts will provide informed consent for tumor tissue samples (archival tumor tissue or fresh biopsy) to be collected and tested for HER2 status. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (no BM at baseline) and cohort 2 (BM at baseline). Pts must have previously treated HER2-positive BC that has progressed on or after ≥1 prior anti-HER2–based regimen (including disease progression ≤6 months after adjuvant treatment with HER2-targeted therapies) and received ≤2 lines of therapy in the metastatic setting (excluding pts with prior tucatinib). Cohort 1 will be limited to include ≤25% third-line pts. Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 per ICR). Secondary endpoints in both cohorts are overall survival, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and quality of life. Incidence of new symptomatic central nervous system (CNS) metastasis is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNS metastasis are secondary endpoints in cohort 2. Citation Format: Nancy U. Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Manoj Prahladan, Nadia Harbeck. Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-02.

Abstract OT2-03-01: heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer

Abstract BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-01.

RELATIVITY-106: A phase 1/2 trial of nivolumab (NIVO) + relatlimab (RELA) in combination with bevacizumab (BEV) in first-line (1L) hepatocellular carcinoma (HCC).

TPS636 Background: The current standard of care for 1L treatment of patients with advanced/metastatic HCC is atezolizumab + BEV, which demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to sorafenib in treatment-naïve patients. However, only 29.8% of patients show objective responses and additional therapy options are needed in the 1L setting. Programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) are distinct inhibitory immune checkpoint pathways that synergistically reduce T-cell function. RELA is a first-in-class human immunoglobulin G4 LAG-3-blocking antibody that binds to LAG-3 and restores the effector function of T cells. Dual checkpoint inhibition of the PD-1 and LAG-3 pathways with NIVO + RELA has the potential to boost immune surveillance in HCC. Preclinical data presume that BEV, a human vascular endothelial growth factor inhibitor, reverses abnormal vascularization to allow NIVO + RELA to inhibit hypoxia-induced programmed cell death ligand 1 and LAG-3 expression and enhance depth of response and OS in HCC. Here we describe the RELATIVITY-106 study investigating the triplet therapy of NIVO + RELA + BEV in the 1L treatment of advanced/metastatic HCC. Methods: RELATIVITY-106 (NCT05337137) is a phase 1/2, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of NIVO + RELA + BEV compared with NIVO + BEV in treatment-naïve patients with advanced/metastatic HCC. Key inclusion criteria include age ≥ 18 years; histologic confirmation of advanced/metastatic HCC in patients naïve to systemic therapy for advanced/metastatic HCC (prior neoadjuvant or adjuvant immunotherapy permitted if recurrence occurs ≥ 6 months after treatment completion); Child-Pugh A; and ECOG performance status 0 or 1. Key exclusion criteria include known fibrolamellar HCC, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma; prior allogenic stem cell or solid organ transplantation; untreated symptomatic central nervous system metastases; clinically significant ascites; increased risk of bleeding; significant vascular disease or inadequately controlled hypertension; and major surgical procedure within 4 weeks prior to study treatment. Primary endpoints include incidence of dose-limiting toxicities assessed for up to 6 weeks and PFS by blinded independent central review (BICR) per RECIST v1.1 in all randomized patients in phase 1 and phase 2, respectively. Secondary endpoints include overall response rate (ORR) by BICR and OS in all randomized patients; ORR and PFS by BICR and OS in all randomized LAG-3-positive patients (≥ 1% by immunohistochemistry); and safety. Key exploratory endpoints include pharmacokinetics and immunogenicity assessed by antidrug antibody positivity. The study, initiated in May 2022, is currently enrolling globally. Clinical trial information: NCT05337137 .

Abstract A019: Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma

Abstract Background: CDK9 blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as MCL1 and MYC. TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. The anti-tumor activity of alvocidib has previously been shown in vitro in a Ewing sarcoma cell line and in vivo in a mouse Ewing sarcoma xenograft model. TP-1287 is being investigated in a phase 1 dose escalation and dose expansion study in patients with solid tumors (escalation) and sarcoma (expansion) (NCT03604783). The design of the expansion part of the phase 1 study in patients with sarcoma is herein described. Methods: Thirty patients with sarcoma will be enrolled. Key eligibility criteria are age ≥18 years (≥16 years if ≥40 kg); histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma, dedifferentiated liposarcoma, or synovial sarcoma (10 patients each); 1–3 prior lines of therapy (including an anthracycline); Eastern Cooperative Oncology Group performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status. Exclusion criteria include a history of certain cardiovascular diseases (including heart failure and myocardial infarction [≤6 months]); seizure disorder requiring anticonvulsant therapy; presence of symptomatic central nervous system metastatic disease or disease that requires local therapy ≤2 weeks; severe chronic obstructive pulmonary disease with hypoxemia; active infections; or treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives (whichever occurs first). Patients will be treated at the recommended phase 2 dose established during dose escalation (11 mg twice daily orally, continuous dosing) and will continue to receive treatment with the same dose/schedule if they successfully complete a 28-day treatment cycle without significant treatment-related toxicity or progressive disease. Assessments will be performed on Day 1 and Day 15 of each cycle. Assessments for response and tumor burden will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objective is objective response rate; secondary objectives are progression-free survival at 16 and 24 weeks and safety; and exploratory objectives are systemic exposure, antitumor activity (by objective radiographic assessment), and pharmacodynamics. Tumor tissue concentrations may be measured in patients who consent to optional tumor biopsies. Statistical analysis for all safety and efficacy parameters will be primarily descriptive in nature; time-to-event variables will be summarized via Kaplan-Meier. The dose expansion cohort is currently recruiting in the United States. Results: N/A. Conclusions: N/A. Citation Format: Andrew J. Wagner, Gregory M. Cote, Donald Richards, Nicholas J. Vogelzang, William J. Edenfield, Mitchell E. Gross, Lynn Mar, Gil D. Fine, Edward Dow, John A. Charlson. Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A019.

