Owonikoko, Taofeek Kunle

Abstract Importance The addition of agents targeting critical signal mediators of cancer cell proliferation such as cyclin-dependent kinases (CDK) potentiates the efficacy of platinum chemotherapy. Objective To determine the safety and efficacy of palbociclib combined with cisplatin (cis) or carboplatin (carbo) in advanced solid malignancies Design Enrollment on dose escalation (part I) proceeded using the Bayesian adaptive design Escalation with Overdose Control (EWOC). Setting Single institution investigator initiated trial. Participants Patients with any advanced cancer after at least one prior therapy were enrolled on dose escalation to determine recommended phase II doses (RP2D). Expansion cohorts were then opened for pancreaticobiliary tract cancers. Intervention Escalating doses of palbociclib in combination with different doses of cisplatin or carboplatin. Main Outcomes and Measures Primary endpoint was objective response rate (ORR). Secondary endpoints included safety, overall survival (OS), and progression-free survival (PFS). Results We enrolled 39 patients on dose escalation (part I) and 32 additional patients on dose expansion (part II). RP2D of palbociclib 100 mg on Day 2-22 + Cisplatin (cis) 60 mg/m2 IV on Day 1 Q4W (Arm A); and palbociclib 75 mg on Day 2-22 + Carboplatin (carbo) AUC 6 IV on Day 1 Q4W (Arm B). ORR for Part I were 12.5% (Arm A) and 25% (Arm B). Median PFS and OS for dose expansion were 2.1 and 4.9 months, respectively. For PDAC, mPFS was 1.9 months (95% CI: 1.7, 2.4), and OS was 3.7 months (95% CI: 2.7, 5.7). Most common treatment-related adverse events (TRAEs—all grade %): Arm A—neutropenia (66%), thrombocytopenia (26%), nausea, fatigue, and anemia (20% each); Arm B—neutropenia (64.7%), thrombocytopenia (53%), and anemia (29%). There were no grade 4-5 TRAEs. Conclusions and Relevance The combination of palbociclib with cisplatin or carboplatin had an acceptable safety profile and clinical responses in some treatment refractory advanced cancers. There was no objective response, but about half of PDAC patients had disease stabilization. Additional efforts are needed to exploit CDK abnormalities in these patients. Clinical trial registration number: NCT02897375

PURPOSE Despite international medical graduates (IMGs) accounting for up to one third of all practicing oncologists in the United States, and nearly half of fellowship trainees, little is known about their contributions to presentations at international oncology meetings. Therefore, we investigated the representation of IMGs in invited faculty roles at the ASCO Annual Meeting as a representative example. METHODS Presentation data from ASCO 2022 and 2023 Annual Meetings were obtained from program guides. We collected presentation-level and speaker-level variables of invited faculty roles and original research. Speakers were categorized as American medical graduate (AMG), IMG, non–US-based, or non-MD (Doctor of Medicine). Univariable and multivariable analyses assessed factors influencing selection for invited faculty roles. RESULTS A total of 2,590 presentations by 2,109 unique speakers were reviewed, including primary research presenters and invited faculty. Among the 1,352 presentations by AMGs, 30% were primary research and 70% were invited faculty roles. For the 374 presentations by IMGs, 41% were primary research and 59% were invited faculty roles. Notably, first-author IMGs were significantly less likely to receive invited faculty roles relative to their primary research output compared with first-author AMGs (adjusted odds ratio, 0.69 [95% CI, 0.53 to 0.90]; P = .006), even when accounting for academic rank, presumed sex, and year. CONCLUSION Relative to IMGs' original research output, IMGs appear to receive fewer invitations for ASCO Annual Meeting invited faculty roles compared with AMGs. Our findings suggest potential underrepresentation and under-recognition of IMGs in these roles, despite their contributions to the oncology workforce in the United States.

9009 Background: International Medical Graduates (IMGs) are a vital component of the US oncology workforce, representing nearly half of practicing medical oncologists. However, systemic barriers may influence their career trajectories differently. Understanding these challenges is essential for addressing workforce disparities and optimizing cancer care delivery across diverse geographic regions. Methods: We conducted a cross-sectional study of 13,497 medical oncologists using the 2024 Dec CMS Provider Dataset linked with the 2023 Rural-Urban Continuum Codes (RUCC). Medical oncologists were identified by their self-reported primary specialties, including Hematology/Oncology, Medical Oncology, and Hematopoietic Cell Transplant. Physicians were categorized by graduation origin (based on their self-reported medical school), career stage (early: 0–10 years, mid: 11–30 years, late: >30 years post-medical school graduation). The primary outcomes included practice at Main Campus of NCI Designated Cancer Centers (as an indicator of academic practice) and the geographical location of their practice (Metro, Non-Metro, Mixed). We employed chi-squared tests for statistical comparisons and performed stratified analyses by career stage to evaluate transition patterns over time. Results: 6920 IMGs constituted 48.7% of the oncology workforce, with similar gender distributions between IMG and non-IMG oncologists (37.9% vs 36.5% female, p=0.068). Notably, early career oncologists were less likely to be IMGs (IMG vs non-IMGs: 8.2% vs 12.5%, p<0.001). Compared to Non-IMGs, IMG oncologists are less likely to practice at main campuses of NCI Center (19.9% vs. 27.7%, p<0.001), especially as their career advances (all p<0.01). (Table). IMGs had higher representation in non-metropolitan areas than non-IMGs (11.4% vs 9.1%, p<0.001), particularly in late-career stages (14.7% vs 12.3%, p=0.033), indicating their unique role in serving underserved regions. (Table). Conclusions: Our findings reveal that, IMGs are less likely to practice at main campuses of NCI-Cancer Center than their non-IMG colleagues. Meanwhile, IMG oncologists are disproportionately serving rural communities. Supporting IMG pathways in oncology is critical to ensure a balanced cancer care delivery across the United States. Practice setting distribution and academic affiliation among international medical graduates (IMGs) and US graduates (USGs) by career stage. IMG (N=6,577) Non-IMG (N=6,920) IMG (N=6,577) Non-IMG (N=6,920) NCI Center Other NCI Center Other Metro Non-Metro/Mixed Metro Non-Metro/Mixed Total 19.9% 80.1% 27.7% 72.3% 88.6% 11.4% 90.9% 9.1% Career Stage Early (0-10y) 29.1% 70.9% 36.1% 63.9% 91.1% 8.9% 95.4% 4.6% Mid (11-30y) 21.3% 78.7% 28.8% 71.2% 90.1% 9.9% 91.6% 8.4% Senior (30+y) 15.0% 85.0% 22.0% 78.0% 85.3% 14.7% 87.7% 12.3%

PURPOSE International medical graduates (IMGs) are an essential component of the oncology workforce in the United States, comprising a third of all practicing oncologists and almost half of hematology/oncology fellows. In this article, we discuss the contributions of IMGs in the US oncology workforce, review unique challenges faced by IMGs, and propose potential solutions to overcome these challenges. METHODS ASCO's IMG Community of Practice was established with the mission to connect, mentor, guide, raise awareness, and overcome the challenges unique to IMGs interested in pursuing medical oncology in the United States. The content of this article is based on discussions at the IMG Community of Practice meetings at ASCO's 2023 and 2024 Annual Meetings. RESULTS IMGs bring an inherent diversity of thought and experience to the oncology workforce. They provide high-quality, culture- and language-concordant care to a diverse population of patients with cancer. However, IMGs in oncology face significant hardships throughout their careers, including visa-related restrictions, psychosocial and cultural struggles, as well as differential treatment while applying for residency and fellowship training, and early career positions. Greater awareness of these challenges among the members of the hematology/oncology community, along with institutional and individual efforts to support IMGs, is warranted. CONCLUSION We encourage oncology professionals and institutions to join our efforts in recognizing the unique paths of IMGs and providing support and advocacy to maximize the potential of IMGs in the US oncology workforce.

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]

Abstract Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, including GSK3901961 and GSK3845097, incorporate further genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, enhancing T-cell persistence and increasing helper functions such as Type 1 T-helper anti-tumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of these two therapies and possible subsequent ones. Substudy 1 will assess GSK3901961 in patients with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in patients with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Table 1 lists eligibility criteria. Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting. Funding: GSK (209012; NCT04526509) Initial screening criteriaInclusion criteriaExclusion criteriaSubstudies 1 and 2 (SS and NSCLC)≥18 years of agePrior malignancy that is not in complete remission or clinically significant systemic illnessMeasurable disease per RECIST v1.1 criteriaPrevious treatment with genetically modified NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting antibodyExpression of HLA-A*02:01, A*02:05, or A*02:06Prior gene therapy using an integrating vectorExpression of NY-ESO-1/LAGE-1a in tumor archival or fresh biopsyPrevious allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplantSubstudies 1 and 2 (SS only)Histologically confirmed advanced (metastatic or unresectable) SS diagnosisCentral nervous system metastasesPresence of t(X;18) translocation(Allowed for NSCLC participants on a case-by-case basis)Received, completed, or intolerant to treatment with anthracycline or anthracycline with ifosfamide for advanced (metastatic or unresectable) disease and has progressedSubstudy 1 (NSCLC only)Histologically or cytologically confirmed Stage IV NSCLCReceived or failed ≥3 lines of systemic therapyReceiving or previously received ≥1 prior line(s) of standard of care treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to doublet taxane and platinum chemotherapyPresence of actionable genetic aberration (activation epithelial growth factor receptor, anaplastic lymphoma kinase/c-ros oncogene 1) per NCCN guidelines Citation Format: Adam J. Schoenfeld, Mehmet Altan, Taofeek K. Owonikoko, Sandra D'Angelo, Brian H. Ladle, Jonathan Noujaim, Kai He, David Liebner, Adrian G. Sacher, John B.A.G. Haanen, Jeffrey Yachnin, Chao Huang, Brian A. Van Tine, Aisha Hasan, Thomas Faitg, Emily Butler, Aiman Shalabi, Steven Attia, Dejka M. Araujo. Master protocol to assess the safety and recommended Phase 2 dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT219.

e18521 Background: About 40% of the US population are from minority groups. Minority pts are under-represented in oncology clinical trials, which limits the applicability of results to the general population and perpetuates poor relationships between healthcare systems and minority communities. This assessment investigated underlying causes of this lack of minority representation in clinical trials and proposes plans to promote diversity. Methods: To better understand the limited inclusion of under-represented pts in oncology clinical trials, 10 specialists in cancer care were selected to provide their perspectives. Specialists were chosen because of their experience enrolling minority pts in clinical trials and met virtually in Dec 2020 via Within3, a secure digital communication platform, to discuss obstacles faced in recruiting minority pts and potential strategies to address these concerns. Specificity and alignment in responses were achieved through software analytics and follow-up queries. Results: The 10 specialists identified as Asian (10%), Black (30%), White (50%), and Hispanic (10%), and began practicing medicine in the 1980s-2010s. All are involved in clinical research and treat a range of minority pts in both urban and suburban settings. Most specialists (8/10) reported treating > 20 minority pts with cancer annually. However, few specialists (2/10) reported that > 20% of their minority pts have enrolled in clinical trials. Specialists agreed that minority pts experience barriers to participation in clinical research, including lack of trust in the healthcare system, materials in their native languages, financial support, minority investigators involved in clinical trials, and accessible study sites. The specialists proposed strategies that could be implemented to increase minority enrollment. These included study sites where minority populations live and industry funded outreach and educational efforts in minority communities. If sites are more accessible, this can reduce time and financial pressures associated with study participation. The specialists recommended that studies be designed to be more supportive of minority populations, specifically regarding inclusion and exclusion criteria and reimbursement of costs. They also advised that increased diversity among clinical researchers and allied personnel may increase the ability of the clinical team to connect with pts and assist in building trust in their communities. Finally, they emphasized the importance of providing informed consent forms and study materials in pts’ native languages. Conclusions: While challenges exist to increasing diversity in oncology clinical studies, a broad consortium of clinical specialists agreed that they can be addressed by community outreach and education, making study sites more accessible, availability of study materials in pts’ native languages, and improving diversity of clinical teams.

TPS2661 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, such as GSK3901961 and GSK3845097, integrate added genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, improving T-cell persistence and helper functions such as Type 1 T-helper antitumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of these and possible subsequent therapies. Substudy 1 will assess GSK3901961 in patients (pts) with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in pts with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Key inclusion criteria are age ≥18 y; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation and anthracycline-based therapy receipt/completion/intolerance (SS only); and Stage IV NSCLC, receipt of ≥1 prior line(s) of standard of care (SOC) therapy including programmed death receptor- or ligand-1 inhibitors, and SOC chemotherapy receipt/intolerance (Substudy 1 only). Key exclusion criteria are prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene/NY-ESO-1–specific therapy or allogenic stem cell/solid organ transplant; central nervous system metastases (SS only); and actionable genetic aberration and receipt/failure of ≥3 systemic therapy lines (Substudy 1 only). Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable. Analyses will be descriptive. The substudies are enrolling. Funding: GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health; funded by GSK. Previously presented at AACR 2021 (CT219). Clinical trial information: NCT04526509.

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.

3594 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-mutant medullary thyroid cancer (MTC). Methods: Patients with RET-mutant MTC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 55 consecutively enrolled patients previously treated with multikinase inhibitors cabozantinib and/or vandetanib. Patients naïve to cabozantinib and vandetanib treatment were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of prior cabozantinib and/or vandetanib-treated patients with MTC (n = 55), the ORR by investigator assessment was 62% (95% CI 47.7–74.6, n = 34/55) and the median DoR was not reached (95% CI 18.4 months–not estimable) despite a median follow-up of 14.8 months. In cabozantinib/vandetanib treatment-naïve patients (n = 88), the ORR by investigator assessment was 69% (95% CI 58.6–78.7, n = 61/88, including 2 responses pending confirmation). Of the 59 confirmed responding patients, with a median follow-up of 8 months, responses were ongoing for 57 responders at the time of the analysis. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib use was associated with marked and durable antitumor activity in prior cabozantinib and/or vandetanib-treated patients and in cabozantinib/vandetanib-naïve patients with RET-mutant MTC, with the majority of responses ongoing in both cohorts. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .