Citations

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

8545 Background: Brain metastases (BM) correlate with poor prognosis, occurring in 10% of non-small cell lung cancer (NSCLC) patients (pts) at diagnosis and up to 40% over the disease course. Immunotherapy (IO) with or without chemotherapy has become the new standard of care for stage IV NSCLC. However, the survival benefit of IO in pts with BM remains unclear as most studies are limited to small sample sizes or highly selected pts with asymptomatic or treated BMs. This study represents the largest real-world data analysis evaluating the survival benefits of IO in stage IV NSCLC pts with BM. Methods: Demographics, clinical features, and survival were analyzed in stage IV NSCLC pts with BM from the National Cancer Database (NCDB) from 2014-2020. A multivariate Cox proportional hazards modeling assessed factors impacting mortality. Results: Of 204,249 pts with stage IV NSCLC, 30% had BM. The mean age was 68 years, with 54% male. Most pts were White (82%), followed by Black (12%) and Asian (3.1%). Government insurance covered 70% of pts, and 26% had private insurance. Adenocarcinoma was the predominant histology (62%), followed by squamous cell carcinoma (SCC) (20%). Liver and bone metastases were observed in 19% and 42% of pts, respectively. Among pts with BM, 18% received immunotherapy, 53% received chemotherapy, 66% received whole-brain radiation, and 18% received limited-brain radiation. Multivariate Cox analysis showed that pts receiving IO had a 46% lower mortality risk compared to not receiving IO (HR: 0.54, 95% CI: 0.51–0.56, p < 0.001), demonstrating the independent benefit of IO in pts with BM, regardless of brain radiation or chemotherapy. Females had a lower mortality risk than males (HR: 0.88, 95% CI: 0.85–0.91, p < 0.001). Asian (HR: 0.71, 95% CI: 0.64–0.79), Hispanic (HR: 0.76, 95% CI: 0.65–0.89), and Black pts (HR: 0.88, 95% CI: 0.84–0.93) had improved survival as compared to White. Pts with private insurance have lower mortality risk (HR: 0.94, 95% CI: 0.90–0.98), compared to lack of insurance (HR: 1.19, 95% CI: 1.08–1.31). SCC was linked to worse survival (HR: 1.28, 95% CI: 1.22–1.35). Conclusions: IO significantly improves survival in pts with NSCLC with BM, regardless of brain radiation therapy or chemotherapy. However, survival disparities based on histology, insurance status, and demographic factors persist, highlighting the need for more equitable treatment strategies.

8501 Background: TROPION-Lung02 (NCT04526691) evaluated the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd plus pembro combination with or without Pt-CT in aNSCLC. Here we report primary analyses of pts receiving combination therapy in the 1L setting. Methods: Pts across 6 cohorts were dosed with Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with pembro plus Pt-CT (triplet; cisplatin 75 mg/m 2 or carboplatin AUC 5) Q3W. PD-L1 expression (tumor proportion score) was assessed locally by immunohistochemistry (22C3 assay). Primary objectives were safety and tolerability; efficacy was a secondary objective. Results: As of Apr 29, 2024, 96 pts received either the doublet (n=42) or triplet (n=54) combination as 1L therapy; 29% and 15% of pts were ongoing, respectively. Median ages were 65 (doublet) and 64 years (triplet). Median treatment durations were 9.7 and 5.8 months, respectively. Stomatitis (doublet, 57%; triplet, 33%) and nausea (doublet, 42%; triplet, 48%), primarily Gr 1–2, were the most common adverse events (AEs) across both regimens. Treatment related serious AEs occurred in 5 (12%) and 12 (22%) pts in each cohort and no deaths related to study drug were seen. Efficacy outcomes, including by histology, are summarized in the Table. Biomarker analyses, including efficacy by PD-L1 status, will be presented. Conclusions: In this largest data set to date evaluating an ADC combined with an anti-PD-1/L1 agent in the 1L setting, the combination of Dato-DXd plus pembro treatment both with and without Pt-CT elicited durable antitumor activity in pts with aNSCLC. Tolerability of the combinations was as expected, based on known profiles of the individual agents. Clinical trial information: NCT04526691 . All 1L (n=96) 1L, Nonsquamous (n=75) 1L, Squamous (n=21) Response, n (%) Doublet (n=42) Triplet (n=54) Doublet (n=33) Triplet (n=42) Doublet (n=9) Triplet (n=12) Confirmed objective response rate 23 (55) 30 (56) 17 (52) 24 (57) 6 (67) 6 (50) Complete response 1 (2) 2 (4) 1 (3) 2 (5) 0 0 Partial response 22 (52) 28 (52) 16 (49) 22 (52) 6 (67) 6 (50) Stable disease 14 (33) 18 (33) 12 (36) 14 (33) 2 (22) 4 (33) Progressive disease 3 (7) 2 (4) 3 (9) 1 (2) 0 1 (8) Disease control rate a 37 (88) 48 (89) 29 (88) 38 (91) 8 (89) 10 (83) Median duration of response, mo (95% CI) 20.1 (9.7–NE) 13.7 (5.7–NE) 24.9 (9.7–NE) 18.0 (8.0–NE) 12.0 (5.5–NE) 5.5 (4.1–NE) Median PFS, mo (95% CI) 11.2 b (8.2–21.3) 6.8 c (5.5–11.1) 11.2 (6.1–21.3) 10.8 (5.5–17.3) 10.2 (0.4–NE) 6.7 (1.0–8.2) a Proportion of pts with confirmed CR + PR + SD at 12 wks. b.c Median (95% CI) PFS follow-up, mo: b 17.3 (11.3−26.8); c 23.5 (17.3−27.9). mo, months; NE, not evaluable.

TPS1657 Background: Cancer treatments are traditionally administered in clinical settings, which can isolate patients from their familiar environments and exacerbate physical, psychosocial, and financial burdens. Travel requirements further amplify these challenges, particularly for underserved populations. Studies indicate that patients prefer receiving care at home, and international models have demonstrated the safety of home-delivered chemotherapy since the 1990s; however, no U.S. clinical trial data exists. In response, Mayo Clinic has developed the Cancer CARE (Connected Access and Remote Expertise) Beyond Walls (CCBW) program, a distributed cancer care delivery model that expands access to quality cancer care by bringing it to the home environment, providing in-home cancer treatment, lab testing, telemedicine, and community paramedic support. This trial evaluates the safety, acceptability, and impact of home-based subcutaneous (SC) nivolumab (Nivo) administration compared to in-clinic treatment within the CCBW initiative. Methods: This open-label, single-arm trial evaluates the impact of SC Nivo administration location—home versus infusion center—on patient reported cancer care experience, patient-preferred treatment location, acceptability, safety, and patient-reported outcomes. Eligible adult patients (ECOG 0-1) receiving IV Nivo for an FDA-approved indication and residing within 75 miles of Mayo Clinic Florida will transition to SC Nivo, receiving two initial in-clinic cycles. If tolerated without injection reactions, four cycles will be administered at home before resuming in-clinic treatment. Exclusion criteria include concurrent investigational/standard treatments or contraindications to immunotherapy. Fifty patients will be enrolled, with an estimated 75% (n=38) providing cancer care ratings after 8 weeks in-clinic and 8 weeks at-home, offering 85% power to detect a mean difference in ratings of 0.50 standard deviations. The primary endpoint is within-patient change in cancer care rating (0–10 scale, CAHPS Cancer Care Survey) comparing 8 weeks of in-clinic vs. at-home care. Secondary endpoints include patient-preferred treatment location, comfort with home injections, safety (grade 3+ adverse events), function (EORTC QLQ-F17), symptoms (PRO-CTCAE), side effect impact (GP5), and healthcare utilization (ER visits, hospitalizations). Cost will be assessed as a tertiary endpoint. The trial has FDA approval (IND #170079), Mayo Clinic IRB approval (#23009663), and ClinicalTrials.gov registration (NCT06265285). Enrollment began in April 2024, with an expected accrual period of 24 months. To date, 10 patients have been enrolled, and final analysis is expected 2.5 years after trial activation. Clinical trial information: NCT06265285 .

3040 Background: EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN, which is normally expressed in the mesothelium and can be upregulated in many solid tumors. A2B694 is designed to overcome challenges of on-target, off-tumor toxicity that have limited other MSLN-targeted approaches by combining a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells (Tokatlian, et al. J Immunother Cancer. 2022). Methods: Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy are eligible for EVEREST-2. Enrollment to EVEREST-2 and collection of T-cells occurs through the ongoing prescreening study BASECAMP-1 (NCT04981119). When clinically appropriate, A2B694 is manufactured from cryopreserved T cells, and patients undergo lymphodepletion before A2B694 infusion. The dose-escalation phase is evaluating the safety and tolerability of A2B694 to identify the recommended phase 2 dose (RP2D). Dose escalation was started at 1x10 8 Tmod positive cells (dose level [DL] 1) and will increase up to 14x10 8 in combination with low-dose IL-2 (DL 5). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Results: As of January 15, 2025, 5 participants (median age: 60 years; range, 50-84) have enrolled on EVEREST-2 and received A2B694 at DLs 1-2; participants had ovarian cancer (n = 3), pancreatic cancer (n = 1), and non-small cell lung cancer (n = 1) and had received a median of 4 prior lines of therapy (range, 1-7). Lymphodepleting chemotherapy was well tolerated with no significant cytopenias observed. The most common adverse events were lymphopenia (7 [14.6%]) and decreased appetite (6 [12.5%]). There were no dose-limiting toxicities, cytokine release syndrome, nor related neurotoxicity. One participant was admitted to the hospital for decreased appetite. No long-term toxicities have been noted up to 7.5 months post-infusion. Of the participants who have received A2B694, 5 were efficacy evaluable at DLs 1-2. A2B694 was detected post-infusion in the peripheral blood in all patients. Additionally, A2B694 was detected in an abdominal tumor biopsy from a patient with pancreatic cancer 42 days post-infusion. Conclusions: The logic-gated approach was successful at reducing toxicity seen with prior MSLN-targeted CAR T therapies, and A2B694 showed successful CAR T expansion and tumor infiltration. The maximum tolerated dose has not been reached, and results from the dose-escalation phase continue to determine the RP2D. Clinical trial information: NCT06051695 .

e16610 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 1-2 per million per year. The optimal treatment remains unclear as does the benefit of chemotherapy (chemo) in patients (pts) with resectable ACC. Methods: The SEER database (2000–2021) was used to identify ACC pts > 18 years. Variables of interest included age, race, household income, rural-urban classification, stage, chemo, radiation therapy (RT), and surgery. Statistical analyses were conducted using ANOVA, Kruskal-Wallis, and Kaplan-Meier methods to compare survival outcomes according to variables of interest. Results: Of the 2,598 pts identified, 1,564 (60%) were female. The majority of pts (85%) were white, followed by black (9%). Most pts (87%) resided in metropolitan areas. Pts with localized, regional, or distant metastatic disease comprised 25%, 17% and 36% of the group, respectively. 40% of pts underwent radical or total surgical removal of the primary site disease while 9%, 2%, and 1% underwent partial surgical removal, excision, or debulking surgery, respectively, and 30% did not undergo surgery. 34% of pts received chemo and 8% received RT. The median overall survival (mOS) for the entire cohort was 15 months (m) (95% CI: 14–17 m). No significant differences in OS were observed among pts of different races or household incomes. Distant metastatic disease was significantly associated with worse mortality when compared with regional or localized diseases (mOS: 5 m vs. 20 m vs 60.6 m, respectively, p < 0.001). Surgical intervention of any kind was associated with longer survival when compared to those who did not undergo surgery (18 m vs. 3 m, HR 0.33, p < 0.0001). Among the 971 pts with distant metastatic disease, pts who received chemo had a superior mOS compared to those who did not receive chemo or with unknown chemo status (8 m vs. 2 m, p < 0.0001). This OS advantage remained significant even after excluding pts who underwent surgery (5 m vs. 2 m, p < 0.0001). While chemo was also associated with longer mOS (29 m vs. 27 m, p < 0.0001) in localized disease, this survival advantage was not present in pts with localized disease managed with surgery (27 m vs. 27 m, p = 0.061). Although chemo was associated with numerically longer mOS in pts with regional disease, the difference was not significant. Conclusions: ACC with distant metastatic disease carries a poor prognosis yet demonstrates superior survival in pts who receive chemo. Surgery is associated with better survival outcomes, but there is no additive benefit from chemo in those with localized disease managed with surgical resection.

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.