Baseline Central Nervous System Metastases Research Articles

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. ClinicalTrials.gov number, NCT03849768.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC

ObjectivesFirst-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. Materials and methodsPatients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). ResultsA total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. ConclusionsOur real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1&lt;12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

Lazertinib Versus Gefitinib Tyrosine Kinase Inhibitors in Treatment-Naíve Patients With EGFR-Mutated Advanced NSCLC: Analysis of the Asian Subpopulation in LASER301

IntroductionLazertinib is a third-generation central nervous system–penetrant tyrosine kinase inhibitor targeting mutant EGFR in NSCLC. Lazertinib exhibited improved efficacy versus gefitinib in the LASER301 study; this subset analysis compared lazertinib with gefitinib among Asian patients. MethodsThe phase 3 LASER301 study evaluated lazertinib efficacy and safety in treatment-naive patients with EGFR-mutated (exon 19 deletion or L858R) locally advanced or metastatic NSCLC. Patients were randomized one-to-one and received either lazertinib or gefitinib. The primary end point was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included overall survival, objective response rate, duration of response, and safety. ResultsBetween February 13, 2020, and July 29, 2022, among 258 patients of Asian descent, the median progression-free survival was significantly longer with lazertinib than gefitinib (20.6 versus 9.7 mo; hazard ratio: 0.46; 95% confidence interval [CI]: 0.34–0.63, p < 0.001), and the benefit was consistent across predefined subgroups (exon 19 deletion, L858R, baseline central nervous system metastases). Objective response rate and disease control rates were similar between treatment groups. The median duration of response was 19.4 months (95% CI: 16.6–24.9) versus 9.6 months (95% CI: 6.9–12.4) in the lazertinib versus gefitinib group. Adverse event rates in Asian patients were comparable with the overall LASER301 population. Adverse events leading to discontinuation in the lazertinib and gefitinib groups were 13% and 12%, respectively. ConclusionsIn LASER301, efficacy and safety results in Asian patients were consistent with the overall population. Lazertinib exhibited better efficacy than gefitinib in Asian patients with a tolerable safety profile.

Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer.

3141 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a broad array of tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various non-primary CNS cancers. Here, we report data on an expanded cohort of adult pts with TRK fusion cancer treated with larotrectinib. Methods: Adults with non-primary CNS TRK fusion cancer treated in three larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687) were included. Larotrectinib was administered at 100 mg twice daily in most pts. Responses were assessed per Independent Review Committee (IRC) using RECIST v1.1. Data cut-off: July 2022. Results: As of July 2022, there were 194 adult pts enrolled, with 180 eligible for efficacy analyses by IRC; 22 pts had known brain metastases at baseline. There were 24 different tumor types; the most common were lung (n=30; 15%), soft tissue sarcoma (n=30; 15%), thyroid (n=28; 14%), salivary gland (n=25; 13%), and colon (n=23; 12%). Median age was 57 years (range 19–90). The gene fusions involved NTRK1 (n=90; 46%), NTRK2 (n=7; 4%), or NTRK3 (n=97; 50%). Pts had previously received a median of one systemic therapy (range 0–10). ORR was 57% (95% CI 50–65): 29 (16%) complete response (including one pathological complete response), 74 (41%) partial response, 39 (22%) stable disease, 23 (13%) progressive disease, and 15 (8%) not evaluable. ORR in 22 evaluable pts with baseline CNS metastases was 68% (95% CI 45–86). Median time to response was 1.8 months, and median duration of response was 43.3 months (95% CI 29.2–not estimable [NE]) at a median follow-up of 32.3 months. Median progression-free survival was 24.6 months (95% CI 11.3–34.5) at a median follow-up of 28.5 months. Median overall survival was 48.7 months (95% CI 38.5–NE) at a median follow-up of 33.8 months. At data cut-off, 39 of the 73 pts who had disease progression continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs occurred in 27 (14%) pts. Treatment discontinuation due to TRAEs was reported in one pt (increased alanine aminotransferase and aspartate aminotransferase). Conclusions: In this expanded dataset with extended follow-up, larotrectinib continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in adults with TRK fusion cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pts with solid tumors; this ensures that pts are offered the right medicine for their disease as soon as possible. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.

9110 Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .

Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9056 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated rapid, deep, and durable responses in patients (pts) with TRK fusion lung cancer (Drilon et al. ASCO 2022) and is considered a preferred first-line therapy option for these pts (Owen et al. J Clin Oncol 2022). We report updated data from a larger cohort with longer follow-up. Methods: Pts with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02576431 and NCT02122913) were included in this analysis. Larotrectinib was administered at 100 mg twice daily, and response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2022, 30 pts with a median age of 55.5 years (range 25–81) with TRK fusion lung cancer enrolled, including 12 pts with CNS metastases at baseline. The gene fusions involved NTRK1 (n = 24; 80%) or NTRK3 (n = 6; 20%). Pts received a median of 2 prior lines of systemic therapies, with 20 pts (67%) receiving ≥2. Among 27 pts eligible for IRC assessment, the objective response rate (ORR) was 74% (95% CI 54–89): 3 complete responses, 17 partial responses (PR), 4 stable disease (SD), 2 progressive disease (PD), and 1 not evaluable. Among the 12 pts with baseline CNS metastases, the ORR was 67% (95% CI 35–90): 8 PR, 2 SD, and 2 PD. The median time to response for all responders was 1.8 months. Median duration of response (DoR) was 33.9 months (95% CI 9.5–not estimable [NE]); median follow-up was 22.9 months. Median progression-free survival (PFS) was 33.0 months (95% CI 11.3–NE); median follow-up was 24.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2–NE); median follow-up was 23.1 months. For the 12 pts with CNS metastases, the medians for DoR, PFS, and OS were 9.5, 9.9, and 19.4 months, with median follow-ups of 17.4, 19.3, and 22.2 months, respectively. Duration of treatment for all pts evaluable per IRC ranged from 0.3+ to 75.2+ months. At data cut-off, 10 pts had progressed, with 6 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in 5 pts (2 each increased aspartate aminotransferase, increased weight; 1 each increased alanine aminotransferase, myalgia, hypersensitivity). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset with longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival, and favorable long-term safety in pts with advanced TRK fusion lung cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing testing for NTRK1–3 gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 , NCT02122913 .

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer.

Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+NSCLC patients. Patients who started treatment with osimertinib for EGFRm+NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p=0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p=0.010). ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. No funding was received for this trial.

Biomarkers and factors in small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

The aim of this meta-analysis was to summarize the available results of immunotherapy predictors for small cell lung cancer (SCLC) and to provide evidence-based information for their potential predictive value of efficacy. We searched PubMed, EMBASE, Web of Science, The Cochrane Library, and ClinicalTrials (from January 1, 1975 to November 1, 2021). The hazard ratios (HR) and its 95% confidence intervals (CIs) and tumor response rate of the included studies were extracted. Eleven studies were eventually included and the pooled results showed that programmed cell death ligand 1 (PD-L1) positive: objective response rate (ORR) (relative risk [RR]=1.39, 95% CI [0.48, 4.03], p=0.54), with high heterogeneity (p=0.05, I2 = 56%); disease control rate [DCR] (RR=1.31, 95% CI [0.04, 38.57], p=0.88), with high heterogeneity (p=0.04, I2 = 75%); overall survival (OS) (HR=0.89, 95% CI [0.74, 1.07], p=0.22); and progression-free survival (PFS) (HR=0.83, 95% CI [0.59, 1.16], p=0.27), with high heterogeneity (p=0.005, I2 = 73.1%). TMB-High (TMB-H): OS (HR=0.86, 95% CI [0.74, 1.00], p=0.05); PFS (HR=0.71, 95% CI [0.6, 0.85], p< 0.001). Lactate dehydrogenase (LDH) >upper limit of normal (ULN): OS (HR=0.95, 95% CI [0.81, 1.11], p=0.511). Asian patients: OS (HR=0.87, 95% CI [0.72, 1.04], p=0.135); White/Non-Asian patients: OS (HR=0.83, 95% CI [0.76, 0.90], p < 0.001). Liver metastasis patients: OS (HR=0.93, 95% CI [0.83, 1.05], p=0.229); PFS (HR=0.84, 95% CI [0.67, 1.06], p=0.141). Central nervous system (CNS) metastasis patients: OS (HR=0.91, 95% CI [0.71, 1.17], p=0.474); PFS (HR=1.03, 95% CI [0.66, 1.60], p=0.903). The available research results do not support the recommendation of PD-L1 positive and TMB-H as predictors for the application of immune checkpoint inhibitors (ICIs) in SCLC patients. LDH, baseline liver metastasis and CNS metastasis may be used as markers/influencing factors for predicting the efficacy of ICIs in SCLC patients. Non-Asian SCLC patients had better efficacy with ICIs in our results.

Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies

BackgroundFurmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies.MethodsThis was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively.ConclusionsFurmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC.Trial registrationBoth studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Abstract P4-01-23: Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic breast cancer

Abstract Background: Patients with HER2 positive (+) breast cancer and central nervous system (CNS) metastases often have poor prognoses. DZD1516 is designed as a reversible and selective HER2 tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Methods: DZD1516 is being developed in a phase 1 study (NCT04509596) in patients with HER2+ advanced or metastatic breast cancer relapsed from the standard of care. Key overall eligibility criteria were previously presented. DZD1516 was given orally twice daily (BID) in a continuous 21-day cycle (except Cycle 0). The primary objective is to evaluate the safety and tolerability of DZD1516 monotherapy and define the maximum tolerated dose (MTD). Results: As of June 23, 2022, twenty-three patients with HER2+ MBC from the USA and China were enrolled and dosed with DZD1516 monotherapy (25 mg ~ 300 mg, BID). Fifteen patients (65.2%) had baseline CNS metastases. Patients were heavily pre-treated, with a median of 7 lines of prior systemic treatment. All patients had been treated with HER2 large molecules, and 82.6% of patients also received prior HER2 TKI treatment. DZD1516 was well tolerated at doses up to 250 mg BID. Two dose-limiting toxicities were reported in the 300 mg cohort. As a result, 250 mg was defined as the MTD. Treatment-emergent adverse events (TEAEs) were reported in 91.3% of patients. Grade 3 drug-related TEAEs were reported in two patients. No grade 4 or 5 TEAEs were reported. The most common TEAEs included headache, vomiting, and hemoglobin decreased. The majority of the TEAEs could be managed and were reversible. The longest treatment duration was &amp;gt; 3 months. Following single oral dosing, DZD1516 was eliminated with a mean half-life of 13.4 – 22.5 hrs. After twice-daily dosing for 15 days, moderate accumulation of DZD1516 systemic exposure was observed at doses ≤ 200 mg BID and negligible accumulation at 250 mg BID. The combined molar exposure of DZD1516 and its active metabolite DZ2678 increased with dose between 50 mg to 250 mg dose range. In patients (n = 6), mean Kpuu,CSF was 2.1 for DZD1516 and 0.76 for DZ2678 across the dose range, indicating full penetration of DZD1516 and DZ2678 into human CNS. Nineteen patients (82.6%) had at least one post-treatment RECIST assessment. With a median of 7 lines of prior systemic treatment, the best antitumor efficacy in intracranial, extracranial, and overall lesions was stable disease. Conclusion: DZD1516 is a full BBB-penetrant HER2 inhibitor. Consistent with its high selectivity, no wild-type EGFR-related AEs have been reported. The updated data will be presented at the meeting. Citation Format: Nicholas P. McAndrew, Xichun Hu, Jian Zhang, Xiaojia Wang, Wenlei Yu, Xiaomei Pan. Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic 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 P4-01-23.

Real-World Comparative Effectiveness of First-Line Alectinib Versus Crizotinib in Patients With Advanced ALK-Positive NSCLC With or Without Baseline Central Nervous System Metastases

IntroductionAlectinib was found to have superior efficacy to crizotinib in the phase 3 ALEX study and is a preferred initial treatment for patients with advanced ALK-positive NSCLC. To understand the efficacy of alectinib in U.S. clinical practice, we conducted a retrospective real-world comparative effectiveness analysis of first-line alectinib versus crizotinib. MethodsAdults with advanced ALK-positive NSCLC who received first-line alectinib (from December 11, 2015) or crizotinib (from January 1, 2014) were included from a real-world database. Propensity scores were applied to balance baseline characteristics. Real-world data (RWD), including real-world progression-free survival (rwPFS), real-world overall survival, real-world time to new central nervous system (CNS) metastases, and outcomes in patients with or without baseline CNS metastases were analyzed. The ALEX-like RWD cohort (filtered by ALEX laboratory eligibility criteria) was used to compare real-world comparative effectiveness with ALEX. ResultsThe RWD cohort comprised 364 patients (141 alectinib; 223 crizotinib); rwPFS (weighted hazard ratio [wHR] = 0.46, 95% confidence interval [CI]: 0.33–0.65) and real-world overall survival (wHR = 0.46, 95% CI: 0.31–0.69) were significantly improved with alectinib versus crizotinib. In patients with baseline brain scans, a substantial rwPFS benefit was found regardless of baseline CNS metastases. Real-world time to new CNS metastases was delayed with alectinib versus crizotinib in patients with (wHR = 0.28, 95% CI: 0.16–0.52) and without (wHR = 0.42, 95% CI: 0.24–0.76) baseline CNS metastases. The ALEX-like RWD cohort comprised 325 patients (120 alectinib; 205 crizotinib); alectinib was found to have similar rwPFS benefits with ALEX. ConclusionsOutcomes were significantly improved with first-line alectinib versus crizotinib in patients with advanced ALK-positive NSCLC in the U.S. real-world setting.

Updated efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9024 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated an objective response rate (ORR) of 73% across 15 investigator-assessed patients (pts) with lung cancer (Drilon et al, JCO Precis Oncol 2022). We report data on an expanded cohort of pts with TRK fusion lung cancer treated with larotrectinib. Methods: Pts with TRK fusion lung cancer enrolled in two larotrectinib clinical trials (NCT02576431 and NCT02122913) were included for this analysis. Larotrectinib was administered at 100 mg twice daily. Response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2021, a total of 26 pts with TRK fusion lung cancer (24 non-small cell lung cancer, 1 atypical carcinoid, 1 neuroendocrine) were enrolled, including 10 pts with CNS metastases at baseline. Median age was 51.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n =21; 81%) or NTRK3 (n =5; 19%). Pts received a median of 2 prior lines of systemic therapies with 19 (73%) receiving ≥2. Among 23 pts evaluable per IRC, the ORR was 83% (95% confidence interval [CI] 61–95): two complete responses, 17 partial responses (PR), and four stable disease (SD). The median time to response was 1.8 months. Among 10 evaluable pts with baseline CNS metastases, the ORR was 80% (95% CI 44–97): eight PR and two SD. Median duration of response (DoR) and progression-free survival (PFS) were not reached; median follow-up was 12.9 and 14.6 months, respectively. The 24-month rates for DoR and PFS were 72% and 67%, respectively. Median follow-up for overall survival (OS) was 12.9 months. The 24-month and 36-month rates for OS were both 72%. For the 10 evaluable pts with CNS metastases, the 12-month DoR, PFS, and OS rates were 26%, 22%, and 78%, respectively. Duration of treatment for all pts evaluable per IRC ranged from 2.1 to 52.7+ months. At data cut-off, six pts had progressed, with all six continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in five pts (increased alanine aminotransferase, increased aspartate aminotransferase, hypersensitivity, myalgia, and increased weight). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results support testing for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431, NCT02122913.

Indirect comparisons of brigatinib and alectinib for front-line ALK-positive non-small-cell lung cancer.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naiveALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.

Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort

IntroductionThe Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. MethodsPatients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response. ResultsIn total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6–18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5–93.5) by investigator and 92.0% (95% CI: 84.1–96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6–88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9–98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1–87.7). Safety data were consistent with the known tolerability profile of alectinib. ConclusionsThese results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.

Neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC) and central nervous system (CNS) involvement: Findings from the SUMMIT basket trial.

9068 Background: The phase 2 SUMMIT basket trial (NCT01953926) demonstrated efficacy of neratinib in patients with EGFR exon 18-mutant NSCLC [Boni et al. WCLC 2020]. Neratinib also has documented activity in HER2+ metastatic breast cancer with CNS metastases [Saura et al. SABCS 2020 &amp; J Clin Oncol 2020]. Here we report neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant NSCLC and CNS involvement from SUMMIT. Methods: Patients with EGFR exon 18-mutant NSCLC were treated with single-agent neratinib (240 mg po daily). Prior EGFR tyrosine kinase inhibitors (TKIs), chemotherapy, and checkpoint inhibitors (IO) were allowed. Patients with stable, asymptomatic CNS metastasis were enrolled. Study endpoints: objective response rate (ORR) at week 8 (±1 week); ORR (RECIST 1.1 confirmed); duration of response (DOR); clinical benefit rate (CBR); progression-free survival (PFS); safety; biomarkers. Results: Baseline characteristics of 11 patients with EGFR exon 18-mutant NSCLC: median age 67 (range 56–83) years; ECOG PS 0/1 (45%/55%). Prior lines of therapies: 2 (range 1–3): EGFR TKIs (91%); chemotherapy (55%); IO (27%). 3/11 patients had baseline CNS metastasis and received radiation 8–22 months prior to study enrollment. Best CNS response in these 3 patients was stable disease with overall individual PFS of 1.9 (censored), 6.9 and 9.1 months and OS of 2.6 (censored), 17.7 (censored), and 17.9 months. Efficacy is summarized in Table. Efficacy summary: TKI-pretreated EGFR exon 18-mutant NSCLC cohort receiving neratinib monotherapy. Conclusions: Activity of single-agent neratinib was observed in prior TKI-exposed patients with EGFR exon 18-mutant NSCLC. Despite the small sample size of only 3 patients with baseline CNS metastases, findings suggest a potential role for neratinib as a systemic treatment option for patients with NSCLC and difficult-to-treat uncommon mutations with CNS involvement. The SUMMIT trial continues to enroll patients with EGFR exon 18-mutant NSCLC. Clinical trial information: NCT01953926. [Table: see text]

Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib.

BackgroundMost patients treated with anaplastic lymphoma kinase (ALK)‐tyrosine kinase inhibitors for ALK‐positive non‐small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood‐brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies.AimsWe compared the clinical‐radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK‐positive NSCLCs.Methods and resultsWe retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK‐positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty‐three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra‐CNS progression‐free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups.ConclusionWe observed no significant difference in the clinical‐radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

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.

Survival outcomes and symptomatic central nervous system (CNS) metastasis in EGFR-mutant advanced non-small cell lung cancer without baseline CNS metastasis: Osimertinib vs. first-generation EGFR tyrosine kinase inhibitors

ObjectivesCentral nervous system (CNS) metastases are common complications in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). However, for patients without baseline CNS metastasis, data regarding the incidence of symptomatic CNS metastasis with EGFR-TKI treatment and its risk factors are still rare. Materials and MethodsPatients with EGFR-mutant advanced NSCLC without baseline CNS metastasis who are receiving first- and/or third-generation EGFR-TKIs were included. Overall survival (OS), cumulative incidence of symptomatic CNS metastasis upon treatment failure, and their risk factors were evaluated. ResultsThere were 813 patients enrolled, with 562, 106, and 32 received first-line gefitinib, erlotinib, and osimertinib, respectively, while 113 received second-line osimertinib. At a median follow-up of 18.1 months, the median OS was 45.5 months. There were 38 patients developed symptomatic CNS metastases. Osimertinib-treated patients tended to have a lower risk of CNS metastases compared with those treated with first-generation EGFR-TKIs (p = 0.059). However, the cumulative incidence curves of symptomatic CNS metastasis tended to reach a plateau after approximately 3 years regardless of which generation was used, and incidences beyond that period were similar in the two groups. Patients with L858R mutation exhibited a higher risk of developing CNS metastasis than patients with 19del mutation (p = 0.001). Interestingly, the presence of baseline neuroimaging was not associated with the risk of developing CNS metastasis or OS. ConclusionCompared with first-generation EGFR-TKIs, osimertinib can delay but not prevent the development of symptomatic CNS metastasis. L858R mutation is an independent risk factor for CNS metastasis.

Preventing Symptomatic Central Nervous System Metastasis in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Comparison of First- and Third-Generation EGFR Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Central nervous system (CNS) metastases, including brain parenchymal metastasis (BM) and leptomeningeal metastasis (LM), are common in the EGFR-TKI treatment failure. The different generation EGFR-TKIs have variant potencies of penetrating into the blood-brain-barrier. This study aims to compare the efficacy of first- and third-generation EGFR-TKIs in preventing symptomatic CNS metastases and to identify their risk factors. Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis and receiving EGFR-TKI treatment were selected. The cumulative incidence of symptomatic CNS metastasis upon treatment failure, and overall survival (OS) of patients who developed CNS metastasis, were measured from the initiation of EGFR-TKIs, using the Kaplan-Meier method. The risk factors for CNS metastasis, and predictors of OS were identified using Cox proportional hazard regression. 935 patients from two academic medical centers were enrolled, with 633, 143 and 35 receiving first-line gefitinib, erlotinib and osimertinib, respectively, the remain 124 patients received osimertinib for acquired T790M mutation. On baseline, 19del, L858R and uncommon mutations were detected in 427, 386 and 122 patients, respectively. At the median follow-up of 10 months, treatment failure was observed in 517 patients, of whom 45 developed symptomatic CNS metastasis, with 37 developing BM, 4 LM, and 4 with both BM and LM. The 1-year, 2-year and 3-year cumulative rate of symptomatic CNS metastasis, were 4.2%, 7.9% and 14.4%, respectively. There was no significant difference in symptomatic CNS metastasis among patients receiving gefitinib or erlotinib, while osimertinib treatment was found to have a lower rate compared to first-generation TKIs (HR 0.45; 95%CI 0.20-0.99, p = 0.049). However, cumulative rate of symptomatic CNS metastasis at 3-year in osimertinib group reached the similar level as the first-generation TKIs. Of interest, the curves of CNS metastasis tend to reached a plateau after three years no matter which generation was used. Patients harboring L858R mutation were at a higher risk of developing CNS metastasis, than other mutations (p = 0.003). Among the 45 patients with CNS metastasis, median OS was 22 months, and patients with single cranial lesion had a significant longer OS (p = 0.011). Compared with first-generation EGFR TKIs, osimertinib significantly delays the development of symptomatic CNS metastasis in the EGFR-mutant advanced NSCLC without baseline CNS metastasis. L858R mutation is a risk factor for CNS failure during EGFR-TKIs treatment.