Parikh, Kaushal

Abstract Rationale Critically ill lung cancer patients are a growing, high-risk population. However, prognostic tools to guide intensive care unit (ICU) decision-making are limited. Objectives To identify oncologic and critical illness factors associated with 90-day mortality following ICU admission in patients with lung cancer. Methods We conducted a retrospective cohort study of lung cancer patients admitted to the ICU across Mayo Clinic Health System between 2018 and 2024. The primary outcome was 90-day mortality. Two complementary Cox proportional hazards models were developed: a focused model including cancer-specific variables (stage, time since diagnosis, time since last systemic therapy, prior thoracotomy, Eastern Cooperative Oncology Group [ECOG] performance status prior to admission, body mass index, cause of critical illness, code status at admission) and a full model that added broader clinical factors (age and Sequential Organ Failure Assessment [SOFA] score). We also evaluated discharge disposition and transitions in code status. Results Among 528 patients, 90-day mortality was 58.7%. In the focused model (C-index 0.67), independent predictors of mortality included late-stage disease, cancer-specific reason for ICU admission, limitations in resuscitation orders, and ECOG >1. In the full model (C-index 0.95), only age and SOFA score remained significant. Among early-stage patients, recent targeted or combination therapy was associated with higher mortality, though this association may reflect underlying disease characteristics or treatment selection rather than direct treatment effects. Patients who changed code status during admission had high mortality (83%) and a low rate of discharge home (11%). Conclusion Lung cancer patients admitted to ICU experience high short-term mortality, with outcomes shaped by both oncologic status and the severity of acute illness. A dual-model approach suggests a risk hierarchy: Cancer-specific factors inform baseline mortality risk with an ICU admission, but age and physiologic derangement are the dominant drivers of survival once critical illness develops. These findings support dynamic, multidisciplinary prognostication and underscore the need to integrate oncology and critical care expertise in ICU decision-making.

AbstractThe discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR‐mutant non‐small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression‐free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co‐mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR‐mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

1652 Background: Tarlatamab is a bispecific T-cell engager targeting DLL3 that has shown promise as a therapy in small cell lung cancer. Administering tarlatamab requires careful consideration of immune-related adverse events (AE), including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Prescribing information recommends patients to be monitored for 22-24 hours in an appropriate healthcare setting for cycle 1 (C1), days 1 and 8. At Mayo Clinic in Rochester MN (MCR), tarlatamab is initially administered in a hospital-based outpatient (HBO) setting utilizing an innovative remote patient monitoring system (RPM). In this study, we describe our RPM process and patient outcomes thus far. Methods: We retrospectively reviewed records of patients treated with tarlatamab from August through December 2024. All patients received tarlatamab in the HBO setting and were enrolled into RPM for C1, days 1–10. Patients attended daily HBO visits on days 1–3 and 8–10 of C1 and were required to stay within 30 minutes of the hospital with a 24-hour caregiver for 48 hours following infusion days in C1-2. Data on patient characteristics, frequency of RPM alerts, escalations, rate of CRS & ICANS, and need for hospitalizations were reported using descriptive metrics. Results: As part of RPM, patients are provided with a kit containing preconnected Bluetooth-enabled devices to measure vital signs (VS), including blood pressure (BP), heart rate (HR), temperature (T), and pulse oximetry (SpO2). The kit also includes a cellular-enabled tablet for electronic ICANS questionnaires, which upload directly into our electronic medical record system. Patients are required to log VS four times daily, monitored in real-time by a centralized virtual RPM nursing (RN) team. Embedded decision trees trigger alerts, prompting the RN team to contact patients and follow care pathways for escalations as needed. Among the 16 patients treated, the median age was 68 years, and the median ECOG PS was 1. During the 10-day RPM period, a total of 2,233 VS entries were recorded. Of these, 88% (14/16) of patients had alerts triggered, with a median of 2 alerts per patient. Alerts were mostly for out-of-range systolic BP (56%), HR (56%), and T (25%), with none for SpO2. The RN team escalated alerts in 50% (8/16) of the patients. Overall, 38% (6/16) of patients were managed entirely in the HBO setting. Among the 63% hospitalized, 56% had CRS limited to grade (G) 2, and 31% had ICANS limited to G3. Two patients were hospitalized for other indications. The mean length of stay was 2.6 days, with no ICU admissions. Conclusions: Our experience shows that frequent monitoring required with tarlatamab can be safely and effectively executed in an outpatient setting with the utilization of an RPM system. It can potentially minimize the burden of hospitalizations for patients and the healthcare system.

e20141 Background: TET are rare and challenging entities in clinical practice. Prospective trials in thymoma and thymic carcinoma (TC) are scarce. Limited number of small trials investigated the role of ICI in TET, and showed some clinical efficacy, but also with immune related adverse events (irAE). Guidelines list ICI as a treatment option in the 2 nd line, although no FDA approval was granted. Aside from the small trials, there is limited real world data about the efficacy and toxicity of ICI in TET. Methods: We performed a retrospective chart review of the medical records of all patients (pts) with TET who were treated with ICI between 3/25/2011 and 11/30/2024 at 5 Mayo Clinic sites. We collected data about baseline characteristics, diagnosis, irAE, and outcomes. Kaplan-Meier method was used to calculate median progression free survival (mPFS), and hazard ratio (HR) with Cox proportional hazards regression. Results: 30 pts were included, 28 diagnosed with TC, and 2 with malignant thymoma. 70% of pts were male. Median age at time of diagnosis was 61 years (range: 15 to 82), and median ECOG at the time of diagnosis was 0. 29 pts received Pembrolizumab, and one received Durvalumab. Prior to ICI, 86.67% of patients received chemotherapy. 70% of pts discontinued ICI use, 60% due to progression, and 10% due to irAE. Overall response rate (ORR) was 23.33%, with 3.33% complete response, and 20% partial response. Disease control rate (DCR) was 63.33%. The mPFS was 10.13 months. At the time of analysis 60% of pts were still alive. 40% of patients had irAE. While the two patients with thymoma experienced irAE, only 33.33% of those with TC had these events. 26.67% of pts had thyroiditis. Pancreatitis, pneumonitis, dermatitis, and encephalitis each occurred in 3.33% of pts. The median time to irAE onset was 75 days. 25% of irAE were grade 1, 66.67% grade 2, 0% grade 3, and 8.33% grade 4, represented by the case of encephalitis. Resolution of irAE occurred in 33.33% of cases. When stratified according to the occurrence of irAE, the mPFS was the same in both groups, with or without irAE, being 10.13 months, HR=0.99 (95% CI 0.39 – 2.54). Conclusions: In this real-world cohort of pts with TET, efficacy of ICI matched what has been previously reported, with similar ORR and DCR, but with longer mPFS. However, irAE incidence was higher, but with less grade 3/4 events. Differently than what has been suggested in other diseases, irAE occurrence did not correlate with better outcomes. These results validate the role of ICI in the treatment of TET, especially TC. Nonetheless, improving patient selection, and developing other therapeutic strategies, including combinations of ICI and other drugs, for these malignancies remain essential. Importantly, the high incidence of irAE indicates that future investigations must also focus on safety of interventions and supportive care in TET.

e20120 Background: In May 2024, the FDA approved tarlatamab, a Delta-like ligand (DLL3)/CD3-targeted bispecific T-cell engager, for patients with extensive-stage small cell lung cancer (SCLC) with disease progression following platinum-based chemotherapy and at least one other prior line of therapy. We aim to evaluate the real-world outcomes of agent. Methods: We conducted a retrospective multi-site single center analysis of adult patients who received tarlatamab at Mayo clinic sites including Arizona, Florida, Iowa, Minnesota, and Wisconsin. Data analysis was performed with Blue Sky statistics version 10.4. Results: Twenty patients with a median age 67 years (range 43-76) were included. Patients were predominantly women (55%) and all had a history of tobacco use. Metastatic disease commonly involved liver (55%) and CNS (60%). Majority (90%) had received prior PDL-1 therapy. 25% (5/20) of patients received prior gamma knife and in addition 10% (2/20) received whole brain radiation treatment in our cohort. Median time from CNS radiation and tarlatamab initiation was 4 months (range 3-28). Other characteristics, outcomes, and toxicity are presented in Table 1. Cytokine release syndrome (CRS) Grade (G) 1 was observed in 45% patients. G 2, 3 and 4 CRS were observed in 5% patients respectively. G 1 CRS was managed with acetaminophen initially followed dexamethasone 10mg or methylprednisone 1g if no improvement in 24 hours. Tocilizumab was used 20% patients for G 1,2,3 and 4 CRS depending on clinical course. Immune effector cell-associated neurotoxicity (ICANS) G 1 occurred in 10% patients, followed by G 2 in 15% and G 3 in 5% patients. ICANS was managed in a multidisciplinary fashion. All patients had resolution of CRS and ICANS. Conclusions: In this study investigating the real-world outcomes and toxicity of tarlatamab, a higher incidence of ICANS was observed than that reported in the DeLLphi-301 trial. The association between presence of CNS metastatic disease, prior CNS radiation and incidence of ICANS needs to be explored further. Mayo Clinic report of tarlatamab real world outcomes and toxicity. Patient Characteristics, Tarlatamab Outcomes and Toxicity Mayo Clinic Report DeLLphi-301 trial- Part 1 & 2 DeLLphi-301 trial- Part 3 ECOG no. (%) 2-4 4 (20) 0 (0) 0 (0) Metastatic Disease no.(%) 19 (95) 98 (98) 32 (94) Median no. of previous lines of therapy (range) 3 (2-4) 2 (1-6) 2 (2-6) Objective Response (%) 30% 40% CRS no (%) 12 (60) 49 (49) 19 (56) ICANS no (%) 6 (30) 7 (7) 4 (12) Neutropenia Grade 3 no (%) 2 (10) 6 (6) 2 (6) Fatal CRS, ICANS or Neutropenia 0 (0) 0 (0) 0 (0)

8019 Background: Neoadjuvant and perioperative chemo-immunotherapy studies report 15%-20% of pts initiating NACT-I do not undergo surgical resection. Methods: Real-world data of pts who initiated NACT-I was collected retrospectively for January 1 st 2022 till September 30 th 2024. Pts and treatment details, reason for not undergoing resection (as assessed by the clinicians) and later treatments and outcomes were recorded. Total number of pts who initiated NACT-I in this period was identified from each center's records. Missing data was not imputed. Results: Data was collected from 10 centers in 4 countries (USA, Israel, Switzerland, France). Out of 330 pts that started NACT-I 43 pts (13%; range 4-33% in different centers) did not undergo surgical resection. Of these 43 pts, 34.9% became unresectable due to disease progression (PD). 20.9% in retrospect were non-resectable and did not regress as expected. 11.6% in retrospect were non-operable. 11.6% suffered toxicity and became unfit for surgery. 7% of pts refused surgery, 14% were not resected for other reasons (Table). Of the non-resected pts, 9.3% died prior to any second-line treatment. As a second line, 44.2% of the non-resected pts were treated with chemo-radiation, 14% with radiation alone, 7% chemotherapy and immunotherapy, 4.7% immunotherapy alone and 2.3% chemotherapy alone. 7% received palliative radiation followed by chemo or immunotherapy, 7% had follow-up alone. Conclusions: The rate of no surgical resection in this real-world multi-national cohort was 13%, in line with the rate in reported studies. Most un-resected pts underwent appropriate staging. Most were male, with high rate of T3/T4. Survival rate at 12 months was 73.7%. The most common causes for no surgery were PD or being upfront unresectable. The patients with the worst outcome were those who experienced PD during NACT-I. N (% out of 43 non-resected) Male (%) Age (median) PET Done prior to any therapy (%) Brain MRI staging (%) Documented MDT decision of NACT-I (%) Documented surgeon evaluation prior to NACT-I decision (%) T3-4 (%) N2a/b (9th V TNM; %) Survival rate at 12 month (95% CI) 43 (100.0) 69.8 71 95.3 95.0* 96.6* 86.2* 69.8 40.5 73.7% (50.5-87.2%) PD 15 (34.9) 80.0 67 93.3 100.0* 100.0* 92.3* 80.0 40.0 68.2% (14.2-89.7%) In retrospect not resectable 9 (20.9) 55.6 69 100.0 100.0 100.0* 50.0* 77.8 33.3 76.2% (33.2-93.5%) In retrospect not operable 5 (11.6) 80.0 71 100.0 60.0 100.0* 33.3* 40.0 20.0 100.0% (100.0-100.0%) Toxicity 5 (11.6) 80.0 72 100.0 100.0 100.0* 100.0* 80.0 80.0 80.0% (20.4-96.9%) Patient refusal 3 (7.0) 0.0 72 100.0 100.0 100.0 100.0 66.7 33.3 100% (100.0-100.0%) Other ** 6 (14.0) 83.3 75 83.3 100.0* 75.0* 100.0 50.0 40.0* 50.0% (11.1-80.4%) Percentages relate to the total of each row, besides 1st column relating to total of 43. *% of available data. **Death (n=3), intra-operative decision (n=2), additional malignancy (n=1).

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Perioperative therapy has become a critical component in the management of resectable non–small cell lung cancer (NSCLC), particularly in the era of precision medicine. Although molecular testing is standard in metastatic NSCLC, its incorporation into early-stage disease remains essential for guiding treatment decisions. Reflex molecular testing pathways are necessary to optimize tissue utilization and ensure timely results. However, liquid biopsies, although valuable in advanced disease, have limited sensitivity in early-stage NSCLC, reinforcing the need for tissue-based next-generation sequencing. Targeted therapies have revolutionized treatment for oncogene-driven NSCLC, with adjuvant osimertinib now standard for EGFR-mutant disease and ongoing investigations into ALK tyrosine kinase inhibitors (TKIs). However, unanswered questions remain regarding the inclusion of perioperative TKI therapy, the role of molecular residual disease assessment, and whether specific TKIs offer greater benefit for high-risk subgroups. The role of immunotherapy (IO) in oncogene-driven NSCLC remains controversial. Although perioperative chemo-IO has demonstrated survival benefits in unselected NSCLC, its efficacy in EGFR, ALK, and other actionable alterations is unclear. Tumors harboring KRAS and BRAF mutations may respond better because of a more immune-inflamed microenvironment, and remains an active area of investigation. As the landscape of perioperative therapy continues to evolve, ongoing trials will help define the optimal integration of targeted therapies and IO in oncogene-driven NSCLC. Addressing these unanswered questions will be crucial in refining treatment strategies and improving patient outcomes.

ABSTRACT Background There has been a lack of updated epidemiological data on the incidence and survival outcomes for patients with small cell lung cancer (SCLC) in the United States over the last two decades. Methods A retrospective, population‐based study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program to identify patients with SCLC from 2000 to 2020. Trends in cancer incidence, incidence‐based mortality rates, 1‐year relative survival rates and 1‐year observed survival were evaluated utilizing the SEER database. Results The database identified a total of 188,426 SCLC patients during the study period from 2000 through 2020. The age‐adjusted incidence rate slowly declined, on average, by 3% (95% CI: −3.2% to −2.8%) each year from 9 per 100,000 in 2000 to 4.6 per 100,000 in 2020. The decline is evident for all age groups, sexes, and races. Incidence‐based mortality also declined slowly from 6.6 in 2005 to 3.5 in 2020. However, survival outcomes, including 1‐year relative survival and 1‐year observed survivals, have not improved significantly over the last two decades. Conclusion This study found that the incidence of SCLC has decreased from 2000 to 2020, likely due to a reduction in smoking rates, underscoring the importance of smoking abstinence. An improvement in incidence‐based mortality is likely related to an enhanced medical care and a decrease in the incidence of SCLC, but the lack of improvement in survival outcomes reflects the need for more effective systemic therapy.