Advanced-stage ALK-positive non-small-cell lung cancer (NSCLC) patients: Real-world treatment patterns and outcomes from the Italian biomarker ATLAS database.

IntroductionAnaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy.MethodsFlatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling.ResultsAmong patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41–0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33–0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19–0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24–0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37–1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33–0.98; p = 0.042).ConclusionsPatients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-024-02899-6.

Ensartinib as Treatment for ALK-Rearranged NSCLC

e21113 Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Methods: We retrospectively reviewed 28 ALK positive NSCLC patients who had received pemetrexed-based chemotherapy at Shizuoka Cancer Center, Japan, from January 2011 to October 2020. The efficacies of pemetrexed-based chemotherapy after or before ALK-TKI was evaluated. Results: Eight patients (29 %) were treated with pemetrexed-based chemotherapy before ALK-TKI (ALK-TKI treated group), and 20 (71%) with this regimen after the failure of ALK-TKI (ALK-TKI naïve group). Patients characteristics (ALK-TKI naïve/ALK-TKI treated) were as follows: median age (range) 66 (27-72)/57 (35-73); male 100/45%; PS0-1 100/85%; adenocarcinoma 100/90%; stageⅣ 88/90%; with CNS metastasis 12/40%. The pemetrexed-based chemotherapy was administered in 5 (18%) patients as the 1st line, 11 (39%) as 2nd line, and 12 (43%) as 3rd or latter line. Twenty-five patients received the combination of platinum with pemetrexed and 3 done pemetrexed monotherapy. Regarding previous ALK-TKI, 17 patients received only alectinib and 8 patients did both alectinib and crizotinib. Progression-free survival (PFS) in ALK-TKI treated group was shorter than in ALK-TKI naïve group (median PFS 3.8 months vs 12.4 months Hazard ratio = 0.41; 95%CI 0.16-1.01 by wald test, p = 0.047 by log-rank test). In overall survivals (OS) from first line treatment between two groups, and ALK-TKI treated group tended to be shorter than ALK-TKI naïve group (median OS 29.5 months vs. 48.8 months; Hazard ratio 0.47, 95%CI 0.13-1.7, p = 0.248). OS from pemetrexed-based chemotherapy of ALK-TKI treated group was also significantly shorter than ALK-naïve group (median OS 10.1 months vs. not reached; Hazard ratio 0.20, 95%CI 0.05-0.75, p = 0.01). Overall response rate (ORR) of pemetrexed-based chemotherapy was lower in ALK-TKI treated group than ALK-TKI naïve group (35% vs 50%) and ORR of ALK-TKI was 85% vs 63%. There was no difference in PFS of pemetrexed-based chemotherapy regardless of efficacy of prior ALK-TKI (PFS ≥24 months vs &lt; 24 months; median PFS 4.5 months vs 7.2 months, Hazard ratio 0.99, 95%CI 0.42-2.31, p = 0.99). Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients.

