PURPOSE: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS). METHODS: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334 , HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR -mutant non–small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis. RESULTS: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug. CONCLUSION: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR -mutant NSCLC. The combination is safe and well tolerated.

Tarlatamab, a bispecific T-cell engager, has shown promising results in previously treated small cell lung cancer (SCLC) patients in the DeLLphi-300 and DeLLphi-301 trials. However, reports on outcomes in more diverse, real-world patient populations are limited. We retrospectively evaluated safety and efficacy outcomes of all patients who were treated with tarlatamab at the University of Virginia between May and October 2024. Our analysis included 21 patients with SCLC and 1 patient with DLL-3 positive atypical carcinoid. The median age of patients was 66 years (range, 41-80 years), with 59.1% being females. Most patients (85.7%) had extensive stage SCLC at diagnosis. Brain metastases were present in 9 (40.9%) patients and liver metastasis in 14 (63.8%) patients. A total of 18 (81.8%) patients would not have met the DeLLphi-301 inclusion and exclusion criteria. Cytokine release syndrome (CRS) occurred in 16 (72.7%) patients; the median time of onset was 15.8 hours (9.1-18.8) after tarlatamab infusion. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 (40.9%) patients, with higher rates and grades observed in patients with untreated brain metastases. The median time of onset was 14.8 h ([IQR] 7.7-22.1) after tarlatamab infusion. After a median follow-up of 6.7 months, the overall response rate (ORR) was 42.9% in SCLC patients. Tarlatamab is a promising treatment option for heavily pretreated small cell lung cancer patients. We observed higher rates of CRS and ICANS during the first treatment cycle suggesting that real-world safety outcomes may differ from clinical trial data.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9–17.4) compared to 1.9 months (95% CI: 1.8–2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17–0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8–30.4) compared to 3.8 months (95% CI: 2.7–4.9) for those with high opioid use (HR 0.26 95% CI: 0.17–0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

Introduction: Venous thromboembolism (VTE) occurrence in patients with lung cancer is associated with significant morbidity and mortality. The Khorana Score (KRS) is a validated risk stratification tool developed to estimate risk of VTE in patients with cancer that incorporates clinical and laboratory parameters to calculate individual risk. However, limitations of the KRS in lung cancer have been reported, and identification of other risk factors associated with increased risk of VTE are needed in this population. Methods: We retrospectively evaluated 485 patients with advanced non-small cell lung cancer (NSCLC) and 67 patients with small cell lung cancer (SCLC) treated at our institution between March 2015 and April 2023 to assess the performance of the KRS in estimating risk of VTE in multiple clinically distinct subtypes of lung cancer. Results: The median patient age at diagnosis was 66 years (range, 30-94 years). Patients were predominantly male (51.1%), Caucasian (81%), and had a history of smoking (79.4%). VTE events were observed in 123 patients (22.3%); 51 patients had DVT (41.5%), 50 patients had PE (40.7%), 13 patients had concurrent DVT and PE (7.3%), and other VTE occurred in 9 patients (7.3%). 478 patients (86.6%) had low-risk KRS (score = 0-2) and 74 patients (13.4%) had high-risk KRS (score ≥3). No statistically significant difference in VTE incidence was observed based on baseline KRS. Clinical factors that were noted to be associated with increased risk of VTE were NSCLC histology, Black race, and the presence of an oncogenic driver mutation. No significant differences in overall survival were noted in patients that experienced VTE. Discussion: This study highlights the limitations of the KRS in predicting risk of development of VTE in patients with NSCLC and SCLC and identifies multiple clinical parameters associated with increased risk of VTE. Development of further risk stratification tools incorporating these clinical factors in addition to those in the KRS should be considered.