Citations

9065 Background: Rearranged during transfection ( RET) gene alterations are the oncogenic driver in diverse tumor types, including RET fusions identified in 1-2% of non-small cell lung cancers (NSCLC). While RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are effective, acquired drug resistance remains a challenge. Here, we report the initial results from the RETgistry, an international consortium aimed at elucidating mechanisms of resistance to RET TKIs across RET-altered solid tumors. Methods: This was a retrospective analysis performed across 16 institutions. Patients (pts) were eligible if they had advanced solid tumor harboring an oncogenic RET alteration, received ≥1 RET TKI with disease progression, and underwent resistant tumor or liquid biopsy for next-generation sequencing (NGS). Results: A total of 103 time-distinct biopsies (62 tissue, 30 plasma, 11 paired tissue/plasma) were included in analysis, obtained from 88 pts with progression on a RET-selective TKI [selpercatinib (n = 70), pralsetinib (n = 14), selpercatinib and pralsetinib sequentially (n = 4)]. Pts had the following tumor types: 72 NSCLC (69% KIF5B-RET, 21% CCDC6-RET, 10% other RET fusion), 13 medullary thyroid cancer (TC) (54% RET M918T, 46% other RET mutation), and 2 papillary and 1 anaplastic TC (all, RET fusion). Median age was 58 (range, 21-86); 48% were male with 89% never/light smokers. Median duration of RET TKI preceding biopsies [first-line, n = 32 (31%); second-line, n = 42 (41%); third-/greater-line, n = 29 (28%)] was 16.5 months (mos) (95% CI, 14.0-19.6); median PFS was 14.1 mos (95% CI, 9.3-17.0). Resistant biopsies were obtained at median 15.0 mos from TKI initiation (range, 1.8-58.8). Acquired RET mutations were detected in 14 (14%), most common being G810 substitutions in 12 (12%). Potential off-target resistance gene alterations identified in 43 cases (42%) included MET amplification (14%), BRAF V600E or fusion (2%), KRAS gain or mutation (5%), ERBB2 amplification (2%), EGFR amplification (3%), ROS1 fusion (1%), and activating PIK3CA mutation or PTEN loss (4%). No resistant lung cancer biopsy demonstrated small cell transformation. The duration of TKI therapy (HR 0.64, p = 0.11) or PFS (HR 0.75, p = 0.33) did not differ according to the presence of on-target vs off-target resistance. NGS analyses of pre-RET-selective TKI tumors (n = 92) revealed frequent co-occurring alterations in TP53 (29%) and CDKN2A/B (12%). Conclusions: On-target resistance to RET inhibition due to acquired RET mutations was less common than off-target resistance, identified in 14%. The majority of RET TKI resistance is mediated by off-target mechanisms such as bypass receptor tyrosine kinase activation. Further studies are warranted to enable the development of therapeutic strategies to address resistance in pts with RET-altered tumors. The RETgistry accrual and data analyses continue.

