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e21161 Background: Patients with stage IV NSCLC undergo frequent restaging scans (RS). While vital to assess treatment response, RS add anxiety and financial burdens to patients. The ideal frequency of RS is unclear. The numerous treatment options available, such as targeted therapy (TT) and immunotherapy (IO), and the variability in frequency of RS in the trials that led to their approval reflect this uncertainty. Due to the lack of clear guidelines about their ideal interval in daily practice, we reviewed the heterogeneity in frequency of RS in those trials, comparing it to the reported progression-free survival (PFS). Methods: In this study, we reviewed the FDA-approved drugs for stage IV NSCLC since 10/18/2016 and selected the TT and IO. Each trial that led to approval was reviewed, collecting the frequency of RS and the median PFS for the intervention (IA) and control arms (CA). Results: 18 TT drugs and 12 IO regimens, with and without chemotherapy (chemo), were found. Among them, the frequency of RS varied from every 4 to 9 weeks (w) upfront, later modified to every 6 to 12 w until disease progression. The median PFS for both groups in the IA ranged from 2.8 to 19.4 months (m), and from 3.0 to 12.4 m in the CA. The TT group had drugs directed at 7 different mutations, and it presented more discrepancy in terms of restaging frequency. The period between RS varied from every 4 to 8 w initially, later modified to every 6 to 12 w. However, 11 of 18 trials had an interval of every 6 w. The shortest median PFS in the IA arm was 5.4 m, and 5.6 m in the CA. While the longest median PFS was 19.4 m in the IA and 12.4 m in the CA. The IO group included 5 regimens with chemo and 7 without. The interval between RS varied from 6 to 9 w originally, to every 8 to 12 w later. Yet, 8 of 12 regimens’ trials scanned patients every 6 w initially. The median PFS in the IA ranged from 2.8 to 10.3 m, and between 3.0 to 6.5 m in the CA. Conclusions: We observed notable heterogeneity among trials regarding the frequency of RS in patients treated for stage IV NSCLC. When comparing these intervals to the median PFS, we noted the shortest PFS reported is longer than most adopted intervals. This may indicate RS were obtained more frequently than needed. The increased frequency of RS raises a burden for patients and the medical system, while contributing to disparities. This finding, coupled with further comparisons between the frequency of RS in trials and in daily practice, may pave the way for prospective studies analyzing the ideal interval for RS. This can lead to a more efficacious and less burdensome strategy for patients. [Table: see text]

e21157 Background: Atezolizumab is superior to docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) who are pretreated with platinum-based chemotherapy based on the POPLAR and OAK trials. However, patients who received prior immunotherapy (IO) were excluded from these trials. The preferred subsequent therapy for these patients remains to be docetaxel +/- ramucirumab. The efficacy and safety of atezolizumab as a subsequent therapy in IO-pretreated patients are unknown. Methods: We conducted a retrospective study of all patients with locally advanced/metastatic NSCLC who were pretreated with IO at Mayo Clinic Florida/Rochester in 2016 - 2022. Patients who received subsequent therapy of atezolizumab alone (Atezo), docetaxel (Doce), or docetaxel + ramucirumab (Doce+Ram) were included. Kaplan-Meier method and log-rank test were used for survival analysis. Results: Among 169 patients included, 51.5% were female, 91.7% were Caucasian. The median age was 67 (35 – 92). The histology was predominantly adenocarcinoma (76.3%). The most common metastatic sites were bone (51.5%), followed by CNS (44.4%). The median number of prior therapies was 2 (1 – 8). Pembrolizumab was the most used prior IO (87%), followed by durvalumab (10.7%) and nivolumab (8.3%). 13.6% (n = 23), 49.1% (n = 83), and 37.2% (n = 63) patients received subsequent Atezo, Doce, and Doce+Ram, respectively. PFS was improved in the Atezo group compared with Doce group (median PFS 3.9 vs. 3.7 months, HR 0.57, 95% CI 0.37 – 0.87, p = 0.015*). Notably, a prominent percentage of patients in the Atezo group appear to have long-term PFS benefits, demonstrated by 1-year PFS rates of 26.1%, 3.6%, and 4.8% (p = 0.003**), and 2-year PFS rates of 17.4%, 0%, and 0% (p = 0.002**), in the Atezo, Doce, and Doce+Ram groups, respectively. The median OS (months) in the Atezo, Doce, and Doce+Ram groups were 17.5, 7.6, and 11.5, respectively; and were 29.5, 7.2, and 6.9, respectively in the PD-L1 > 50% subgroups. The Atezo group showed significantly greater OS improvement compared with the Doce group (HR 0.42, 95% CI 0.26 – 0.66, p = 0.001**). This benefit appears greater and remains statistically significant in the PD-L1 > 1% (HR 0.39, 95% CI 0.22 – 0.71, p = 0.005**) and PD-L1 > 50% (HR 0.37, 95% CI 0.15 – 0.91, p = 0.022*) subgroups. 5 of 23 (21.7%) patients in the Atezo group developed immune-related adverse events. 3 patients were grade 3 or 4. No grade 5 event. Conclusions: We observed statistically significant and clinically meaningful PFS and OS benefits of atezolizumab monotherapy compared with docetaxel in patients with advanced NSCLC who were pretreated with IO. The OS benefits of atezolizumab over docetaxel +/- ramucirumab was greater in PD-L1 > 1% and PD-L1 > 50% subgroups. Atezolizumab appears to be tolerable in IO-pretreated patients. These findings need to be verified in a prospective study.

e21156 Background: Immunotherapy (IO) is one of the major treatments for patients with metastatic non-small cell lung cancer (mNSCLC). IO may be discontinued in patients for many reasons, the most common being progression of disease (POD). For those patients who discontinued IO for reasons other than POD, such as immune-related adverse event (irAE), there is limited data that compare progression-free survival (PFS) and overall survival (OS) when IO is continued vs. stopped. Methods: We conducted a retrospective study of all patients with mNSCLC (stage IV) treated with IO at our institution from 2011 to 2022. Patients who discontinued IO due to POD were excluded from the analysis. The clinical outcomes, including PFS, OS, and irAE were investigated among patients with no POD who stopped IO prior to 6 or 12 months (m) vs. those that continued IO > 6 or 12m. Results: The analysis at the 6m timepoint included 92 patients, 82.6% were white, 50% were male, 67.4% had adenocarcinoma, and 82.6% used tobacco. The most common site of metastasis was bone (28.3%), followed by CNS (20.7%). 51.2% of patients had received IO as the first line systemic therapy and 32.6% received it as their second. Pembrolizumab was the most used IO (84.78%). Among these patients, 25 discontinued IO before 6m, and 67 patients continued IO beyond 6m. irAE, of any grade, occurred in 44.0% vs 37.3% when comparing IO discontinued with IO continued group at 6m. Patients who continued treatment beyond 6m had a longer duration of PFS (22.8m vs 11.8m, p = 1.14E-04) with a significant increase in OS (34.5m vs 14.0m, p = 1.34E-07). The analysis at the 12m timepoint included 71 patients, 87.3% were white, 46.5% were male, 78.9% had adenocarcinoma, and 80.3% used tobacco. The most common site of metastasis was bone (29.9%), followed by CNS (22.5%). 62.0% of patients had received IO as the first line systemic therapy and 28.7% received it as their second. Pembrolizumab was the most used IO (87.3%). Among these patients, 30 discontinued IO before 12m, and 41 patients continued IO beyond 12m. irAE, of any grade, occurred in 36.7% vs 41.5% when comparing IO discontinued with IO continued group at 12m. Similarly, patients who continued treatment beyond 12m had a longer duration of PFS (28.4m vs 14.2m, p = 1.91E-06) with a significant increase in OS (39.9m vs 17.6m, p = 3.45E-09). Conclusions: We observed that patients with mNSCLC and no POD, who continued IO beyond 6m and 12m, experienced a significant increase in PFS and OS than those who discontinued IO, with more significant increases in those who continued IO past 12m. These findings need to be verified in a larger cohort.

9093 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance invariably emerges in the majority of patients. Potential mechanisms include activation of compensatory pathways. The inhibition of sonic hedgehog signaling (sHH) was previously shown to induce intra-tumoral (IT) infiltration by CD4+, CD8+ and HLA-DR class II cells. Our preclinical data showed sHH inhibitor enhanced IT penetration by monoclonal antibodies and induced PD-L1 expression. We conducted a phase I study using a novel sequential pulse dosing of sonedegib followed by pembrolizumab in aST with an expansion cohort to determine the maximum tolerated dose (MTD), tolerability and preliminary efficacy. Methods: The dose escalation utilized a 3+3 design to determine the MTD and proceeded to expansion cohort upon determination of the MTD. Patients enrolled to each dose level were observed for dose limiting toxicities (DLTs) during the 1st cycle. The expansion cohort consisted of NSCLC and head/neck squamous cell carcinoma (HNSCC) previously treated by anti-PD1/-L1. The recommended phase 2 dose (RP2D) was determined following the review of the toxicity profile of the combination from all cycles. The study treatment consisted of sonidegib oral daily from day 1 to 8 and pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle. The sonidegib dose levels explored were 400, 600 and 800 mg. Archival tumor and blood specimens were collected for correlative studies. Adverse events (AEs) were categorized and graded per CTCAE v5.0, and tumor response by RECIST v1.1. Results: The study enrolled a total of 33 patients and 29 received treatment (13 in escalation and 16 in expansion), including patients with NSCLC, HNSCC, skin cancer, gastric cancer and melanoma. The enrollment to the NSCLC cohort is complete and HNSCC continues. No DLT was encountered during dose escalation and the MTD was not reached. The highest planned dose level was selected to proceed to expansion (sonidegib 800mg days 1-8 in combination with pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle). The expansion cohort proceeded to enroll 15 patients evaluable for AEs (10 NSCLC and 5 HSNCC). Grade 3 and above treatment-related AEs across all patients were hyperglycemia, fatigue, dyspepsia, abdominal pain. The mature efficacy data will be reported at the meeting. Conclusions: The study successfully determined the RP2D of sonidegib when dosed sequentially with pembrolizumab in advanced solid tumors. The AE profile of the combination is similar to that for respective agents given individually. The efficacy data among anti-PD1/-PDL1-treated NSCLC will be reported at the meeting. Clinical trial information: NCT04007744 .

e20540 Background: Mesothelioma is an aggressive malignancy with few approved treatment options. Rare malignancies are often seen in higher volume at academic centers which are considered equipped with better expertise. Outcomes of mesothelioma in the novel therapeutic era and impact of initial treatment at academic versus community centers have not been reported. Methods: Mesothelioma cases from 2004-2019 were collected from The National Cancer Database (NCDB). Epidemiologic factors including sex, age, income, education, insurance status and location were assessed as well as overall survival across academic and community centers. Overall survival (OS) was plotted by type of treatment facility, accounting for several factors available in NCDB. Results: A total of 30136 mesothelioma patients were included in the analysis. 13482 (44.7%) were treated in academic centers and 16654 (55.3%) were treated in community practice locations. A higher proportion of patients with comorbidity scores of 2 or higher were seen in the community setting as compared to the academic setting (12.2% vs 7.6%). The distribution of diagnostic stages was similar between academic and community settings (14.1% vs 14.5% Stage I; 28.5% vs 30.7% Stage IV). A higher number of patients received surgery (39.6% vs 21.3%), chemotherapy (59% vs 45.3%), and immunotherapy (5.2% vs 3.5%) when presenting to academic rather than community settings, respectively (p value < 0.001). OS for all patients was 1.093 years (range: 0-16.47 years) for those treated in an academic center and 0.66 years (95% CI: 0-16.690; p < 0.001) for those treated in the community. Conclusions: Data from NCDB database shows that treatment of mesothelioma at academic centers was associated with improved overall survival when compared to receiving treatment in the community despite seeing similar proportions of early and late-stage disease at presentation. Patients were more likely to receive treatment of any kind if presenting to academic centers.

e20535 Background: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 600 new cases per million people diagnosed annually in the U.S. High incidence of germline mutations has been reported in MPM patients (pts) without asbestos exposure. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in MPM pts. Methods: Using the Mayo Clinic Cancer Registry, we identified 64 pts who were treated for MPM from January 2002-December 2022 with updated follow-up data until 01/15/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 25 pts were male, and 39 pts were female. 14/64 (22%) pts were found to have at least one additional malignancy, including breast cancer (4/14, 29%), colon cancer (3/14, 21%), lymphoma (3/14, 21%), ovarian cancer (2/14, 14%), melanoma (2/14, 14%), anal squamous cell carcinoma (1/14, 7%), papillary thyroid cancer (1/14, 7%), Chronic lymphocytic leukemia (1/14, 7%), renal cell carcinoma (1/14, 7%), squamous cell carcinoma of tongue (1/14, 7%), hepatocellular carcinoma (1/14, 7%) and pituitary macroadenoma (1/14, 7%). 4/14 (29%) pts had more than one (2-4) non-MPM malignancies. The median age at diagnosis of MPM was 65 years (44-82). The median age at diagnosis of non-MPM malignancies was 66 years (18-81). Most of the patients (11/14) were diagnosed with non-MPM malignancy within 12 months of diagnosis of MPM. Most pts (11/14, 78%) were diagnosed with non-MPM malignancy first, among which 5 pts (45%) were found to have MPM on surveillance scans. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and Li-Fraumeni syndrome. FH was available in 29 pts, out of which 28 pts had FH of cancer identified in first-degree relatives. Among the 14 pts with additional malignancies, 9 pts had FH of cancer in first-degree relatives. Among all pts, 15 (18%) pts had a history of asbestos exposure. Among pts who also had non-MPM malignancies, 3/14 (21%) pts had a history of asbestos exposure. Among the 21 non-MPM cancers, 1/21 (5%), 11/21(52%), 1/21(5%), 3/21(14%), and 5/21(24%) non-MPM malignancies were stage 0, stage I, II, and III, or unknown at the diagnosis respectively. All except 1 pt underwent curative treatment for their non-MPM malignancies, and 12 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of multiple primary malignancies in pts with MPM is high, indicating possible genetic predisposition associated with this disease. Early genetic consultation and evaluation for germline mutations may need to be considered for these pts to improve long-term outcomes.

e18097 Background: Sorafenib and lenvatinib are FDA-approved MKIs for locally recurrent or metastatic, progressive, DTC refractory to radioactive iodine treatment. Cabozantinib showed a survival benefit in radioiodine-refractory DTC previously treated with sorafenib and/or lenvatinib and was granted FDA approval. Our study aims to investigate the benefit of other MKIs in DTC beyond the first-line setting. Methods: DTC patients (pts) treated with multiple lines of MKIs from August 2018 to July 2022 at Mayo Clinic across all sites were identified. Electronic medical records were reviewed. 6-month, 12-month, and 18-month progression-free survival (PFS) were calculated for all lines of therapy using RECIST 1.1 criteria. Results: Among the 9 pts identified, 4 were male. The median age was 65 years (43-75). Most pts (60%) had papillary thyroid cancer. All pts received lenvatinib as first line treatment. The 6, 12 and 18-month PFS were 89%, 89%, and 55% respectively. 6 pts discontinued lenvatinib due to progression of disease (PD). 3 pts discontinued it due to adverse effects (AEs), which included hemoptysis (1 pt), severe rash (1 pt) and multiple psychiatric manifestations (1 pt). 8 pts received pazopanib, and 1 patient received cabozantinib with ipilimumab (1 dose) and nivolumab (6 months - discontinued due to myocarditis) as second-line therapy. Among them, 1 patient received pembrolizumab plus everolimus for 2 months before receiving pazopanib. The 6, 12 and 18-month PFS were 55%, 22%, and 11% respectively. All pts ceased treatment due to eventual PD, and there were no toxicity-related discontinuations. 5 pts subsequently received third-line MKIs, including cabozantinib (3 pts), pazopanib (1 pt), and lenvatinib (1 pt). The pt who received lenvatinib had discontinued it as first line therapy due to toxicity. The 2 pts treated with third-line cabozantinib and the pt rechallenged with lenvatinib showed no PD at 12-months and no toxicity related discontinuation. Conclusions: Pazopanib was associated with durable PFS and good tolerability when offered after PD or intolerance on lenvatinib in this retrospective analysis, warranting a randomized prospective study. [Table: see text]

e16621 Background: Adrenocortical carcinoma (ACC) is an exceedingly rare aggressive endocrine malignancy with about 1 new case per million people diagnosed annually in the US. Higher incidence of ACC has been reported in patients (pts) with inherited syndromes such as Lynch syndrome and Li-Fraumeni syndrome. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in ACC patients. Methods: Using the Mayo Clinic Cancer Registry, we identified 63 pts who were treated for ACC from 2010- 2018 with updated follow up data until 01/31/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 22 pts were male. 18/63 (29%) pts were found to have at least one additional malignancy, including basal cell carcinoma (3/18, 17%), melanoma (3/18, 17%), thyroid cancer (3/18, 17%), prostate cancer (3/18, 17%), squamous cell carcinoma of skin (2/18, 11%), renal cell carcinoma (2/18, 11%), breast cancer (2/18, 11%), leukemia (2/18, 11%), lung cancer (1/18, 6%), transitional cell malignant neoplasm of kidney (1/18, 6%), squamous cell carcinoma of tonsil (1/18, 6%), ovarian cancer (1/18, 6%), seminoma (1/18, 6%) and bladder cancer (1/18, 6%). 8/18 (45%) pts had more than one (2-3) non-ACC malignancies. The median age at diagnosis of ACC was 56 years (02-83). The median age at diagnosis of non-ACC malignancies was 54 years (25-72). Most of the patients (13/18) were diagnosed with non-ACC malignancy within 5 years of diagnosis of ACC. Most pts (13/18, 72%) were diagnosed with non-ACC malignancy first. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and 2 pt with a known FH of Li-Fraumeni syndrome. FH was available in 38 pts, out of which 29 pts had FH of cancer identified in first-degree relatives. Among the 18 pts with additional malignancies, 12 pts had FH of cancer in first-degree relatives. All except 2 pts underwent curative treatment for their non-ACC malignancies, and 14 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of other multiple primary malignancies in pts with ACC is high, indicating possible genetic predisposition associated with this disease; Early genetic consultation and evaluation for known and novel germline mutations may need to be considered for these pts to improve long-term outcomes.

TPS3159 Background: ELU001 is a novel first-in-class nanoparticle drug conjugate that consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing for more efficient penetration into solid tumors compared to ADCs and a rapid elimination by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface of cancer cells that express any level of antigen (low to high). ELU001 then internalizes into the tumor cell and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. ELU001 has demonstrated efficacy in preclinical models with low, moderate and high levels of FRα. The first-in-human trial, ELU-FRα-1, is currently recruiting patients with ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma cancers, and, in the opinion of the Investigator, have no meaningful life-prolonging therapy option available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors, (ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma) will be enrolled. FRα expression is determined retrospectively. ELU001 is administered either weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Initial Part 2 expansion cohorts are planned in ovarian cancer with high FRα expression, ovarian cancer with moderate or low FRα expression, and endometrial cancer with any positive FRα expression. Here, FRα will be prospectively determined. Other cancer types may be assessed in the future. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 2-5 patients at each dose for each regimen (QW; Q2W; Q3W). Part 2 Stage 1 will recruit about 15 patients per tumor group expansion cohort and is expected to begin recruitment in the second half of 2023. The study is enrolling in Part 1 Q2W Cohort 301 and Q3W Cohort A in the US. Clinical trial information: NCT05001282 .

2529 Background: Tumor expression of the antiphagocytic protein CD47 (integrin associated protein) may lead to immunotherapy resistance (IO-R). PF-07257876 is a novel, IgG1, Fc-active, bispecific antibody targeting CD47 and PD-L1 designed to reverse IO-R, decrease anemia risk, and eliminate a priming dose. We report a Phase 1 dose escalation study (NCT04881045) in patients (pts) with advanced solid tumors, both IO-refractory and IO-naïve. Methods: The study enrolled pts ≥18 yrs with advanced non–small-cell lung carcinoma (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 expression >1% post anti-PD-1/PD-L1 therapy. Pts with other PD-L1+ tumors known to express CD47 were included (prior IO not required). Pts received PF-07257876 at escalating dose levels in 28-day cycles. Primary objectives were safety (dose-limiting toxicity [DLT] rate), tolerability, and determination of Recommended Phase 2 Dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), blood receptor occupancy (RO), CD47 levels by immunohistochemistry (IHC), tissue biopsy findings, and objective response rate (ORR) per RECIST v.1.1. Results: As of 20OCT2022, 18 pts were enrolled (NSCLC: n = 6; SCCHN: n = 4; other: n = 8). Median (range) age 68 (46–79) yrs. PF-07257876 was given at ascending doses, 150-2400 mg by subcutaneous (SC) injection or SC infusion every 2 weeks. 16 (89%) pts had treatment-related adverse events (TRAEs): Grades 1/2: n = 12 (67%); Grade 3: n = 1 (6%); Grade 4: n = 3 (17%); no Grade 5. Most common TRAEs: injection site reaction/erythema (n = 13, 72%), thrombocytopenia (n = 6, 33%), anemia (n = 5, 28%), and nausea (n = 4, 22%). DLTs occurred in 2 of 3 pts at the highest tested dose (Grade 4 neutropenia and thrombocytopenia, n = 1; Grade 4 thrombocytopenia, n = 1; both pts recovered). One pt with IO-R SCCHN had a confirmed partial response (duration of response 16 wks). ORR was 5.6% (1/18). Drug exposure increase after 1st dose was not dose proportional. Blood RO was > 95% for PD-L1 and > 70% for CD47 with drug exposure. All pts’ baseline CD47 IHC levels were moderate to high. Pharmacodynamics cytokine profiling showed notable dose-response increases of IFNg, TNFa, CXCL9/10, CCL3/4, without IL-6 increase. Conclusions: PF-07257876 was well tolerated with manageable toxicity. Incidence and grade of anemia or thrombocytopenia were manageable. Target engagement of CD47 and PD-L1 in peripheral blood was high. Innate and adaptive cytokine modulation was observed. Antitumor activity was modest. Expansion is ongoing at 1800 mg. Clinical trial information: NCT04881045 .