e20077 Background: Stage III non-small cell lung cancer (NSCLC) is highly heterogeneous and ALK+ patients (pts) lack of standard treatment model. Thus, there is a huge unmet need to understand real-world treatment patterns, and relationship to survival outcomes in stage III ALK+ NSCLC patients. Methods: This study is a multicenter retrospective study to assess the real-world treatment patterns and outcomes of Chinese patients with stage III ALK+ NSCLC. Treatment naïve stage III ALK+ NSCLC patients were included and assigned to cohort 1 (surgery) and cohort 2 (non-surgery). The primary endpoint is treatment pattern, secondary endpoints are progression-free survival, overall survival, and ALK testing rate at stage III. Results: Between July 2018 and June 2024, 254 pts were included from 23 centers in China, with 144 pts in C1 and 110 pts in C2. Median age was 57 years (range: 24-80), 96.1% were adenocarcinoma or adenosquamous carcinoma (adenocarcinoma: 94.5%, adenosquamous carcinoma: 1.6%). The testing rates for ALK at stage III were 84.6%. In Cohort 1, all 144 patients have received surgery and 23.6% (34/144) received neoadjuvant therapy. Of patients after surgery, 84.0% (121/144) further received adjuvant therapy, among which 40.5% (49/121) was targeted therapy. In Cohort 2, 45.5% (50/110) patients have received chemoradiotherapy (CRT), including 40.0% (20/50) concurrent CRT (cCRT) and 60.0% (30/50) sequential CRT (sCRT). For CRT patients, 64.0% (32/50) received consolidation therapy, with targeted therapy as the majority (96.9%, 31/32) (table). Furthermore, 54.5% (60/110) patients have received systemic therapy only, including 90.0% (54/60) targeted therapy or targeted combined therapy and 10.0% (6/60) chemotherapy or immunochemotherapy. As of January 1, 2025 (data cut-off), the median follow-up times were 34.8 months for C1, 31.0 months for C2. For pts in C1, the overall median PFS (mPFS) for C1 and C2 were 32.1 months (95% CI, 21.2-43.0) and 24.9 months (95% CI, 20.8-29.0), respectively. Median OS was not reached in either group. The 3-yr OS rate for C1 and C2 were 91.7% and 88.2%, respectively. Conclusions: This study presents the real-world treatment pattern for stage III ALK+ NSCLC in China, showing that treatment options for this subset are varied in clinical practice due to disease heterogeneity. Further survival correlations with different treatment patterns are ongoing. Treatment patterns in two cohorts. Cohort 1 (144 pts) Surgery only 19/144 (13.2) Neoadjuvant treatment → Surgery 4/144 (2.8) Surgery → Adjuvant treatment 91/144 (63.2) Neoadjuvant treatment → Surgery → Adjuvant treatment 30/144 (20.8) Cohort 2 (110 pts) CRT 50/110 (45.5) cCRT 20/50 (40.0) sCRT 30/50 (60.0) Systemic therapy only 60/110 (54.5) Note: data are presented as n/N (%) except specifically notified.

Alectinib, brigatinib, and lorlatinib are all preferred first-line (1L) therapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in National Comprehensive Cancer Network (NCCN) guidelines. Although clinical trials have demonstrated their efficacy, real-world evidence on treatment patterns, costs, and outcomes may help differentiate these therapies and inform optimal 1L treatment selection in the absence of head-to-head comparisons. To evaluate real-world outcomes for patients with ALK+ NSCLC receiving 1L ALK tyrosine kinase inhibitors (TKIs), focusing on drug acquisition costs, health care utilization, and clinical outcomes. This retrospective observational cohort study used data from Optum's deidentified Clinformatics Data Mart Database (2016-2021). Patients were identified using International Classification of Diseases, Tenth Revision codes for lung cancer and ALK TKI pharmacy claims. Eligible patients were aged 18years, with at least 6 months of continuous enrollment prior to the index date and at least 1 ALK TKI prescription fill. Health care resource utilization (proxied by claim counts) and associated costs (2024 US dollars) were measured per-patient-per-month (PPPM). Time to treatment discontinuation or death (TTD) and overall survival (OS) were assessed using the Kaplan-Meier method. Among 696 patients, the 1L therapy distribution was crizotinib (n = 366), alectinib (n = 267), brigatinib (n = 22), ceritinib (n = 25), and lorlatinib (n = 16). Total PPPM costs were $28,216 (SD: $29,017). Average 30-day supply costs for ALK TKIs were $17,766 (SD: $2,797). Median OS was 25.5 months (95% CI: 21.1-32.5), and median TTD for 1L therapy was 8.0 months (95% CI: 6.4-9.6). Only 24.3% of patients transitioned to another ALK TKI in a second-line (2L) setting, highlighting high discontinuation rates. Alectinib and lorlatinib were the most common 2L therapies. This study highlights the economic burden and variable clinical outcomes among patients with advanced ALK+ NSCLC. These real-world estimates inform cost-effectiveness analyses and clinical decision-making regarding treatment sequencing, particularly given uncertainty surrounding multiple preferred 1L options in clinical guidelines.

Lung cancer is the leading cause of cancer-related deaths in North America. Non-small cell lung cancer (NSCLC) is the most common type; most cases are advanced/metastatic at diagnosis. Available first and second lines of treatment include platinum-based chemotherapeutics, therapies targeting driver oncogene mutations, and immune checkpoint inhibitors, with limited options at later lines. Understanding the current treatment landscape to define unmet needs will benefit research and development of novel therapies for advanced/metastatic NSCLC. The LUMINATE-101 retrospective cohort study evaluated real-world treatment patterns and outcomes for patients with non-squamous epidermal growth factor receptor (EGFR) wild type (WT) advanced/metastatic NSCLC diagnosed 1 January 2017 to 31 August 2022 that progressed on previous therapies. Patient data were pooled from US-based electronic health records-derived databases: Flatiron Health NSCLC real-world, ConcertAI Patient360 Lung Cancer, and ConcertAI RWD360NLP; redundant records were removed using tokenization. Overall, 620 patients were included; median age 67 years, >34% ECOG performance status ≥2, 19% had brain metastasis, 10% had liver metastasis, and 91% were current/ex-smokers. Most patients (54%) received a first-line platinum-based regimen ± immunotherapy and second-line docetaxel + ramucirumab/bevacizumab. Real-world outcomes included median overall survival (OS) = 6.4 months, median time to next treatment/death = 5.0 months, median time to treatment discontinuation = 2.3 months, and median progression-free survival = 3.5 months. ECOG performance status ≥2 correlated with poorer real-world outcomes overall; males had poorer survival and greater progression risk. Real-world median OS of second-line patients on the current standard of care was < 7 months, highlighting an unmet need for more effective therapeutics in non-squamous EGFR WT advanced/metastatic NSCLC.

e23261 Background: Treatment accessibility for patients (pts) with MM is variable based on care setting. Most novel therapies are approved for RRMM in late lines of therapy (LoT). Starting from 2021, CAR-T and bispecific antibody (BsAb) therapies became available for MM. Herewe evaluate real-world (RW) treatment patterns and outcomes for TCE pts with RRMM receiving care in community care setting (CCS) and academic care setting (ACS), after ≥2 prior LoT. Methods: This retrospective observational study used the COTA Vantage MM database. Care setting was assigned based on the provider site at time of data abstraction. Adults were included if they had TCE (proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody exposure) and initiated 3L therapy in the US between November 2015–May 2024. Index date was defined as start date of each line of interest post-TCE. Pt demographics, clinical characteristics, and RW outcomes were assessed, stratified by care setting. Additional analyses are ongoing. Results: Of the 681 pts included, 34.5% were in ACS and 65.5% in CCS. The mean (SD) age at diagnosis was 64 (10.4) and 65 (10.5) years, and 48.1% and 48.4% were female for ACS and CCS, respectively. Selected pt characteristics and unadjusted RW outcomes by care setting are reported in the Table. In addition, among the observed 631 ACS and 1054 CCS treatment regimens, the top regimens were daratumumab-pomalidomide-dexamethasone and carfilzomib-pomalidomide-dexamethasone; top reasons for treatment discontinuation (DC) were physician-reported progression (31% vs 28%) and toxicity (21% vs 19%); death accounted for 3% and 9% of regimen DC in ACS and CCS, respectively. During the study period, the proportions of pts receiving CAR-T and BsAb were low in both settings but samples sizes were small. Conclusions: RW pt demographics and clinical characteristics differ by care setting for TCE RRMM pts in 3L+, and outcomes are suboptimal in both settings. Despite advances in MM management, this study highlights the need for more efficacious and accessible novel treatments for these pts regardless of treatment setting and may add to the body of evidence for evaluating emerging data from novel therapies (including BsAbs) in RRMM. Setting Academic (n=235;476 patient-lines) Community (n=446;781 patient-lines) ECOG PS a at diagnosis ≥1, n (% among nonmissing) b 79 (59.4%) 178 (52.5%) Median prior LoT, (range) b 4 (3–5) 3 (2–4) Ever received CAR-T post-index date, n (%) b 11 (4.7%) 8 (1.8%) Ever received BsAb post-index date, n (%) b 7 (3.0%) 7 (1.6%) Median rwPFS, months (95% CI) c 3.91 (3.1–5.7) 3.22 (2.8–3.9) Median time to next treatment, months (95% CI) c 4.07 (3.3–4.7) 4.50 (4.0–5.03) Median rwOS, months (95% CI) c 14.9 (12.4–19.5) 11.01 (9.5–12.4) a ECOG PS was missing 43% and 24%. b Assessed at the pt level. c Assessed at the pt-line level.

9067 Background: Second-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first- and second-line therapies in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). After progression on second-gen TKI(s), standard options include platinum (PT)-based chemotherapy (chemo) or the third-gen ALK TKI lorlatinib. The efficacy of PT-based chemo is established in treatment-naive pts but is undefined in pts who have failed prior ALK TKIs. Here we evaluate the efficacy of PT/pemetrexed (pem)-based chemo in pts with ALK+ NSCLC refractory to second-gen TKIs. Methods: A retrospective study was performed at three institutions. Pts were eligible if they had advanced ALK+ NSCLC refractory to ≥1 second-gen TKI, and received PT-pem-based chemo. Medical records and imaging were reviewed to determine outcomes. Results: Among 55 eligible pts, chemo regimens included: PT/pem (31/55, 56%), PT/pem/bevacizumab (bev) (6/55, 11%), PT/pem/PD-1 inhibitor (3/55, 5%), PT/pem with ALK TKI (8/55, 15%), PT/pem/bev with TKI (6/55, 11%), and PT/pem/PD-1 inhibitor with TKI (1/55, 2%). Pts had received one (6/55, 11%), two (38/55, 69%), or more (11/55, 20%) prior TKIs. Six pts (11%) previously received adjuvant or neoadjuvant chemo. Radiographic data for response evaluation was available for 39 pts. Among 36 pts with measurable baseline disease, confirmed ORR was 31% (11/36; 95% CI, 16-48%); 13 (36%) had stable disease. The median duration of response was 5.4 months (95% CI, 1.5-7.1 months). The median progression-free survival (PFS) for the entire cohort was 4.0 months (95% CI, 2.8-4.6 months). Chemo (PT/pem +/- bev or PD-1 inhibitor) plus ALK TKI (n = 15) was associated with a significant increase in PFS compared to chemo without TKI (n = 40) (median PFS 6.8 vs 3.2 months; HR 0.306; p = 0.002). Similarly, PT/pem plus ALK TKI (n = 8) was associated with increased PFS compared to PT/pem without TKI (n = 31) (median PFS 6.8 vs 2.9 months; HR 0.358; p = 0.036). Conclusions: The efficacy of PT-pem-based chemo is limited after failure of second-gen ALK TKIs but may be higher in pts who receive chemo plus ALK TKI, suggesting a potential role for ongoing ALK inhibition. The modest benefit of PT-pem-based chemo highlights the need for other therapeutic strategies for pts refractory to second-gen TKIs.

Real-World Treatment Patterns and Outcomes of Proteasome Inhibitor (PI: Bortezomib [V], Carfilzomib [K], or Ixazomib [I])-Lenalidomide/Dexamethasone (Rd)-Triplets By Prior Lenalidomide-Exposure in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Engaged in Routine Care in the United States (US)

e20604 Background: ALK rearrangements are present in 5% of NSCLC patients and its identification is of relevance as it confers sensitivity to ALK tyrosine kinase inhibitors (ALK-TKI). This study pretends to show treatment response and survival outcome in ALK+ patients treated in clinical trials at Vall Hebron Institute of Oncology (VHIO). Methods: This retrospective study includes 109 patients with ALK+ stage IV NSCLC, treated between 2010 and 2020 in the clinical trial setting. Objective response rate (ORR), progression free survival (PFS), overall survival from metastatic diagnosis (OS-d) and overall survival from targeted therapy start (OS-t) were assessed. A Multivariate Cox regression was applied to determine correlations between clinical features and OS-d. Results: Out of 109 patients with ECOG 0-1, 67% were women and 33% men. Median age at diagnosis was 53 yr, 64% were never-smokers, 30% former smokers, 5% current smokers. Histology was mainly adenocarcinoma (96%) and brain metastases were present in 58% cases at clinical trial treatment initiation. 13% of patients were treatment-naive, 42% were ALK-TKI naïve, 39% had previously received crizotinib, 21% had previously received second-generation ALK-TKIs. Most patients were treated in phase I clinical trials (54%), followed by phase II (22%), III (19%) and IV (5%). 7% were treated with crizotinib, 66% were treated with second-generation ALK-TKIs, 27% were treated with third-generation ALK-TKIs. Global ORR was 69% (83% in ALK-TKI naïve patients, 69% in patients previously treated with crizotinib and 56% in patients previously treated with a second-generation ALK-TKI) with no differences between patients with and without brain disease at study entry (68% vs. 70%). Median PFS was 16 months (m) (95% CI 11-24), 30m in ALK-TKI naïve patients (p = 0.06), 10m in patients previously treated with crizotinib (p = 0.04) and 10m in patients previously treated with second-generation ALK-TKIs (p &lt; 0.001). No significant differences were seen between patients with and without brain metastasis at study entry (11 m vs. 16 m, p = 0.64). Global OS-d was 71m. Global OS-t was 60m. Multivariate Cox analysis showed smoking history [HR = 0.66 p = 0.358], presence of brain metastatic disease at clinical trial inclusion [HR = 0.87 p = 0.73] or gender [HR = 1.74 p = 0.231] did not affect OS-d. Having received, at least, a second generation ALK-TKI prolonged OS-d (p = 0.007) as well as having received third generation ALK-TKIs [HR 0.09, p &lt; 0.001]. Conclusions: Clinical trials represent an opportunity of access to novel therapies and may provide an alternative for patients with no treatment options. This study, with 54% of patients treated in phase I clinical trials, has shown high ORR and prolonged PFS and OS for ALK + patients, regardless of brain disease extension. Sequential therapy with ALK inhibitors has also been proven important for OS.

Background: Approximately 50% of HER2+ metastatic breast cancer (MBC) patients will develop brain metastases (BMs). While traditional treatment for BMs consisted of radiation +/- surgery, optimal treatment now involves a multi-disciplinary approach of local and CNS-penetrating Her-2 targeted systemic therapies since their FDA approval in 2020. First line systemic therapy for HER2+ MBC is trastuzumab (H), pertuzumab (P), and Taxol (T). Subsequent therapy options include trastuzumab emtansine (T-DM1), tucatinib/H/capecitabine triplet therapy (TUC), and trastuzumab deruxtecan (T-DXd). This study aimed to examine real-world treatment patterns and clinical outcomes of HER2+ breast cancer BMs. Methods: This single institution retrospective study included HER2+ MBC patients with BMs treated between Jan 2017 - Feb 2024, with at least 6 months of follow-up after BM diagnosis. Primary objective was to evaluate treatment sequence and duration after BM diagnosis. Overall survival (OS) was defined from date of BM diagnosis to date of death. Systemic progression-free survival (PFS) and CNS-PFS were defined from systemic therapy initiation date to systemic or CNS disease progression, respectively. Kaplan-Meier method was used for survival analysis. Time to systemic therapy discontinuation (due to toxicity or progression) was also evaluated. Radiation necrosis (RN) was diagnosed by MRI perfusion imaging +/- biopsy and multi-disciplinary review. Results: 78 patients with HER2+ MBC with BM met the eligibility criteria, including 36 (46.2%) patients with BMs at initial MBC diagnosis and 42 (53.8%) subsequently diagnosed with BMs. Median number of systemic therapies received prior to BMs diagnosis was 3 (range 0-13). Patients had a median of 2 BMs (range 1-40) at diagnosis, and median total BM volume was 7.29 (range 0.09-105.22) cm3. 72 (92.3%) patients received stereotactic radiosurgery (SRS); 25 (32.1%), WBRT; and 40 (51.3%), neurosurgical resection. Of 129 total SRS courses, 40 (31.0%) were treated with 18-22 Gy in 1 fraction (fxn), 67 (51.9%) with 21-24 Gy in 3 fxns, and 17 (13.2%) with 25-30 Gy in 5 fxns. For patients with a diagnosis of BM before 2020 (n=45), the 1st systemic therapy prescribed after BM diagnosis consisted of HPT (n=6; 13.3%), T-DM1 (n=2; 4.4%) or other (n=37; 82.3%). After 2020 (n=33), the 1st systemic therapy prescribed after BM diagnosis was HPT (n=4; 12.1%), T-DM1 (n=2; 6.1%), TUC (n=8; 24.2%), T-DXd (n=8; 24.2%), or other (n=11; 33.4%). The median duration for each systemic therapy was 6.0 mo, 12.9 mo, 7.3 mo, and 3.2 mo for T-DM1, TUC, T-DXd, and other treatments, respectively (p=0.27). For the entire cohort, median OS was 36.8 mo (95% CI 21.9-79.2), median systemic PFS was 13.4 mo (95% CI 8.7-16.0), and median CNS-PFS was 14.7 mo (95% CI 11.3-25.5). Twenty-three (29.5%) patients developed RN (any CTCAE grade) with a median time to RN after initial SRS treatment of 26.5 months (range 2.0-220.5 months). Of the patients with RN, 7 (30.4%) received antibody-drug conjugates (ADC) concurrently with SRS. Conclusions: Since 2020, TUC and T-DXd were increasingly prescribed as initial systemic treatment after BM diagnosis. The combination of SRS and HER2 targeted systemic therapies in this cohort resulted in excellent survival outcomes but some risk of RN. Interestingly, TUC trended toward a longer treatment duration than T-DM1 or T-DXd. Further investigation into reasons for discontinuation of each systemic therapy (toxicity vs. progression) is warranted. Limitations of this study include the retrospective design, small cohort size, and limited follow-up. Future studies and longer follow-up will allow for a better understanding of how treatment patterns affect survival outcomes and patient quality of life. Citation Format: Mariella Mestres-Villanueva, Yevgeniya Gokun, Sierra Daniel, Rituraj Upadhyay, Sachin Jhawar, Therese Andraos, Rebekah Young, Jacob Eckstein, Erin Healy, Nicole Williams, Joshua Palmer, Sasha Beyer. Real World Treatment Patterns and Outcomes in Her-2 Positive Metastatic Breast Cancer Patients with Brain Metastases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-01.

BACKGROUND Traditionally, patients with melanoma brain metastasis (MBM) have poor survival outcomes. We investigated real-world treatment patterns and outcomes of patients with MBM. METHODS We conducted a retrospective, single-institution analysis of patients with malignant melanoma who received immunotherapy and developed synchronous or metachronous MBM. Real world treatment patterns, therapy sequencing and outcomes were analyzed in detail. RESULTS Of 453 patients with melanoma who received immunotherapy at our center, 138 developed brain metastases. Median age was 59 years, 63% were male, and 91% were white. 72% had cutaneous melanoma, 5% had mucosal, 4% had acral, and 19% had other subtypes. BRAF V600 mutation was positive in 36%. 44% had synchronous MBMs (within 30 days of diagnosis of unresectable/metastatic disease), and 56% had metachronous MBMs. 3% had solitary MBMs without concurrent extracranial disease. For patients with metachronous MBMs, median time to CNS metastasis from stage IV diagnosis was 11 months (range, 1 – 211 months). 69% of patients had 1 – 5 MBMs, 20% had 6 – 10 MBMs, and 11% had 11 or more MBMs. For first-line therapy, 66% received stereotactic radiosurgery (SRS) or gamma-knife radiosurgery (GKRS), 14% underwent surgical resection, 12% received whole-brain radiation therapy (WBRT), 88% received systemic therapy (with or without other therapy), and 72% received systemic therapy and loco-regional therapy. Systemic therapies included ipilimumab/nivolumab (36%), nivolumab alone (10%), pemboliaumab alone (20%), ipilimumab alone (23%), BRAF/MEKi (6%), or other (11%). 54% of patients who received treatment and/or were followed with imaging experienced disease progression. Median overall survival (OS) for the entire cohort was 66 months (range, 1 – 407 months). CONCLUSION Most patients with MBM receive a combination of loco-regional interventions and systemic therapy. Real-world outcomes for patients with MBMs have improved with newer treatments.

e21501 Background: Programmed death-1 (PD-1) receptor inhibitors significantly increase survival rates for advanced melanoma, yet first-line PD-1 inhibitor therapy shows limited overall response rates (32.6%) and progression-free survival (4.6 months). Relatimab (RELA) was recently approved for the treatment of metastatic and unresectable stage III to IV melanoma in combination with nivolumab (NIVO). RELATIVITY-047 showed an ORR of 43% as a first-line treatment while RELATIVITY 020 showed an ORR of 9-12% in patients progressed on anti-PD-1 therapy. Although clinical trials have demonstrated NIVO-RELA provides benefit for patients with advanced melanoma, little is known about real-world treatment patterns and outcomes. Methods: We performed a retrospective review of all patients with stage III and IV melanoma treated with NIVO-RELA as first-(1L) or second-line or beyond (2L+) therapy at Inova Schar Cancer Institute between September 2021 to September 2023. Primary endpoints were overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) which were evaluated using the RECIST v1.1 criteria. The Kaplan–Meier method was used to generate overall survival (OS) and progression free survival (PFS) median values. Results: Eighty-eight patients were followed for an average of 6.5 months following NIVO-RELA initiation. For 1L treated patients, ORR was 58% (21% PR, 37% CR). Median PFS was 11 months (95% CI 3.1-11). For 2L+ treated patients, ORR was 33% (14% PR, 19% CR). Median PFS was 9.8 months (95% CI 4.7-17.2). Subgroup analyses observed significantly different ORR between patients previously treated with versus without anti-CTLA4 therapy (29% v 44%; p = 0.017), patients treated with NIVO-RELA more than vs within 6 months from their last other therapy (50% v 27%; p = 0.004), and among patients with stage III vs stage IV disease (67% v 30%; p = 0.031) (Table 1). Conclusions: These real-world results support the use of NIVO + RELA in patients with advanced melanoma and emphasize the impressive efficacy of the drug combination in the IL and 2L+ settings compared to RELATIVITY-020 and 047. PFS and OS for 1L and 2L+ therapy with NIVO + RELA in this study aligned with or superposed results from previous trials. Further analyses with increased sample sizes and longer follow-up is warranted. [Table: see text]

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]

Background:Third generation EGFR TKIs have emerged as a first line treatment of choice for aNSCLC patients with qualifying EGFR mutations due to high and durable response rates; however most patients will progress on therapy and may receive further treatment. Second line (2L) options include other EGFR TKIs, chemotherapy (C) and chemoimmunotherapy (C-IO). An optimal treatment strategy and utility of biomarkers in this 2L setting remain uncharacterized. In this study, we aim to describe the real-world treatment patterns and outcomes of patients with aNSCLC after treatment with first line (1L) EGFR TKIs to elucidate the potential for biomarker-guided approaches. Methods:We selected patients with non-squamous aNSCLC treated with 1L EGFR TKIs on or after April 1, 2018 (based on 1L approval of osimertinib) within the US-based de-identified Flatiron Health-Foundation Medicine (FMI) real world clinico-genomic database. Real world overall survival (rwOS) and progression free survival (rwPFS) curves and estimates of median survival time were generated using the Kaplan-Meier method. PD-L1 and tumor mutational burden (TMB) were summarized overall and by 2L treatment regimen. Results:Among 428 patients who received 1L EGFR TKI treatment, 386 (90%) received osimertinib, 30 (7%) received afatinib and 11 (3%) received erlotinib. For patients with known 2L treatment information (n=139, 32%) most received EGFR TKI alone (n=43, 31%), followed by C-IO (n=38, 27%), and C alone (n=14, 10%). Median rwOS following 2L treatment with EGFR TKI, C-IO, and C was 21.0 (95% CI 17.4-28.7) months, 9.9 (95% CI 7.7-19.8) months, and 17.4 (95% CI 4.3-NA) months respectively. Median rwPFS for the EGFR-TKI, C-IO, and C cohorts was 5.1 (95% CI 3.4-12.5) months, 5.5 (95% CI 3.3-7.0) months, and 3.5 (95% CI 1.9-NA) months. 416 (97%) of 428 patients harbored an EGFR mutation detected by FoundationOne®CDx, including 361 (84%) patients with at least one EGFR mutation in NCCN Guidelines. Among patients with available PD-L1 status (n=254, 59%), PD-L1 positivity (≥1% tumor proportion score) was more common among patients who received 2L C-IO (88%) compared to patients overall (59%). 30 (7%) of 428 patients had high TMB (≥10 mut/Mb); prevalence of high TMB was similar regardless of 2L therapy choice. Conclusions:This real-world data analysis confirmed that among patients with aNSCLC treated with EGFR TKIs, the vast majority received 1L osimertinib. Among 2L treatment options, additional EGFR TKI use was the most common and patients in this cohort had robust outcomes, with a median rwOS of 21 mos. Further analyses will describe the clinical characteristics of patients receiving different 2L treatment strategies and evaluate the association of PD-L1 status and select EGFR mutations with outcomes across therapeutic classes. Citation Format: Ericka Ebot, Jie He, David Fabrizio, Ivy Altomare, Neha Jain, Davey Daniel, Thomas Stricker, Edward Arrowsmith. Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 933.