9037 Background: The clinical outcomes for patients with NSCLC remain suboptimal despite recent advancements in anti-PD-1/PD-L1 immunotherapies. Thus, identification of rational combinations of novel immune checkpoint (IC) strategies is imperative. This study aimed to comprehensively characterize the expression of IC targets to inform drug development and design effective combinatorial strategies, to advance the search for optimized therapies for NSCLC. Methods: We analyzed the differential gene expression of IC targets in 537 primary lung adenocarcinoma (LUAD) samples and 59 normal lung tissue samples pre-immunotherapy receipt using RNA-sequencing data from The Cancer Genome Atlas. Gene expression of IC-targets including PDCD1 (PD-1), CD274 (PD-L1), CTLA4, TIGIT, LAG3, HAVCR2 (TIM-3), VSIR (VISTA), ICOS, CD276 (B7-H3), BTLA, IDO1, KLRD1 (CD94/NKG2A), NT5E (CD73), TNFRSF4 (OX-40), TNFRSF18 (GITR), and TNFRSF9 (4-1BB) were obtained. Differential gene expression was determined intra-tumorally by comparison of transcripts per million and inter-tumorally using the DESeq2 algorithm. Log2 fold change >0.5 and false discovery rate adjusted P<0.05 were used as criteria for significant differential expression. Hierarchical clustering was used to identify subsets of tumors with similar profiles of IC-targetable gene expression. Results: Tumors showed significantly increased expression of TNFRSF18 (GITR), NT5E (CD73), TNFRSF9 (4-1BB), LAG3, TIGIT, CTLA4, PD-1, BTLA, B7-H3, and OX-40 (Table 1). On the other hand, tumors exhibited significant downregulation of CD274 (PD-L1), HAVCR2 (TIM-3), ICOS, KLRD1 (CD94/NKG2A), and VSIR (VISTA). Hierarchical clustering revealed recurrent patterns of IC gene overexpression which were characterized by: 1) IDO1-hi, 2) CD276-mid + TNFRSF18-mid, 3) VSIR-hi, 4) CD276-hi, 5) NT5E-hi, and 6) CD276-mid + NT5E-mid. Interestingly, patterns of IC gene expression distinguish tumors from controls. Of note, high VSIR expression was specific to normal tissue rather than tumors. Conclusions: Our study identified many IC targetable genes that were significantly overexpressed in tumors. However, subsets of tumors showed distinct and segregable combinations of overexpressed IC genes. These results suggest heterogeneous mechanisms of immune evasion in NSCLC, which may explain suboptimal outcomes with anti-PD-1/PD-L1 based strategies in this patient population. Our findings emphasize the importance of biomarker-guided approaches for the optimal selection of ICs and the development of rational combinatorial immunotherapies in NSCLC.

9029 Background: Molecular biomarkers such as EML4-ALK fusion variant 3 (V3) and TP53 mutation are associated with poor prognosis in patients (pts) with anaplastic lymphoma kinase fusion positive ( ALK+) non–small cell lung cancer (NSCLC). We evaluated the effect of EML4-ALK fusion variants and TP53 mutation status on time to treatment discontinuation (TTD) of first-line (1L) treatment with a next-generation ALK tyrosine kinase inhibitor (TKI) in pts with ALK+ NSCLC in the real-world setting. Methods: Pts with advanced/metastatic NSCLC who were ALK+ in circulating tumor DNA by Guardant360 (G360) liquid biopsy test from Jan 1, 2018, to Dec 31, 2021, and received 1L monotherapy with a next-generation ALK TKI (alectinib, brigatinib, ceritinib, lorlatinib) were identified in the Guardant INFORM clinical-genomics database. Median TTD of 1L ALK TKI treatment was determined by Kaplan-Meier (KM) methods. The impact of EML4-ALK fusion variant and TP53 mutation status on TTD was evaluated. Results: Database search identified 495 pts with advanced/metastatic NSCLC who had ALK fusion by G360; of these, 214 pts received 1L treatment with a next-generation ALK TKI; 164 had G360 testing before treatment (alectinib, n=147; brigatinib, n=7; ceritinib, n=2; lorlatinib, n=8). Among these 164 pts, median age was 58.6 y, 53% were female, and 29% had baseline brain metastases. Median follow-up from start of 1L treatment was 14.8 mo. Median TTD was 19.6 mo (95% CI: 13.6–not reached [NR]). TP53 mutations were detected in 66 pts (40%). Median (95% CI) TTD in pts with TP53 mutation vs WT was 17.1 (9.5–28.5) vs 21.9 mo (14.3–NR; log-rank P=0.1712). Of 130 pts with EML4-ALK fusion variant type detected, 63 (48%) had V1, 54 (42%) V3, 8 (6%) V2, 4 (3%) V5, and 1 (1%) V8. In pts with EML4-ALK fusion V1 vs V3, median (95% CI) TTD was 19.0 (13.6–NR) vs 21.8 mo (8.7–NR; HR: 0.73; log-rank P=0.3039), with the KM plot showing numerically longer TTD in pts with V1 vs V3 during the first 18 mo and lines crossing at the tail end. Of 117 pts with both an EML4-ALK fusion variant (V1/V3) and TP53 data, 21 (18%) had both V3 and a TP53 mutation. Pts with co-occurring EML4-ALK V3 and TP53 mutation had the shortest TTD (median TTD 8.7 [3.9–NR; HR: 2.59; P=0.0219]; Table). Conclusions: Among pts with NSCLC and ALK fusion, co-occurrence of EML4-ALK V3 and TP53 mutation is common and associated with poor prognosis and high risk of early discontinuation of 1L treatment with a next-generation ALK TKI, most likely due to disease progression. Additional novel or combination therapies are warranted for this subpopulation. [Table: see text]

9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable tetrapeptide-based cleavable linker. Dato-DXd had encouraging efficacy and manageable safety in heavily pretreated aNSCLC. Dato-DXd + immunotherapy yielded greater preclinical activity than either agent alone. Methods: TROPION-Lung02 (NCT04526691) is a phase 1b, global, dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) + pembro 200 mg ± Pt-CT (cisplatin 75 mg/m2 or carboplatin AUC 5) every 21 days across 6 cohorts. Pts in escalation may have received ≤2 prior lines of therapy for aNSCLC. Pts in expansion were primarily treatment (tx) naive (pts receiving Dato-DXd + pembro may have ≤1 prior Pt-based tx). The primary objective is to assess safety and tolerability, including dose-limiting toxicities (DLTs). Secondary objectives include evaluation of efficacy, pharmacokinetics, and immunogenicity. Results: As of the Oct 31, 2022, data cutoff (DCO), 120 pts were treated. All cohorts met DLT criteria to move to escalation. Median age was 65 years. PD-L1 expression was <1%, 1%-49%, and ≥50% in 40%, 33%, and 26% of pts, respectively. Median tx duration was 4.6 mo, with 55% receiving tx at DCO. The most frequent any-grade (gr) tx-emergent adverse events (TEAEs) were nausea (45%) and stomatitis (45%). Gr ≥3 TEAEs occurred in 61% of pts; most frequent were neutrophil count decreased (8%) and amylase increased (8%). TEAEs that were serious, associated with discontinuation, or associated with death occurred in 31%, 24% (16% associated with Dato-DXd), and 6% of pts, respectively. Dose reductions due to TEAEs associated with Dato-DXd occurred in 17%. Drug-related interstitial lung disease occurred in 12 pts (10%; 9 gr 1/2; 3 gr 3). The objective response rate (ORR) with 1L Dato-DXd + pembro doublet and Dato-DXd + pembro + Pt-CT triplet tx was 60% (95% CI, 36%-81%; 12 [2 unconfirmed]/20) and 55% (95% CI, 39%-70%; 23 [5 unconfirmed]/42), respectively. The ORR for any line of therapy was 38% (95% CI, 25%-54%; 18 [2 unconfirmed]/47) with doublet and 47% (95% CI, 34%-60%; 28 [5 unconfirmed]/60) with triplet tx. In both subsets, the disease control rate was 85% and median duration of response was not reached. Responses were observed in all 3 PD-L1 expression level subgroups. Although immature, median progression-free survival (95% CI) was 10.8 (8.3-15.2) and 7.8 mo (5.5-NE) with doublet and triplet tx, respectively. Conclusions: Dato-DXd + pembro ± Pt-CT demonstrated tolerable safety with notable 1L activity in this first and largest dataset with an ADC + immunotherapy ± Pt-CT in aNSCLC pts. Clinical trial information: NCT04526691 .

e20646 Background: Thymic carcinomas tend to be aggressive malignancies with variable patterns of immunostaining. We aimed to assess whether the outcome of patients with thymic carcinomas was associated with immunoreactivity for conventional and emerging immunohistochemical markers of thymic carcinoma versus thymoma. Methods: Scoring of CD5, CD117, EZH2, POU2F3, BAP1, and MTAP immunohistochemistry on whole slide sections was compared to overall survival (OS) and progression free survival (PFS) for 36 thymic carcinoma patients, 28 of whom had complete tumor resection and 8 of whom had incomplete tumor resection. Results: Positive CD5 staining (defined as staining in ≥50% of tumor cells) was present in 13/36 cases (36%) and was significantly associated with longer OS (P = 0.005, hazard ratio = 0.18, CI 0.03-0.63) but not PFS (P = 0.14, hazard ratio = 0.48, CI 0.16-1.26), whereas the other markers were not significantly associated with OS or PFS. Positive CD5 staining remained significantly associated with OS in squamous cell carcinoma subgroup analysis (n = 23, HR = 0.17, CI 0.03-0.65, P = 0.009), patients who did not receive neo-adjuvant treatment (n = 24, HR = 0.21, CI 0.03-0.85, P = 0.03) and after adjusting for incomplete resection (HR = 0.20, CI0.03-0.73, P = 0.01), M1 stage (HR = 0.19, CI 0.03-0.71, P = 0.01) or neoadjuvant treatment (HR = 0.19, CI 0.03-0.71, P = 0.01) in bivariate models. Positive CD5 staining was also significantly associated with age ≥60 years, absence of neoadjuvant treatment, and positive POU2F3 staining. Conclusions: CD5 staining in ≥50% of tumor cells was significantly associated with longer OS for thymic carcinoma patients. Our study supports the notion that CD5 immunohistochemistry may have utility as a prognostic marker for thymic carcinomas.

e20602 Background: DICER1 encodes a miRNA processing enzyme involved in regulation of cell proliferation and differentiation. The role of DICER1 pathogenic variants (PVs) in non-small cell lung cancer (NSCLC) is relatively unknown. Germline and/or somatic PVs have been reported in pleuropulmonary blastoma, pulmonary blastoma (PB), and low-grade/well-differentiated fetal adenocarcinoma (WDFLAC), with clustering of somatic PVs at specific metal ion binding residues referred to as hotspot alterations. PVs in CTNNB1, resulting in constitutive activation of the WNT signaling pathway, have also been implicated in PB and WDFLAC. This study seeks to establish the frequency of somatic DICER1 hotspot PVs that occur in all NSCLCs, their co-occurrence with other PVs in DICER1 and with alterations of CTNNB1/WNT signaling, and their histologic correlates. Methods: Molecular sequencing data collected from 12,146 NSCLCs at Caris Life Sciences were queried for cases featuring somatic DICER1 variants. For those tumors harboring hotspot PVs, sequencing for CTNNB1 and APC mutations was performed, as well as histological review, including examination of beta-catenin immunohistochemical (IHC) staining. Results: Of the 12,146 NSCLCs analyzed, 235 (1.9%) were found to have one or more DICER1 PVs. Of these 235, 225 cases demonstrated one variant, while 10 tumors featured two. Gene analysis revealed that 8 of the observed PVs cases contained hotspot alterations: 2 in the single variant cases and 6 in the double variant cases. The remaining 4 double variant cases harbored a combination of truncating, non-hotspot missense, or splice variants. No significant differences were observed for age or smoking status between DICER1 hotspot-positive and hotspot-negative groups. All but one tumor were considered to be in histologic spectrum of PB/WDFLAC. Of the 8 DICER1 hotspot-positive cases, 1 had a PV in APC, 4 had a CTNNB1 PV, 1 had a PV in both APC and CTNNB1, and 2 had neither. Beta-catenin IHC showed nuclear positivity in 5 tumors that had a PV in either CTNNB1 and/or APC.. Conclusions: This study demonstrates that DICER1 somatic hotspots select for morphologic features of tumor types such as PB and WDFLAC, but are not implicated in the most common forms of NSCLC. Furthermore, DICER1 hotspot-positive NSCLCs frequently harbor CTNNB1 and/or APC alterations, with many cases exhibiting nuclear staining by beta-catenin IHC, suggesting a possible synergistic relationship between DICER1 hotspot PVs and activation of the WNT signaling pathway in the formation of pulmonary tumors. These findings emphasize the importance of molecular testing in clinical practice such that detecting somatic DICER1 hotspot alterations aids in the diagnosis of rare lung cancers, which ultimately require special consideration with respect to disease severity and treatment.

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.

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .