Rare Cancer Research Articles

NTRK positivity and conversion to appropriate personalized treatment.

e15163 Background: The field of precision medicine continues to grow in size and complexity. In oncology alone, the FDA has approved companion diagnostics for 53 unique biomarkers across 28 different indications linking to 59 separate drugs to treat cancer patients beyond traditional options (FDA 21 December 2023). Two of these drugs, entrectinib and larotrectinib, are approved across all tumor types for NTRK fusions, which while rare in common cancer indications are more common in understudied, rare cancers (Cocco et al Nature 2018). These treatment options have significant outcomes for patients, however, there is still a large barrier for patients to access the right treatment (Sadik et al JCO 2022). We hypothesized not all patients with identified NTRK alterations are being prescribed these treatments and assessed this in real-world data for US oncology patients. Methods: Diaceutics proprietary DXRX database contains real-world claims, specialty pharmacy and laboratory data that enables the identification of patients positive for biomarker alterations and resultant treatment pathways in the US. The result-level laboratory data was filtered to solid tumor patients who were positive for NTRK alterations in the 2-year window between 2022 and 2023. The identified NTRK positive patients were then tokenized and joined to our medical claims and pharmacy data to assess which treatment combinations these patients received. Results: A total of 4,251 cancer patients were identified as having tumors with NTRK alterations. Of the patients that could be linked to treatment (800 patients), 1.5% (n = 12) patients went on to receive a targeted treatment for their NTRK alteration, either entrectinib (n = 8), larotrectinib (n = 3), or both entrectinib and larotrectinib (n = 1). When not prescribed either of these, 43.25% (n = 346) patients received different targeted treatment, possibly because of other alterations identified. There were still 55.25% (n = 442) receiving no targeted treatment, either being prescribed chemotherapy (chemo) alone (28.25%, n = 226), immunotherapy (IO) alone (21.1%, n = 169), or an IO/chemo combination (5.9%, n = 47). Conclusions: Despite the established significant disease control from targeted NTRK treatments, most patients with these alterationsdo not have an opportunity to benefit from the most effective personalized treatment for their cancer. These findings may suggest that targeted therapy for rarer and/or tissue agnostic alterations may get deprioritized or overlooked. Therefore, we advocate that a new, different approach for bringing targeted treatments for rare biomarkers to patients is still needed. Different economic models and an optimized approach to engage and inform key stakeholders including oncologists of the presence and benefit of targeted treatments is critical and needs further investigation.

Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p<0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.

Uncovering actionable genetic alterations and immune predictive biomarkers for anal squamous cell carcinomas in the era of immunotherapy: PD-L1 and beyond.

3518 Background: Squamous cell carcinoma of the anal canal (SCAC) is a rare cancer with limited treatments. Immune checkpoint inhibitors (ICIs) use is routine for recurrent/refractory disease, but predictive biomarkers remain elusive. We analyzed the largest dataset of SCAC to date, focusing on PD-L1 expression. Methods: Next-generation sequencing of DNA (592 genes or WES) and RNA (WTS) was tested at Caris Life Sciences (Phoenix, AZ). PD-L1 was tested by immunohistochemistry (IHC) (SP142) and grouped as high (2+ and ≥5%), low (1-2 and 1-5%), and negative (0) CPS. dMMR/MSI-H was tested by IHC/NGS and tumor mutation burden (TMB)-High was defined as >10 mt/MB. RNA expression data was used to estimate the tumor microenvironment (TME) using QuantiSEQ. RNA signatures predictive of ICI response (interferon gamma [IFNγ]; T-cell inflamed signature [TIS]) were tested. X2/Fisher-Exact was used with significance shown as P-value adjusted for multiple comparisons (Q<0.05). Real-world overall survival (rwOS) was from insurance claims and calculated from tissue collection to last contact; time-on-treatment (TOT) was from start to finish of ICI. Results: Of 1242 SCAC samples, 64.3% (798) expressed PD-L1, 41.7% (518) showed high PD-L1 expression, 1.2% were dMMR/MSI-H and 14.5% were TMB-high. TMB-H trended higher in PD-L1 low vs PD-L1 negative (16.3% vs 10.2%, p=0.036). No trend was seen for dMMR/MSI-H. Mutations in PIK3CA (38.3% vs 21.7%) and CASP8(5.3% vs 0.3%) were significantly higher in PD-L1 high vs negative. Similar trends were seen in NF1 (2.4% vs 0.4%) and ARID1A (2.7% vs 0.6%). The opposite was noted for JAK2 (0% vs 2.6%), BAP1 (1.1% vs 3.6%) mutations, and FGFR3 amplifications (0% vs 2.2%). For PD-L1 high vs negative, infiltration of Tregs, M1 macrophages, neutrophils, CD8+ cells, and cancer-associated fibroblasts decreased with PD-L1 expression (fold change [FC]: 0.67-0.80, Q<0.05). Expression of immune-oncology (IO) markers IDO1, PDCD1, IFNG, CD274, HVACR2, CTLA4, LAG3, CD80, CD86 and PDCD1LG2 decreased with PD-L1 expression (FC:0.35-0.73, Q<0.05). Similarly, TIS and IFNg scores decreased with PD-L1 IHC (Q<0.05). In 316 SCAC patients treated with ICIs, PD-L1 high had longer TOT compared to PD-L1 negative (N=168 vs 80, 5.5m vs 2.9m, HR 0.758, 95% CI 0.579 to 0.992, p=0.044) while PD-L1 low (N=68) showed a TOT in between (3.2m) but not significantly different compared to high or negative. No differences in rwOS were observed. Conclusions: PD-L1 is expressed in over 50% of SCACs, while dMMR/MSI-H is rare. High PD-L1-expressing tumors have higher PIK3CAand CASP8 mutations and overexpress IO markers, are inflamed, and have prolonged treatment times with ICIs. This is the largest study to date reporting SCAC genomic profiles and identifies the utility of PD-L1 as a predictive biomarker of IO efficacy. This discovery needs to be confirmed in prospective trials.

Correlation of cost in teaching hospital with outcomes in patients with cardiac myxoma: A retrospective study using the national in-patient data sample (NIS).

e23062 Background: Cardiac myxoma (CM) is a rare cancer, benign but functionally malignant. It is the most common cardiac tumor and is more frequent in females in North America and Europe. Mortality has been associated with cardiac burden complications and the resolving capacity of the medical center to diagnose and treat these complications. Methods: A retrospective cohort analysis focused on adults admitted to hospitals between 2016 and 2020 with a primary diagnosis of CM. Data for this study were obtained from the NIS Database. The primary outcome was to determine if higher cost in teaching hospitals has an impact on mortality outcomes compared with non-teaching teaching hospitals. We looked at sociodemographic characteristics, length of stay (LoS), and complications as secondary outcomes. Hypothesis testing for categorical variables was tested with Chi-Square. Continuous variables were tested with a Student t-test. Statistical significance was defined as a two-tailed P value of < 0.05. Results: A total of 3,744 patients met inclusion criteria: 3014 were within teaching hospitals (TH), and 730 were within no-teaching hospitals (NTH). The median age was similar in both settings: 64 years in TH and 68 years in NTH (p < 0.001). LoS was higher in TH, 7.6 days, vs. NTH, 6.3 days (p = 0.05). Hospitalization costs were higher in TH, for a mean of $156,658 than in NTH, for a mean of $109,328 (p < 0.001). Most patients were females, 1850 in TH and 405 in NTH (p = 0.24). Mortality was higher in TH 75 vs. NTH 45 (p = 0.02). The population was composed of mostly White patients (68% in TH vs. 73% in NTH), followed by Back (14% in TH vs. 9% in NTH), Hispanics (11% in TH vs. 9% in NTH), Asian (3% in TH vs. 6% in NTH) and Native American patients (5% in TH vs. 0% in NTH) (p = 0.22). Patients were located mainly in the south region (39% in TH vs. 43% in NTH), followed by a similar distribution between the West (20% in TH vs. 27% in NTH), Central (23% in TH vs. 20% in NTH) and East regions (20% in TH vs. 10% in NTH) (p = 0.02). The most frequent payer was Medicare, 56% in TH vs 64% in NTH and private insurance, 28% in TH vs 24% in NTH (p < 0.001). Cardiac pathologies were the most frequent comorbidities: Congestive Heart Failure (p = 0.39), Cardiovascular disease (p = 0.18), hypertension (p = 0.1), and coronary artery disease (p = 0.44). The most common complications were cardiovascular, as demonstrated in previous studies. Conclusions: Cardiac Myxoma is a benign tumor with fatal severe complications that affect the more elderly female white population. Our study revealed a lack of significance between the outcome and the type of hospital in which patients received treatment. Similarly, mortality was not found to be driven by sociodemographic characteristics in our analysis.

Protein expression of claudin 18.2, Nectin-4, HER-3, and PD-L1 in small bowel adenocarcinoma: Exploring potential targets of antibody drugs.

4176 Background: Small bowel adenocarcinoma (SBA) is a rare cancer and improved treatment strategies are needed. To explore potential targets of existing antibody drugs for SBA, we examined the protein expression of Claudin 18.2, Nectin-4, HER-3, and PD-L1 in SBA and analyzed the associated clinicopathological features and prognosis. Methods: We retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy between July 2010 and July 2023 at our hospital. Immunohistochemistry staining of Claudin 18.2, Nectin-4, HER-3, and PD-L1 was performed for pathological samples. We also assessed overall survival (OS) in patients receiving palliative chemotherapy to examine the association between prognosis and expression of each protein, excluding patients with microsatellite instability-high (MSI-H) treated with immunotherapy. Results: Pathological samples and clinical data were available for 51 patients aged 23–82 years. The primary lesion was in the duodenum in 49% of these patients and in the jejunum or ileum in 51%. There was no recurrence after surgery and adjuvant chemotherapy in 12% of the patients, while 88% received oxaliplatin-based palliative chemotherapy for unresectable SBA. Among those with unresectable SBA, 4 (8%) had MSI-H and were treated with immunotherapy. Claudin 18.2, Nectin-4, and HER-3 positivity was 35%, 82%, and 88%, respectively. All cases had expression of at least one of these molecules, and 25% had expression of all three. Two molecules were co-expressed in 55% of the patients, most frequently Nectin-4 and HER-3. Nectin-4 expression was observed in all primary lesions in the jejunum or ileum (100%), compared with 60% in the duodenum ( p < 0.001). The distribution of combined positive score (CPS) for PD-L1 was < 1, 1-5, and ≥ 5 for 33%, 32%, and 35%, respectively. CPS was higher in Nectin-4 positive samples compared with negative samples (median CPS 2.5% vs 0%, p = 0.077). Among patients receiving palliative chemotherapy, OS did not differ according to the Claudin 18.2 expression (17.0 vs. 13.7 months, HR 0.91, p = 0.800) or HER-3 expression (17.0 vs. 9.7 months, HR 0.40, p = 0.166). However, patients with Nectin-4 expression had significantly shorter OS than those without Nectin-4 expression (12.6 vs. 43.2 months, HR 5.12, p = 0.006). Similarly, OS was shorter in patients with PD-L1 CPS ≥ 5 compared with CPS < 5 (9.7 vs. 18.0 months, HR 2.60, p = 0.028). Multivariate analysis revealed that Nectin-4 expression (HR 4.55, p = 0.020) was an independent adverse prognostic factor for OS. Conclusions: Claudin 18.2, Nectin-4, and HER-3 are highly expressed in SBA, indicating they are potential targets for existing antibody drugs. In particular, Nectin-4-positive SBA exhibited poor prognosis and high PD-L1 expression, suggesting that a combination of immunotherapy and Nectin-4-targeting therapy may be effective.

Disease monitoring using plasma-based circulating tumor DNA (ctDNA) assays in rare malignancies.

e15046 Background: ctDNA assays can be used to assess molecular residual disease, and the value of ctDNA monitoring in disease surveillance and treatment response assessment has been demonstrated in colon, breast, lung, and bladder cancers. However, the data of ctDNA in rare cancers has been lacking. We conducted this retrospective study to investigate the potential roles of ctDNA monitoring in rare tumors in both surveillance and response evaluation. Methods: ctDNA assay results of 12 patients (pts) with rare cancers including adrenocortical carcinoma (ACC) (4 pts), salivary gland cancers (3 pts), pleural or peritoneal malignant mesothelioma (4 pts), and anaplastic thyroid cancer (ATC) (1pt) undergoing treatment or surveillance in 2023 at Mayo Clinic Florida were analyzed. The trends of ctDNA levels were correlated with radiographic images findings. Results: Among the 12 patients, ctDNA was detected in at least one time point in 9 (75%) pts, including 1 (100%) ATC pt, 2 (66%) salivary gland pts, 3 (75%) malignant mesothelioma pts, and 3 (75%) ACC pts. Among these 9 pts, 5 pts had ctDNA collected at more than one timepoints, and the trends of ctDNA levels were consistent with image findings in all 5 pts. Among these 5 pts, one pt received definitive surgery for ACC with clearance of ctDNA after the surgery and one salivary gland cancer pt was undergoing surveillance and later developed disease progression. The other 3 pts were undergoing palliative systemic therapy and had responded to treatments. Conclusions: ctDNA was detectable in majority of the patients with rare malignancies reviewed in this study, including ACC, ATC, pleural or peritoneal malignant mesothelioma, and salivary gland cancers. Further study is warranted to investigate the role of ctDNA monitoring in surveillance and treatment response evaluation in rare malignancies.

A phase 1/2, safety lead-in and dose expansion, open-label, multicenter trial investigating the safety, tolerability, and preliminary activity of ivosidenib in combination with nivolumab and ipilimumab in previously treated subjects with IDH1-mutated nonresectable or metastatic cholangiocarcinoma.

TPS4197 Background: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options, though molecularly targeted therapies have demonstrated anti-tumor activity in certain subsets. Approximately 15% of patients with intrahepatic CCA harbor activating mutations in isocitrate dehydrogenase-1 (mIDH1), and treatment with the mIDH1 inhibitor, ivosidenib (IVO) improved progression-free survival in the phase 3 ClarIDHy trial. mIDH1 is associated with an immune-excluded tumor microenvironment, and anti-CTLA4 immune checkpoint inhibition (ICI) augments anti-tumor activity when combined with IVO in preclinical models. Preliminary anti-tumor activity of dual immune checkpoint inhibitors (IPI, NIVO) has been reported in biliary tract cancers. Methods: This is a phase 1/2, non-comparative, multicenter, open-label study of IVO, IPI, NIVO, in subjects with unresectable or metastatic CCA with mIDH1. Key eligibility criteria include: a histopathological diagnosis; tumor mIDH1 based on local testing; progression on and/or intolerance to 1-2 prior lines of systemic therapy, at least one of which contained either gemcitabine and/or 5-fluorouracil; prior anti-PD-(L)1 therapy is allowed in the safety lead in; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; at least 1 measurable lesion as defined by RECIST version 1.1. The study has a safety lead-in phase and an expansion phase with 2 different expansion cohorts: cohort 1, ICI-naive; cohort 2, prior ICI allowed. The primary objective is to evaluate the safety and tolerability of IVO in combination with IPI plus NIVO and determine the recommended combination dose (RCD). This phase will enroll ~6 to 12 dose-limiting toxicity (DLT)–evaluable patients. The first 6 patients enrolled will receive IVO 500 mg orally once daily in combination with IPI 1 mg/kg IV infusion and NIVO 3 mg/kg IV infusion concurrently once every 3 weeks for 4 doses followed by NIVO at 480 mg IV once every 4 weeks until progression or unacceptable toxicity (up to a maximum of 24 months of NIVO). DLTs will be evaluated during the first 2 cycles of treatment. An additional 6 patients may be enrolled to assess an alternative dose of ivosidenib 250 mg once daily. Upon determination of the RCD, the two expansion cohorts will be initiated to assess the clinical activity of the triplet combination in patients with and without prior ICI. First patient in occurred in November 2023. Clinical trial information: NCT05921760 .

Institutional review of pediatric oncology patients participating in early phase clinical trials.

10042 Background: Phase 1 or phase 1/2 trials are a first step in pediatric cancer drug development with a primary objective of evaluating safety and dosing of new therapies or new combinations. They most commonly enroll patients with relapsed/refractory or very rare cancers and currently there is a paucity of information regarding outcomes for pediatric patients enrolled on phase 1/2 trials. Thus, we sought to describe clinical outcomes of pediatric patients enrolled in phase 1 clinical trials over a 9-year period at a single institution. Methods: We queried our clinical trials management system to generate a list of all pediatric patients who were enrolled and treated on phase 1 or phase 1/2 trials from 2011-2019. We reviewed the electronic medical record to collect baseline demographic and clinical data. We also collected key efficacy and safety endpoints post-enrollment including: time to death (if applicable); objective response to trial therapy; duration on therapy; need for dose modification; and occurrence of DLT. Overall survival was calculated using Kaplan-Meier methods. Results: A total of 224 unique patients accounted for 258 enrollments and 253 episodes of treatment on trial. The median age at trial enrollment was 11 years (range 0-27 years) and 56.2% were male. The majority of patients were white (85.7%) and non-Hispanic (88.2%). English was the primary language for 86.3% of patients and 65.8% of patients had private insurance. Solid tumors were the most common malignancy at 41.0%, followed by brain tumors (34.1%), and hematologic malignancies (24.9%). The majority of patients (60%) had metastatic disease at time of first enrollment. Among episodes of treatment, 51.4% received targeted monotherapy. Median overall survival from first enrollment for 210 patients treated with available vital status was 12.8 months. Among episodes of treatment, 25.2% of patients had an objective response to trial therapy. Stratified by disease type, objective response was documented for 52.9% of patients with hematologic malignancies, 20.5% of patients with CNS tumors, and 15.8% of patients with solid tumors. Patients on trials with cytotoxic-only treatment had the highest objective response (47.5%), while patients treated with cytotoxic plus targeted therapies combinations had the lowest rate (18.9%). The median duration of therapy was 1.5 months. Twenty-seven patients (11.0%) required dose modification and 22 patients (9.0%) had DLT. Conclusions: We present clinical outcomes for a recent cohort of pediatric patients treated on early phase clinical trials. We identified differential response rates to phase 1 therapy by disease and trial-type in a single-center cohort treated over the past decade. These data are immediately informative to discussions between providers and patients/parents regarding expected phase 1 trial outcomes.

SWOG S2012: Randomized phase II/III trial of first line platinum (P)/etoposide (E) with or without atezolizumab (NSC #783608) in patients with advanced or metastatic poorly differentiated extrapulmonary neuroendocrine carcinomas (NEC).

TPS4201 Background: Poorly differentiated, extrapulmonary NEC are rare cancers with median overall survival (OS) <1 year. Treatment is extrapolated from small cell lung cancer (SCLC) with use of P (cisplatin or carboplatin) + E. More effective treatment regimens and predictive biomarkers are needed to improve outcomes. In SCLC, induction therapy with combination of P/E + PD-L1 checkpoint inhibitor atezolizumab and maintenance atezolizumab improved OS (12.3 months vs 10.3 months; HR 0.70, 95% CI 0.54 – 0.91, P=0.007) vs P/E alone (1). No study to date has compared PD-1/PD-L1 inhibition during induction only vs during induction and maintenance therapy. In SCLC, distinct molecular subtypes can be identified by the presence of specific transcription factors (e.g., ASCL1, NEUROD1, POU2F3) or an inflamed gene signature (SCLC-I), with SCLC-I pts more likely to benefit clinically from the addition of immunotherapy (2). In this study we plan to test the benefit of adding atezolizumab to induction P/E as well as the role of adding maintenance atezolizumab after induction P/E plus atezolizumab. We also plan to correlate tumor- and blood-based subtype biomarkers with response to therapy. Methods: Eligible pts ≥18 years old have evaluable, histologically confirmed extrapulmonary NEC, Zubrod PS ≤2, and are allowed to have up to 1 cycle of P/E prior to enrollment. P (cisplatin 75 mg/m2 or carboplatin AUC 5, iv) on day 1, E 100 mg/m2 iv on days 1-3, and atezolizumab 1200 mg iv on day 1 of q21 day cycles. Pts are randomized to 1 of 3 arms: A) Induction P/E + atezolizumab -> maintenance atezolizumab B) Induction P/E + atezolizumab -> observation C) Induction P/E -> observation. The primary objective is to compare the overall survival (OS, from randomization) between arms in a fixed sequence: A vs C -> B vs C -> A vs B. Secondary objectives include comparing OS (from start of maintenance/observation), progression free survival, response rate, duration of response, and safety/tolerability across arms. Tumor and blood samples will be banked for future biomarker analyses, including immunohistochemistry of transcription factors on tissue and whole exome sequencing on tumor and circulating tumor DNA. With 189 pts (168 eligible), the study has 84% power to detect an improvement in 12-months OS from 35% to 57.5% (HR 0.53). This study was activated December 2021 with 3 pts enrolled over 1 year due to restricting enrollment of NEC of small cell histology only. The protocol was amended in January 2023 to broaden eligibility to all NEC subtypes (small cell, large cell, and undefined histology with Ki-67 ≥55%). As of January 2024, 35 patients have been enrolled. A protocol amendment is planned to remove the need for Ki-67 index for NEC of genitourinary origin to improve accrual. 1. Horn L, et al. N Engl J Med 2018. 2. Gay CM, et al. Cancer Cell 2021. Clinical trial information: NCT05058651 .

Demographic and Clinicopathological Spectrum of Gallbladder Carcinoma in a Tertiary Care Centre in Jharkhand: A Retrospective Study.

Introduction Gallbladder carcinoma is a rare but aggressive cancer of adults that affects females more than males. Its occurrence is more common in the regions of South America and Asia. Chronic inflammation and cholelithiasis are frequently associated risk factors of gallbladder carcinoma. The incidental discovery of a gallbladder carcinoma during cholecystectomy, gross or microscopic examination of the unsuspected gallbladder specimens is termed incidental gallbladder carcinoma (IGBC). Considering the lack of extensive studies on gallbladder carcinoma in the Eastern region of India, especially in Jharkhand, this study has been done to present the demographic and clinicopathological characteristics of gallbladder carcinoma in this region. Methods A retrospective and descriptive study was done at Rajendra Institute of Medical Sciences (RIMS), Ranchi, a tertiary care center in Jharkhand. The study sample comprised 2386 gall bladder casesreceived in the Department of Pathology over five years, from December 2018 to December 2023. Results Of 2368 specimens, 25 cases (n=25) were reported as primary gallbladder carcinoma. The female-to-male ratio was 4:1. Pain was the most common complaint by the patients. Of the 25 cases, 12 were suspected intra-operatively or diagnosed microscopically (IGBC). Most showed a mass at the neck. In six cases, no gross mass/lesion was seen. Cholelithiasis is present in 19/25 cases.Most cases showed adenocarcinoma (not otherwise specified). Out of the adenocarcinoma cases, most were well differentiated. At the time of diagnosis, most were at the pT2 stage. Twelve cases of IGBC were found. Eight out of 12 IGBC were early-stage carcinoma when diagnosed. Conclusion Twenty-five cases of gallbladder carcinoma were diagnosed in the last five years in our center, with 19 (76%) of them associated with cholelithiasis. Twelve (48%) of the cases were incidentally diagnosed either preoperatively or during gross/microscopic examination, and eight (66%) of those were discovered early, out of which five (62.5%) were observed to be in the T1b stage. At this stage, there is a diversion from the general surgical management of gallbladder carcinoma for a better prognosis. This underscores the significance of routine histopathological examination of gallbladder specimens, even if there is no preoperative suspicion of gallbladder carcinoma.

A phase 2 study to determine the pathological (path) response to neoadjuvant nivolumab (nivo) and relatlimab (rela) in stage I to III resectable Merkel cell carcinoma (Neo-MCC).

TPS9613 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin with viral and sun related aetiologies, and an overall mortality rate twice that observed in cutaneous melanoma (33% vs 15%). The 5-year disease specific survival is 60% to 87% for those presenting with local disease, 39% to 62% for nodal disease and 11% to 20% for metastatic disease (1). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers. In melanoma, using International Neoadjuvant Melanoma Consortium (INMC) path response criteria (2), a major path response to immunotherapy (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III disease (Menzies et al., 2021), and improved survival and EFS when immunotherapy is given neoadjuvantly as compared to adjuvant (adj) treatment (Patel et al., 2022). In a study of NAT anti-PD1 monotherapy with nivolumab, in patients (pts) with resectable IIA-IV MCC (N=36), 47.2% of pts achieved a complete path response (pCR) (Topalian et al., 2020). Other benefits of NAT include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance. The Neo-MCC trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity in pts with resectable stage I-III MCC. Methods: Pts with histologically confirmed resectable clinical stage I (≥ 10 mm), II or III Merkel cell carcinoma, are eligible (N=20). All pts undergo complete resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV) at wk 0 and 4. Standard of care sentinel lymph node biopsy will be completed as indicated. Pts with non-path response (>50% viable tumor) or partial path response (>10% - ≤50% viable tumor) at RES will receive adj radiotherapy (RT) to all disease sites, including the draining lymph node basin. Pts with pCR (0% viable tumor) or near-pCR response (≤10% viable tumor) will receive no further adj treatment. Pts with involved RES path margins will be considered for adj RT, following multidisciplinary team consultation to determine the role of further surgery. CT, and FDG PET/CT will be performed at baseline (BL), prior to RES to measure NAT response, and 6-monthly over a 10-year follow-up period. Tumor and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after NAT using INMC response criteria. Secondary endpoints include RFS, OS, safety/tolerability, surgical outcomes, QOL, and biomarker analyses. 1. Mistry, et al., 2022. 2. Tetzlaff et al., 2018. Clinical trial information: NCT06151236 .

Clinical utility and accessibility of functional precision medicine for relapsed/refractory pediatric and adult cancers.

1551 Background: Pediatric and adult patients with rare, relapsed, or refractory cancers often have few treatment options. Precision medicine approaches are often the first strategy used to identify salvage therapy options when standard treatments fail. Despite the significant clinical benefit to advanced cancer patients, multiple genomics precision medicine trials have revealed important constraints for patients that lack treatments matched to mutations or biomarkers and have highlighted challenges in drug accessibility associated with novel targeted therapies identified through genomics precision medicine. Current clinical findings from large-scale studies demonstrate ~10% of cancer patients receive clinical benefit from genomics-guided therapies - in part due to limited insight into the complex relationship between tumor molecular characteristics and patient response. Methods: We implemented a functional precision medicine (FPM) approach combining genomic tumor profiling with high-throughput drug sensitivity testing (DST) of FDA-approved agents on patient-derived tumor cells to identify treatment options when standard-of-care is exhausted. Clinical utility and benefit of this program was investigated via a clinical trial (NCT03860376) at Nicklaus Children’s Hospital in Miami, FL. Results: We were returned DST data on 21 of 24 patients DST (median = 102 agents per sample) and genomic profiling on 20 of 24 patients. DST turnaround time was significantly below the 14 days required for clinical use (median = 10 days, p = 0.0012). FPM recommendations were returned to 19 (76%) patients, of which 14 patients underwent therapeutic intervention. Six patients received FPM-guided treatments, and five (83%) patients experienced a >1.3-fold improved progression-free survival over their previous therapy, significantly above the rate from physician’s choice (p = 0.0104). We subsequently opened pan-cancer FPM clinical studies for adults (n = 36 patients) and children (n = 65 patients). A key objective in these trials is optimizing our DST protocol for tissue samples of various sizes. Here, we report preliminary efforts to optimize our DST approach for tissue samples from resections, core biopsies, and fine-needle biopsies from primary and metastatic lesions. Conclusions: The findings from our feasibility study illustrate the potential for FPM to positively impact clinical care for pediatric/adolescent patients with relapsed/refractory cancers, and have supported initiation of currently enrolling clinical studies. An NIMHD-funded expansion cohort now enrolling at Nicklaus Children’s Hospital (NCT05857969, n = 65 patients), and a rare/relapsed/refractory adult patient cohort at Cleveland Clinic Florida (NCT06024603, n = 36 patients). These studies aim to further investigate the impact on clinical outcomes through the use of FPM to recommend treatment options. Clinical trial information: NCT06024603 , NCT05857969 , NCT04956198 , NCT03860376 .

Safety and immunological effects of ablative radiotherapy followed by pembrolizumab in patients with advanced adrenocortical carcinoma.

TPS4630 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with poor prognosis. While pembrolizumab is a NCCN recommended treatment, our prior study showed no benefit in patients with liver metastases (NCT02673333).1 Preclinical evidence suggests combining liver-directed radiation therapy (RT) with pembrolizumab might enhance anti-tumor immunity.2 Our current study will assess the safety and describe preliminary efficacy data for ablative RT to symptomatic liver metastases followed by treatment with pembrolizumab in patients with advanced ACC. Methods: This is a single-center pilot study. Main inclusion criteria include: adult patients with metastatic ACC with symptomatic liver metastases, presence of extrahepatic metastases, ECOG 0-1. Ablative RT in 5 or 10 once daily fractions will be delivered over 1 to 2 weeks; pembrolizumab treatment (200mg Q3W) will begin one week after RT completion. The primary objective is to evaluate the safety of treatment with ablative RT followed by pembrolizumab. The study will include a 6 patient safety lead-in, with 10 to 12 patients enrolled in total. The secondary endpoint, efficacy, is defined as the objective response (partial and complete response) according to RECIST v1.1, in the hepatic and extrahepatic disease. Correlative objectives include evaluation of the innate and adaptive immune response during treatment through analysis of pre- and on-treatment blood and tumor tissue samples, circulating tumor (ct) DNA analyses, and PD-L1 and next-generation sequencing testing in pre-treatment tumor tissue samples to evaluate for biomarkers of response and resistance. This trial began enrollment in 9/27/2023, with 3 patients enrolled to date.

Pharmacological Profile of Novel Anti-cancer Drugs Approved by USFDA in 2022: A Review.

For any drug molecule, it is mandatory to pass the drug approval process of the concerned regulatory authority, before being marketed. The Food and Drug Administration (FDA), throughout the year, approves several new drugs for safety and efficacy. In addition to new drug approvals, FDA also works on improving access to generic drugs, aimed to lower the cost of drugs for patients and improve access to treatments. In the year 2022 twelve new drug therapies were approved for managing varying cancers. This manuscript is focused to describe the pharmacological aspects including therapeutic uses, mechanisms of actions, pharmacokinetics, adverse effects, doses, indication for special cases, contraindications, etc., of novel FDA-approved anticancer drug therapies in the year 2022. FDA has approved about 29% (11 out of 37) novel drug therapies for varying types of cancers such as lung cancer, breast cancer, prostate cancer, melanoma, leukemia, etc. The Center for Drug Evaluation and Research CDER has reported that 90% of these anticancer drugs (e.g. Adagrasib, Futibatinib, Mirvetuximabsoravtansinegynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Olutasidenib, Pacritinib, Tebentafusp-tebn, Teclistamab-cqyv, and Tremelimumab-actl) as orphan drugs and recommended to treat rare or uncommon cancers such as non-small cell lung cancer, metastatic intrahepatic cholangio-carcinoma, epithelial ovarian cancer, follicular lymphoma, metastatic melanoma, metastatic uveal melanoma, etc. CDER has identified six anticancer drugs (e.g. Lutetium (177Lu)vipivotidetetraxetan, Mirvetuximabsoravtansine- gynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Tebentafusp-tebn, Teclistamab-cqyv) as first-in-class drugs i.e. drugs having different mechanisms of action from the already existing ones. The newly approved anticancer drugs shall provide more efficient treatment options for cancer patients. Three FDA-approved anticancer drugs in the year 2023 are also briefly described in the manuscript. This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

Prognostic factors of relapse in surgically resected small cell neuroendocrine carcinomas of the urothelial tract (SCNEC-URO).

4605 Background: SCNEC-URO are rare aggressive cancers with limited treatments. Although they frequently co-exist (60-70%) with urothelial carcinoma (UC) at diagnosis, most metastatic biopsies of relapsing patients (pts) show pure small cell (SC) morphology. There are major unmet needs to predict relapse after definitive surgery. Methods: Data was extracted from a historical cohort of n=216 pts with surgery for surgically resectable disease (cT1-T4, N0 or N+, M0) at MD Anderson between November 1985 and June 2021. Morphology at resection was defined as: ‘pCR’ (pathological complete response, including no residual carcinoma or carcinoma in situ), ‘Any SCNEC’ (persistence of SC with UC in sample) or ‘Non-SCNEC’ (UC only). Relapse events after surgery were analyzed as time-to-event (TTE) outcome with competing risk non-parametric method. Univariable and multivariable analyses identified prognostic factors of relapse. Results: In TTE analysis, cohort events (n=216) included: n=70 censored (alive and relapse-free), n=92 failure events (with relapse), and n=54 competing events (death without known relapse). n=154 (71.3%) received neoadjuvant chemotherapy, including SCNEC regimens in 125/154 (81.2%) and UC regimens in 16/154 (10.4%). The 5-year cumulative incidence function (CIF) of relapse for all pts was 41.92% [95% CI: 35.2% - 48.5%]. CIF rates were significantly different per morphology at resection (Gray’s test, p<.0001). Pts with pCR had the lowest 5-year CIF rate for relapse (18.5%) [11.1% - 27.4%], while pts with ‘Any SCNEC’ had the highest CIF (69.6%) [58.6% - 78.9%]. Pts with Non-SCNEC had an intermediate CIF risk (31.6%) [17.6% - 46.7%]. Staging at resection also showed different CIF rates (Gray’s test, p<.0001). Pts with pT0N0 had the lowest CIF rate (12.8%) [5.6% - 23.2%], with CIF rates increasing with higher staging: pTisN0 (25%) [11.6% - 41%]; pT1N0 (25%) [5.4% - 51.7%]; pT2 or greater, but N0 (52.4%) [41% - 62.7%]. Pts staged node-positive (pN+) did not have an estimated 5-year CIF as most died within 5 years. In multivariable analysis, clinical staging at diagnosis, pathological staging and cellular morphology at resection were associated with relapse (Table). Conclusions: Besides staging at diagnosis and surgery, morphology at resection is a key predictor of relapse. Persistence of the SC component predicts a higher chance of relapse than its eradication and persistence of the UC component. While adjuvant therapy in UC has made significant progress recently, a tailored adjuvant approach addressing the residual SC component at definitive surgery is needed to improve outcomes and decrease relapse. [Table: see text]

First-line treatment of EGFR mutation adenosquamous carcinoma of the lung with aumolertinib: A multicenter, single-arm, prospective study (ARISE Study).

e20541 Background: Adenosquamous carcinoma of the lung (ASC), which composed of squamous cell carcinoma and adenocarcinoma, is a rare lung cancer. In Asian population, the mutation rate of epidermal growth factor receptor (EGFR) in ASC is approximately 15.4% to 44%. There were no large prospective clinical studies using EGFR tyrosine kinase inhibitors (TKI) to treat ASC. Methods: We conducted a prospective, multicenter, single-arm clinical trial, designed to evaluate the efficacy and safety of Aumolertinib for ASC patients with EGFR mutations without prior systemic therapy (originally designed as a randomized controlled study versus chemotherapy; the protocol was revised to single-arm study due to insufficient enrollment; Clinical Trial Registry No. NCT04354961). Eligible participants of stage IIIB/IV ASC with EGFR mutations from six Chinese medical centers received Aumolertinib 110mg orally once daily. Follow-up were performed every 6 weeks conducted by independent central review (ICR), based on the RECIST 1.1 criteria. Primary endpoints was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: Of the 18 patients recruited, 12 were evaluated for efficacy and safety. The median follow-up was 13.3 months, with 17 (range 4-26) doses of Aumolertinib treatment. The median PFS was 6.2 months (95% CI 5.0-8.2), while the median OS has not been reached. Of the 12 patients, 7 (58.3%) achieved PR, 3 (25.0%) achieved SD, and 2 (16.7%) were PD. The ICR-confirmed ORR and DCR were 58.3% (95% CI: 62.6%-74.6%) and 83.3% (95% CI: 89.6%-96.2%), respectively. A total of 9 patients (75%) experienced at least one treatment-related adverse events (TRAEs). the most common TRAEs were anemia (27.3%) and elevated aminotransferase (18.2%). three patients (25%) experienced grade 3-4 TRAEs in the form of paralysis, neutropenia and hypokalemia. No treatment-related deaths occurred. Conclusions: This is the first prospective clinical study showing that Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for ASC with EGFR mutations, with favorable ORR and general PFS. In future, head-to-head comparisons of EGFR TKI with chemotherapy and combination therapy would be needed to be explored. Clinical trial information: NCT04354961 .

Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma (IHCC).

e16217 Background: Intrahepatic cholangiocarcinoma (IHCC), a rare biliary tract cancer, has been rising in incidence and is associated with poor survival. With the advent of new treatment modalities and various ongoing research, population-based perspective can be helpful to reflect the progress in managing this deadly disease and provide updated outcome information as a reference for comparison during upcoming clinical studies. We would like to provide a 20-year update on incidence and survival with reference to landmark trials, with a focus on survival outcomes of the recent 5 years for future insights. Recent and ongoing clinical trials will be discussed. Methods: This study extracted population data from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rate (AAIRs) and survival rate (SR) trends were calculated from January 2000 to December 2020 using 22 registries for the US population. Incidence and survival rates were collected from the SEER database, reported per 100,000 population and age adjusted to the 2020 US standard population. The annual percent change (APC) was used to report long term trends. Results: In this analysis of 19,948 IHCC patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 (APC 6.94, 95% CI 6.32 to 7.56), with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted mOS climbed from 5.28 months in 2000 to 9.3 months in 2013, maintaining between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 in 2000-2010 to 9.06 in 2010-2020, which remained statistically significant at 1-year, 3-year, and 5-year OS. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3 months, 12.1 months, and 5.4 months for local, regional, and distant stages, respectively. Conclusions: These results indicate a steady rise in IHCC incidence since 2000, consistent across all subgroups. Survival rates have improved since 2000 but stabilized after 2013, following the publication of the ABC-02 trial published in 2010, which used systemic gemcitabine and cisplatin for unresectable iHCC. Updated survival data from 2015 onwards will serve as a reference of comparison for forthcoming clinical trials.

Characterization of enhancer of zeste homolog 2 (EZH2) expression, activity, and association with the tumor immune microenvironment in olfactory neuroblastoma (ONB).

e14655 Background: ONB is a rare sinonasal cancer with limited therapeutic options. Increased expression and up-regulation of EZH2, a core protein of the epigenetic modifier methyltransferase Polycomb repressive complex 2, have been associated with worse prognosis in several cancer types. EZH2 inhibitors are currently approved in Epithelioid Sarcoma (ES) and Follicular Lymphoma. We examined the expression and activity of EZH2 in ONB, as compared to ES (where EZH2 inhibition is standard-of-care), and its impact on the immune microenvironment. Methods: ONB (N = 35) and ES (N = 78) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1 expression (22C3; Positive (+): TPS ≥1%) was assessed by IHC. Transcriptomic signatures predictive of immunotherapy response (T-cell inflamed [TCI] score) and MAPK pathway activation (MPAS) were applied. Immune cell fractions were estimated using quanTIseq. A transcriptional ‘ EZH2 Repression Score' (ERS, arbitrary units: AU) was examined, with high ERS suggestive of lower EZH2 activity (Morel et al, {2021}). ONB were stratified by their median ERS (high -H, N=17 v low -L, N=18). Three additional score variants were applied (equally weighted, immune regulatory genes excluded, or both) and all produced similar results. ONB were stratified by the median EZH2 transcripts per million (TPM, -H v -L). Mann-Whitney U, Fisher’s Exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p <.05). Results: No pathogenic EZH2 mutations were observed in ONB; EZH2 expression was higher compared to ES (44.4 v 14.1 TPM, p < 0.001), yet ERS was not significantly different (5111 v 5143 AU, p = 0.76). There was no association between EZH2 expression and ERS (Pearson’s correlation = .1). In ONB, there was no difference in the prevalence of PD-L1+ between ERS-H v -L (20% v 20%). ERS-H were associated with increased expression of β2M (2110 v 1019 TPM, p = .01) and immune checkpoint genes: CTLA4 (1.4 v 0.5, p = .03), PD-1 (1.1 v 0.3, p = .04), PD-L1 (4.7 v 1.6, p < .001) and VISTA (22.1 v 6.5, p < .001). ERS-H was associated with increased M2 macrophage infiltrate (5.0 v 2.5%, p < .001). ERS-H had increased MPAS (1.99 v -.42 AU, p < .001) and increased prevalence TCI tumors (29 v 0%, p < .001), while EZH2-H tumors were not associated with differences in immune infiltrate, TCI, MPAS, nor with immune checkpoint gene expression compared to EZH2-L. Conclusions: EZH2 mutations were not detected in ONB or ES, though similar EZH2 activity (by ERS) was observed in both cohorts, thus making ONB an intriguing candidate for EZH2 modulating therapies. High ERS in ONB was associated with expression of immune checkpoint genes suggesting that inhibiting EZH2 activity could enhance the susceptibility of ONB to immune checkpoint blockade.

Periosteal osteosarcoma: A study of demographic and socioeconomic factors.

e23506 Background: Periosteal Osteosarcoma (PO) is a rare primary malignant bone cancer that typically affects the tibia or femur of young adults in their second and third decades of life. This soft-tissue mass causes extrinsic erosion of thickened underlying diaphyseal cortex and perpendicular periosteal reaction extending into soft-tissue components. Despite the rarity of PO, 29% of diagnosed patients do not survive past 10 years following treatment. Further investigation into the diagnostic trends of PO may produce valuable information about its epidemiology. The National Cancer Database (NCDB) was analyzed to identify the demographic factors of patients diagnosed with PO. Methods: A retrospective cohort analysis that utilized data from the 2004–2020 NCDB included 138 patients with a histologically-confirmed diagnosis of PO (ICD-9193-3). Demographic factors (age, sex, race, Hispanic status, educational attainment, insurance status, facility type, distance from facility, and Charlson/Deyo score were analyzed by descriptive statistics, and incidence trends were interpreted via regression analysis. Results: A total of 138 individuals had a confirmed diagnosis of PO between the years 2004-2020 with a relatively constant rate of diagnosis each year (R2 = 0.1749). The average age of diagnosis was 29.7 (SD = 17.5, range = 6-86 years). Males and females were affected at rates of 58% and 42%, respectively. The majority of patients diagnosed with PO identified as White (73%) and non-Spanish/non-Hispanic (86%). The primary sites of diagnosis were the long bones of the lower limb (77%), with an average tumor size of 94.4 mm (SD = 54.2). Most patients (73%) utilized surgical treatment options such as radical excision or resection of the lesion with limb salvage. A higher percentage of patients were privately insured (62%), lived in a metropolitan area (75%), and were treated at an academic/research program (59%). Many individuals (91%) had no concurrent comorbidities (Charlson-Deyo comorbidity score = 0). Following treatment, the survival rates of patients were 91% at 2 years, 78% at 5 years, and 71% at 10 years. Conclusions: To our knowledge, this is the first NCDB analysis concentrating on PO, addressing a substantial gap in our understanding. In congruence with earlier descriptions of PO in case reports, a majority of patients are White and of non-Spanish/non-Hispanic origin and the primary site of diagnosis presents on the lower limbs. This is the first instance in the literature where the socioeconomic factors of PO patients have been clarified: PO patients are more likely to live in densely populated metropolitan areas, receive treatment in academic programs, and have private insurance. Further research is needed to elucidate the influence of demographic and socioeconomic factors on the diagnosis, treatment approaches, and survival outcomes of individuals with PO.

Phase II study of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors.

TPS3183 Background: Advanced sinonasal malignancies are rare and heterogeneous cancers with limited therapeutic options. Tumor types include olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC) and large cell neuroendocrine carcinoma (LCNEC), chondrosarcoma, and sinonasal adenocarcinoma (SNAC). Pathogenic driver mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2) were identified first in glioma and myeloid malignancies. IDH1/2 enzymatic activity catalyzes conversion of isocitrate and NADP+ to α-ketoglutarate (α-KG) and NAPDH, which are critical for cellular metabolism and for α-KG-dependent dioxygenases; mutant IDH1/2 catalyze conversion of α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive antagonist of α-KG in regulating dioxygenases activity, with subsequent impact on DNA histone methylation and cellular differentiation. R172S or R172T IDH2mut have been detected in up to 80% of SNUCs and in a minority of ONB, chondrosarcoma, LCNEC and SNAC. Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation block. It is currently approved for relapsed/refractory IDH2mut myeloid malignancies with proven clinical efficacy. Methods: This is a phase 2, single arm clinical trial conducted at the Center for Cancer Research (CCR) of the National Cancer Institute. The trial investigates the activity of enasidenib in adult patients with histologically or cytologically confirmed locally advanced or metastatic IDH2mut sinonasal cancers (SNUC, ONB, LCNEC, chondrosarcoma, SNAC). Participants must have RECIST 1.1 measurable disease and must have progressed following at least one prior systemic treatment line administered in the recurrent/metastatic setting; those with locally advanced disease must not be amenable to potentially curative approaches. Participants must also have ECOG performance status ≤ 2, be 18 years old or higher, and have adequate organ function. Participants with active, either new or progressive brain metastases or leptomeningeal disease are excluded. Enasidenib will be given continuously at a fixed dose of 100 mg orally daily in a 28-day cycle, until disease progression, unacceptable toxicity, or consent withdrawal. Imaging will be performed every 8 weeks. Baseline and on-treatment research biopsies will be mandatory, where clinically feasible. The trial aims to accrue a total of 25 participants. The primary end point is progression free survival. Secondary outcomes include safety, overall survival, and clinical benefit rate, defined as complete response, partial response and stable disease (per RECIST 1.1) lasting above 4 months. Correlative studies include evaluating changes in 2-HG plasma levels during treatment, and transcriptomic profiling. The study has just started enrolling in the CCR. Clinical trial registry: NCT06176989. Clinical trial information: NCT06176989 .