Citations

9001 Background: With an increasingly diverse patient population in the U.S., the need for a diverse clinician workforce has been exemplified. In 2021, 28% of the practicing physicians in the U.S. were born/trained outside of the continental U.S. Though strides in promoting diversity among oncologists have been made, continuous longitudinal assessments and improvements are important to ensure goals are met. We conducted the first cross-sectional study to understand the challenges and experiences of IMGs and Puerto Rican (PR) medical graduates in oncology in the U.S. Methods: An anonymous online questionnaire via Survey Monkey was developed. Non-U.S. IMGs and PRMGs who trained and/or practicing independently in the U.S. were eligible to participate. The study launched on Twitter with promotional materials, inviting participants to complete the survey. A list of IMGs and PR medical graduates was also compiled and an email invitation with the survey link was sent to. The enrollment period was from Sept-Dec 2023. Data was analyzed using descriptive statistics. Results: 97 participants from oncology-related fields completed the survey. Most were attendings (62.9%), and women (50.5%). 95.9% were IMGs and 5.2% PRMGs. 79.4% participants migrated after medical school and 90.7% were still living In the U.S. The main reasons for migrating were looking for better training (63.9%), seeking professional gains (57.7%), and lack of opportunities in their home country (49.5%). Most had to adapt to new cuisine (51.5%), community (53.6%), traditions (54.6%), and celebrations (58.8%). Participants expressed the need to change their dress code (33%), tone of voice (39.2%), the way they spoke (51.5%), and conducted themselves (49.5%). Participants faced racial/ethnic (54.5%), gender (29.7%), and language (41.9%) discrimination during training in the U.S. Similarly, they experienced racial/ethnic (46.8%), gender (32.8%), and language (24.6%) discrimination during independent practice in U.S. Most participants reported moderate personal (57%), yet extreme professional (57.4%) satisfaction in the U.S. 10.5% of participants had returned to their home country, 27.4% planned to, and 53.7% did not plan to return. The main reasons for going back home were family (67%), quality of life (28.9%), and feelings of isolation/lack of community (22.7%). Conclusions: Our study reveals that the main reasons physicians migrate to the U.S. is for education and professional opportunities. Yet these could come at a high cost, leading foreign-born physicians to compromise their true identities. Despite increasing representation of IMGs and PRMGs in the medical field in the U.S., they remain victims of discrimination at frequent rates. It is imperative to implement changes beyond diversifying the work field and strive for equity to create a more conducive environment for minority physicians.

9000 Background: Despite IMGs accounting for up to one-third of all practicing oncologists in the United States, little is known about their contributions to presentations at international oncology meetings, such as the American Society of Clinical Oncology (ASCO). Therefore, we investigated the representation of IMGs in invited faculty roles at ASCO Annual Meetings. Methods: Speaker presentation details at ASCO 2022 and 2023 Annual Meetings were collected using publicly available program guides. We collected presentation-level variables of invited faculty roles (discussant, moderator, chairmanship, session topic presenter) and original research type (oral abstract, poster discussion, plenary session). Speaker-level variables comprised presumed gender, academic rank, and institution. Speakers were categorized into the following groups - American Medical Graduate (AMG): currently affiliated with a US institution, completed medical school in the US; IMG: affiliated with a US institution, completed medical school outside the US; non-US based speakers: affiliated with an institution outside the US; non-MD speakers. Univariable and multivariable analyses were employed to assess factors associated with the selection of presenters for invited faculty roles. Results: A total of 3337 presentations (1649 from 2022, 1688 from 2023) were included. 71.6% of the speakers were US-based, 56.6% were male and 40.5% were full professors. The highest proportion of podium presentations was by AMGs (48.5%), followed by non-US based (28.3%), IMGs (14.1%), and non-MD (9.1%) speakers. 57% of IMG presentations consisted of original research compared to 48.7% for AMGs (Table). Notably, compared to AMGs, IMGs were significantly less likely to be included in invited faculty roles (odds ratio [OR] 0.72 [95% CI 0.58 – 0.88], p <0.01), a finding that remained significant after accounting for gender and academic rank (adjusted OR 0.75 [0.61 – 0.94], p= 0.01). Conclusions: Relative to IMGs’ original research output, IMGs appear to receive less invitations for ASCO Annual Meeting invited faculty roles compared to AMGs. Our findings suggest potential under-representation and under-recognition of IMGs in these roles, despite their contributions to the oncology workforce in the US. [Table: see text]

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

8617 Background: Dato-DXd is an antibody-drug conjugate (ADC) composed of an anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. We report updated findings from TROPION-Lung02 (NCT04526691) evaluating Dato-DXd plus pembro with or without Pt-CT as 1L therapy for aNSCLC. Methods: Patients (Pts) received Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with Pt-CT (triplet; cisplatin 75 mg/m2 or carboplatin AUC 5) Q3W across 6 cohorts. Pts in the expansion stage were primarily treatment (tx)-naïve. PD-L1 expression was evaluated by tumor proportion score (TPS < 50% or ≥50%) using immunohistochemistry (22C3 assay). The primary objectives were safety and tolerability, with efficacy a secondary objective. Results: 96 pts were treated with doublet (n = 42) or triplet (n = 54) therapy in the 1L setting. At data cutoff (Oct 31, 2023), 45% and 20% of pts receiving doublet or triplet tx were ongoing. Median age was 66 years in both subgroups. Median treatment durations were 6.6 and 5.8 months. Across doublet and triplet tx, the most common any-grade (Gr) treatment-emergent adverse events (TEAEs) were stomatitis (57%, 33%) and nausea (40%, 46%), mainly Gr 1–2. Gr ≥3 TEAEs were seen in 57% and 76% of pts; serious TEAEs in 38% and 44%. TEAEs associated with Dato-DXd discontinuation occurred in 29% and 39% of pts receiving doublet or triplet tx. TEAEs associated with death were seen in 2% and 9%, none considered related to study drug. Efficacy outcomes, including ORR and preliminary PFS, in the 1L setting overall and by PD-L1 status are summarized in the Table. Conclusions: As 1L therapy for aNSCLC, Dato-DXd plus pembro with or without Pt-CT continues to demonstrate durable antitumor activity. Efficacy was observed regardless of PD-L1 expression. Tolerability of the combinations was as expected based on known profiles of the individual agents, with no new safety signals observed. To date, this is the largest dataset reported for any ADC combined with an anti-PD-1/L1 agent in the 1L setting for aNSCLC. Clinical trial information: NCT04526691 . [Table: see text]

8602 Background: LCNECs are a rare subtype of lung cancer, with limited clinical trial data and an unclear consensus on first-line treatment. Even less is known about the optimal treatment approach for pts with mixed LCNECs, a pathologic subtype where tumors contain both LCNEC histology as well as features of adenocarcinoma, squamous cell, or small cell lung cancer. Methods: We conducted an international multi-institutional retrospective analysis (n=13 institutions) of pts with advanced or metastatic mixed LCNECs who received 1st-line systemic therapy with either chemotherapy alone (chemo) or chemo-immunotherapy (chemoIO) between 2010-2023. Clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs). Survival comparisons were made via the log-rank test. Results: Seventy-three pts with mixed LCNECs received either chemo (n=42, 57.5%) or chemoIO (n=31, 42.5%). The most common chemo regimens were carboplatin/etoposide (n=27) and cisplatin/etoposide (n=8), while the most common chemoIO was carboplatin/etoposide/atezolizumab (n=19). Median age at 1st-line therapy initiation was 65 (IQR: 60-72). 64% of pts were male (n=47). The majority were former smokers (n=41, 56.2%), with 22 current smokers (30.1%), and 10 non-smokers (13.7%). Mixed histologies included LCNEC/NSCLC (n=45, 56.2%), LCNEC/SCLC (n=17), LCNEC/carcinoid (n=1), and unspecified mixed LCNEC (n=10). Median PFS for chemo was 5 months (95% CI 2.7-9.2) vs. 6 months (95% CI 4.4-8.3) for chemoIO ( p=0.86). Median OS for chemo was 14.2 months (95% CI 10.4-22.5) vs. 17.2 months (95% CI 9.4-27.2) for chemoIO ( p=0.66). The ORR did not differ between chemo (n=18, 45%) and chemoIO (n=15, 48.4%) ( p=0.81). In the chemo group, 60% (n=25) experienced trAEs of any grade, with 23.8% (n=10) experiencing grade 3+ events and four requiring hospitalizations. For chemoIO pts, 61% (n=19) experienced trAEs, with 25.8% (n=8) experiencing grade 3+ events and six requiring hospitalizations. Neutropenia was the most common grade 3+ trAE for both chemo (n=5) and chemoIO (n=4). Overall, there were no significant differences between chemo or chemoIO groups for ORR ( p=0.81), all-grade trAEs ( p=0.88), grade 3+ trAEs ( p=0.84), PFS ( p=0.86), or median OS ( p=0.66). There were no significant differences in median PFS ( p=0.46) or OS ( p=0.99) for pts with mixed LCNEC/NSCLC vs. LCNEC/SCLC. Conclusions: For mixed LCNECs, there was no significant difference in PFS or OS between first-line treatment with chemo vs. chemoIO, suggesting limited benefit from immunotherapy for these pts. Additionally, survival outcomes did not differ between mixed LCNEC/NSCLC and LCNEC/SCLC, suggesting a biology primarily driven by their neuroendocrine component.

8071 Background: Data from the PACIFIC study demonstrated a 5-yr median progression free survival (PFS) and overall survival (OS) of 16.9 and 47.5 months respectively for patients with stage 3A and stage 3B NSCLC demonstrating a high risk of relapse. The 8th ed. of the IASLC staging project reports that the 60-month OS for stage 3A, B and C disease is 41%, 24% and 12% respectively, indicating that improved treatment options are needed for this patient population. Induction chemo-IO (ID chemo-IO) followed by concurrent chemo-radiation (CRT) has not been fully investigated due to concerns regarding the toxicity profile, but this may representant an important unexplored avenue for research. We aim to describe the outcomes of patients who received ID chemo-IO followed by CRT with or without maintenance IO. Methods: We conducted a retrospective study across all Mayo Clinic sites. Patients were included if they were diagnosed with Stage 3 NSCLC deemed ineligible for resection and/or requiring raditation over a large-field ] by a multidisciplinary team with plans for ID chemo-IO prior to CRT and maintenance IO. A total of 927 cases of stage 3 NSCLC patients were screened and those receiving ID chemo-IO followed by CRT were extracted (n = 36). Clinical endpoints are PFS, OS, overall response rate (ORR) and treatment related adverse events (TrAE) defined using CTCAE 5.0. Results: The median age was 67 years, 52.8% were female, all patients were past smokers and 97.2% identified as white. The tumor histologies were adenocarcinoma (66.67%), squamous (27.8%), mucinous adenocarcinoma (2.8%) and sarcomatoid (2.8%). Majority were Stage 3B (47.2%) followed by 3C (38.9%) and 3A (13.9%). N2 and N3 disease was noted in 36.1% and 55.6% of patients respectively. PD-L1 by IHC was > 1-49% (47.2%), > 50% (22.2%) and < 1% (19.4%). Patients received ID chemo-IO with pembrolizumab (83.3%), nivolumab (11.1%) and atezolizumab (2.78%). Average number of ID chemo-IO cycles were 3.67 cycles. The ORR to ID chemo-IO was 86.11%. The median PFS was 23.67 mths and the median OS was 32.07 months. About 94% of patients received CRT afterwards and 66.67% received maintenance IO with pembrolizumab (53.17%) or durvalumab (45.83%). Any grade TrAE occured in 58.33% of patients. Pneumonitis was the most common event (38.9%). Grade 3 -4 pneumonitis was noted in 28.5% (4/11) patients. Other toxicities included hepatitis (8.3%), colitis (11.1%) and myasthenia gravis (2.8%) and 22% of these TrAE’s were grade 3 or 4. Conclusions: Our results indicate that ID chemo-IO shows promise as a therapeutic approach for patients with unresectable stage III NSCLC, especially for patients deemed ineligible or high risk for upfront radiation. Further investigation is needed through a randomized clinical trial to systematically explore and validate the safety and efficacy of ID chemo-IO.

8013 Background: For patients (pts) with unresectable locally-advanced NSCLC, standard of care involves durva consolidation after concurrent CRT, although its benefit in ALK+ tumors is unclear. The ALINA trial demonstrated adjuvant efficacy of alectinib in resected ALK+ NSCLC, but the optimal consolidation strategy for unresectable locally-advanced ALK+ NSCLC remains elusive. Methods: This multi-institutional international retrospective analysis included pts with stage III unresectable ALK+ NSCLC who received an ALK TKI, durva, or obs alone after concurrent CRT between 2015-2022. Baseline characteristics of age, sex, smoking history, and PD-L1 status were collected. Clinical outcomes including real-world progression-free survival (rw-PFS), overall survival (OS), and treatment-related adverse events (trAE) as defined using CTCAE 5.0 were assessed, and multivariate cox regression models were performed. Results: Sixty-four pts across 16 institutions were included. The median age was 57 (IQR 49-66) and 61% were females. The majority had adenocarcinoma (97%) and had never smoked (58%). 15 received ALK TKI (10 alectinib, 3 crizotinib, 1 brigatinib, 1 lorlatinib), 30 received durva, and 19 received obs alone. There was no significant difference in stage of cancer (IIIA, B, or C) or PD-L1 status among groups. After adjusting for stage and age at CRT initiation, median rw-PFS was significantly longer for ALK TKI (rw-PFS not reached [NR], 95% CI 22.7-NR) vs durva (11.3 months (mo), 95% CI 9.2-18.5, p= 0.005, HR = 0.12) or obs (7.4 mo, 95% CI 3.4-12.5, p < 0.0001). Two (13%) pts progressed on ALK TKI. 25 pts (83%) progressed on durva leading to treatment with ALK TKI in 23, and 18 (95%) progressed while under obs leading to treatment with ALK TKI in 15. 3-year OS was 100% for ALK TKI vs 90.5% for durva vs 63.5% for obs. Median OS was NR (95% CI NR-NR) for both ALK TKI and durva vs 70.6 mo (24.9-NR) in the obs group ( p= 0.03 for both ALK TKI and durva compared to obs). Median duration of therapy was 24.7 mo with ALK TKI and 6.5 mo with durva. Grade ≥3 trAE occurred in 27%, 7%, 6% of pts treated with ALK TKI (1 fatigue, 1 diarrhea, 1 hyperbilirubinemia, 1 pneumonitis), durva (1 fatigue, 1 neutropenia), and obs (1 neutropenia) respectively. Treatment discontinuation due to toxicity occurred in 4 (27%) with ALK TKI and in 3 (10%) with durva. Conclusions: In this retrospective study of stage III ALK+ NSCLC, consolidation ALK TKI demonstrated clinically meaningful improvement in PFS and OS over durva and obs, while showing a slightly higher rate of trAE over dura and obs. Furthermore, we show a high rate of progression following CRT alone in ALK+ NSCLC. These findings underscore the need for prospective molecularly driven trials to determine the optimal consolidation therapy for unresectable ALK+ NSCLC.

6582 Background: Although high symptom burden indicates poor survival and informs treatment decisions, little is known about the impact of demographic, clinical, and laboratory features on total symptom score (TSS) in patients with myeloproliferative neoplasms (MPN). Methods: Patients with MPN (polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)) were identified from the retrospective chart review. TSS, individual symptom scores (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, fever, night sweats, itching, bone pain, weight loss), demographic characteristics (race, ethnicity, age, gender), clinical features (time since diagnosis, depression status, obesity status, spleen size), laboratory results and season at the time of visit were recorded from the clinical encounter when index assessment of TSS was performed for each patient. Normality was assessed using visual inspection of data distribution, whereas multicollinearity was assessed using various inflation factors. A univariable regression followed by a multivariable regression analysis was conducted using a backward selection approach. A p-value <0.05 indicated a statistically significant association of a given feature with TSS. Results: The chart review identified 252 patients (PV: 78; ET: 81; MF: 93). Mean age was 59 (SD: 17.7), 67 (SD: 13.0), and 68 (SD: 10.9) years for ET, PV, and MF respectively. Most patients were white (PV, MF: 92%; ET: 83%) and females (ET: 75%; PV: 60%; MF: 53%). The TSS of patients was highest with PV (mean: 18.5; SD: 16.9) followed by MF (mean: 18.1; SD: 15.4) and ET (mean: 14.3; SD: 15.9). Fatigue was the most reported symptom whereas the least reported symptoms were fever and weight loss. Univariable regression analyses showed depression (B: 17.7; p=0.02), female gender (B: 10.6; p=0.01), platelet count (B: 0.03; p=0.03), and hemoglobin (Hb) (B: -2.6; p=0.01) in PV patients, depression (B: 19.8, p=2x10-5) in ET patients and depression (B: 11.0, p=0.03), white blood cell (WBC) count (B: 0.2; p=0.01), neutrophil count (B: 0.3, p=0.01), and non-neutrophil WBC count (B: 0.6; p=0.02) in MF patients to have significant association with TSS. Multivariable regression analyses ( Table) showed Hb (B: -2.5; p=0.01) and platelet count (B: 0.02; p=0.03) in PV patients, depression (B: 19.7; p=2x10-5) in ET patients and depression (B: 12.3, p=0.01) and WBC count (B: 0.3; p=0.002) in MF patients to have a significant association with TSS. Conclusions: Depression in ET and MF and low Hb in PV were identified as significant drivers of symptom burden. Identifying and managing patients with these comorbidities could improve their quality of life with a potential survival benefit. [Table: see text]

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted—from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.