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.

An open-label, multicenter, phase 2 study of the safety and efficacy of navtemadlin (KRT-232) in patients with TP53 wild-type relapsed/refractory small cell lung cancer.

TPS8600 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early metastasis and a high recurrence rate with currently available treatment options. Although SCLC is generally sensitive to initial chemotherapy, responses are not durable and most patients eventually relapse. Prognosis is poorer in the relapsed/refractory (R/R) setting and currently available treatment options, including checkpoint inhibitors, are associated with a median overall survival of 2-9 months (Chauhan 2020; Trigo 2020; Chung 2020). Approximately 15% of patients have a TP53 wild-type ( TP53WT) gene. In patients with extensive-stage SCLC, TP53WT is paradoxically associated with an inferior response to chemotherapy (Dowlati 2016). Thus, the presence of TP53WT may help identify a small subset of patients with an even greater unmet need. Murine double minute 2 (MDM2) is the key negative regulator of the tumor suppressor protein, p53, which can induce apoptosis of malignant cells by shifting the balance between prosurvival and proapoptotic BCL-2 family members. In SCLC cell lines, MDM2 inhibition restored p53 function leading to downregulation of prosurvival Bcl-2 and Mcl-1 proteins, and upregulation of the proapoptotic Bim protein, thereby inducing cancer cell death (Yu 2019). Navtemadlin (KRT-232) is a potent, selective, orally available MDM2 inhibitor that restores p53 function to drive apoptosis of TP53WT malignancies. Treatment with navtemadlin may be an effective strategy for patients with TP53WT SCLC. Methods: The open-label, multicenter Phase 2 KRT-232-112 study (NCT05027867) is evaluating navtemadlin in TP53WT patients with R/R SCLC. Eligibility criteria include age ≥18 years, ECOG performance status ≤2, presence of measurable disease and demonstrated radiographic progression after ≥1 prior platinum-containing therapy with no curative therapy available. Patients must have received a checkpoint inhibitor if available and not contraindicated. Patients with symptomatic or uncontrolled central nervous system metastases or those with prior MDM2 inhibitor treatment will be excluded. In part 1 of the study, approximately 20 patients will be randomly assigned to receive oral navtemadlin once daily in 21-day cycles at 240 mg 7 days (D) on/14D off (Arm A) or 180 mg 7D on/14D off (Arm B) until disease progression or unacceptable toxicity. In part 2, an additional 18 patients will be enrolled in each arm selected for expansion. The primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. This trial is ongoing and will enroll patients at approximately 40 global sites. Clinical trial information: NCT05027867.

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 (>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]

VP Shunt With Recurrent Malfunction in Two Pediatric Patients: Is the Hydrocephalus Truly Idiopathic?

VP Shunt With Recurrent Malfunction in Two Pediatric Patients: Is the Hydrocephalus Truly Idiopathic?

P76.13 Osimertinib Delays but Not Prevents Central Nervous System Metastasis in EGFR-Mutant Advanced Non-Small Cell Lung Cancer

Central nervous system (CNS) is a common site of EGFR Tyrosine kinase inhibitor (TKI) treatment failure in advanced non-small cell lung cancer (NSCLC). Various EGFR TKIs with distinct potencies against CNS metastasis are approved. This study aims to compare the incidence of symptomatic CNS metastasis in advanced EGFR-mutant NSCLC without baseline CNS lesions and receiving first- or third-generation EGFR TKIs. Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis and receiving standard of care EGFR-TKIs were included. Cumulative incidences of symptomatic CNS metastasis upon EGFR-TKI treatment failure were calculated using the Kaplan-Meier method and significant risk factors of CNS metastasis were identified using the Cox proportional hazards models. Furthermore, radiographic features and clinical outcomes of patients who developed CNS metastasis were analyzed. Among 935 patients enrolled, 633, 143 and 35 received first-line gefitinib, erlotinib and osimertinib, respectively, and the remaining 124 received second-line Osimertinib. At a median follow-up of 10 months (range, 1-93 months), 517 patients developed EGFR-TKI treatment failure, of whom 45 had symptomatic CNS metastasis. The 1-, 2- and 3-year cumulative incidences of symptomatic CNS metastasis were 4.2%, 7.9% and 14.4%, respectively. There was no difference of developing symptomatic CNS metastasis among patients receiving gefitinib or erlotinib (p=0.857), while patients receiving osimertinib (Group B) had a significant lower risk than those receiving first-generation EGFR-TKIs (Group A) (HR 0.45; 95%CI 0.20-0.99, p=0.049). Of note, the survival curves tended to reach a plateau after three years, and the cumulative incidence of symptomatic CNS metastasis beyond that time, as well as the percentage of patients who developed symptomatic CNS metastasis among those who had EGFR-TKI treatment failure, was similar in Group A and Group B. Patients harboring L858R mutation had a higher risk developing symptomatic CNS metastasis than patients harboring other types of sensitizing EGFR mutations (p=0.003). Among 45 patients who developed symptomatic CNS metastasis, 20 had single cranial lesion, 39 had a largest tumor lesion smaller than 3cm and 39 had metastatic lesion outside the hippocampus region. Moreover, among the 45 patients, median overall survival (OS) calculated from the diagnosis of advanced disease was 33.3 (95%CI 24.8-41.8) months, and patients with single cranial lesion had a significantly longer OS (p=0.011). Compared with first-generation EGFR-TKIs, osimertinib significantly delays the development of symptomatic CNS metastasis in EGFR-mutant advanced NSCLC and L858R mutation is an independent risk factor of CNS metastasis.

FP14.05 LIBRETTO-431: Selpercatinib in Treatment-Naïve Patients with RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC).

Selpercatinib (LOXO-292) is a highly selective and potent inhibitor of RET signaling. In the LIBRETTO-001 Phase I/II trial, selpercatinib treatment resulted in a 64% objective response rate (ORR) (95% confidence interval [CI]: 54-73%) in the registration dataset (n=105) of patients with RET+ NSCLC who previously received platinum-based chemotherapy and an 85% ORR (95% CI: 70-94%) in treatment-naïve patients with RET+ NSCLC (n=39). Although the duration of response (DOR) and progression free-survival (PFS) were not yet mature in treatment-naïve patients, in patients who previously received chemotherapy, the median DOR was 18 months (95% CI: 12-not estimable [NE]), median PFS was 17.5 months (95% CI: 12-NE), and CNS ORR per RECIST 1.1 was 91% (95% CI: 59-100%) (n=10/11). The most common adverse reactions included dry mouth (39%), diarrhea (37%), hypertension (35%), and fatigue (35%). The majority of adverse reactions were Grade 1 or Grade 2. The most common lab abnormality was increased alanine aminotransferase (ALT) (51%)/aspartate transaminase (AST) (45%). A total of 5% of patients discontinued due to an adverse reaction. The LIBRETTO-431 trial, is a global, open-label, randomized, controlled, Phase 3 trial evaluating selpercatinib vs platinum-based and pemetrexed treatment +/- pembrolizumab in treatment-naïve patients with locally advanced or metastatic RET+ non-squamous NSCLC (NCT04194944). Patients will be randomized to receive selpercatinib 160 mg BID in 3-week cycles (Arm A) or pemetrexed (500 mg/m2 IV) in 3-week cycles plus investigator’s choice of carboplatin (AUC 5) or cisplatin (75 mg/m2 IV) for 4 cycles (Arm B). For patients in Arm B, at the investigator’s discretion, pembrolizumab (200 mg IV) may also be given for up to 35 cycles and patients may receive maintenance pemetrexed +/- pembrolizumab. Crossover to selpercatinib is allowed for Arm B patients who have disease progression. Treatment will be discontinued for progressive disease, unacceptable toxicity, decision to withdraw or death. Stratification factors include geography: East Asian versus non-East Asian, brain metastases: presence versus absence, and intended treatment if randomized to Arm B: +/- pembrolizumab. RET status may be determined in tumor (by PCR or NGS) or in blood (by NGS) using a qualified local test or a Lilly-enabled regional test. Key eligibility criteria include age ≥18 years; treatment-naïve; non-squamous Stage IIIB-IIIC not suitable for surgery/radiation therapy or Stage IV NSCLC; measurable disease by RECIST 1.1; ECOG performance status 0-2. Key exclusion criteria include presence of other known oncogenic drivers and symptomatic central nervous system metastases. Tumor assessments will be performed until progressive disease, the start of a new anticancer treatment, death or study completion. The co-primary endpoint, PFS by independent review in intent-to-treat (ITT) patients with pembrolizumab (if assigned to control), will act as a gatekeeper to the co-primary endpoint PFS by independent review in the ITT population. Secondary endpoints include investigator assessed PFS, ORR/DOR, intracranial ORR/DOR, overall survival, time to deterioration in pulmonary symptoms, progression after the next line of therapy, RET fusion status: local versus central, and safety/tolerability. The study was initiated in March 2020 and enrollment is ongoing. RET Kinase Inhibitor, Trial in Progress, non-small cell lung cancer (NSCLC)