Malignant Perivascular Epithelioid Cell Tumor Research Articles

Abstract 6486: Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors

Abstract Background: KRAS mutations are found in a variety of tumor types, including non-small cell lung cancer (NSCLC), where KRAS G12C mutation is present in ~12% of NSCLC patients. KRAS G12C inhibitors (KRAS G12Cis), sotorasib and adagrasib, are approved for the treatment of KRAS G12C-mutated, locally advanced or metastatic NSCLC. The mTOR pathway is often activated in patients with KRAS mutations and may contribute to resistance to KRAS G12Cis. nab-Sirolimus is a nanoparticle albumin-bound intravenously (IV) administered form of the mTOR inhibitor (mTORi) sirolimus and is approved for the treatment of patients with advanced malignant perivascular epithelioid cell tumors. This study assessed tumor and blood drug level correlation with antitumor activity of nab-sirolimus or everolimus alone or in combination with KRAS G12Cis. Methods: Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutated NSCLC xenografts (NCI-H2122) were treated with saline, mTORis nab-sirolimus (IV) or everolimus (oral) at clinically relevant and equal weekly dose of 15 mg/kg/wk, or KRAS G12Cis sotorasib (oral) or adagrasib (oral) at 30 mg/kg/day alone or in combination. Tumor volume changes from baseline were assessed; tumor and blood samples were harvested at the end of study (6 wks) for analysis of trough drug levels by LC-MS/MS, and tumor lysates were analyzed for downstream markers for mTOR inhibition by Western blot. Results: In nab-sirolimus plus KRAS G12Ci treated groups, significantly slower tumor growth was observed compared with single agent treated groups and everolimus plus KRAS G12Ci treated groups. Compared with single-agent nab-sirolimus (170.1 ng/g), treatment with nab-sirolimus plus sotorasib resulted in reduced tumor nab-sirolimus drug levels (73.6 ng/g, P=0.0040); while similar tumor nab-sirolimus drug levels were observed for nab-sirolimus plus adagrasib (121.6 ng/g, P=ns). Corresponding to greater antitumor activity, significantly greater tumor trough mTORi drug levels were observed in nab-sirolimus plus either sotorasib or adagrasib treated groups compared with similar everolimus combinations (85-fold, P<0.0001; and 91-fold, P=0.0050, respectively). Correspondingly, stronger mTOR downstream target inhibition of pS6 were observed for nab-sirolimus plus KRAS G12Ci treated groups compared with everolimus plus KRAS G12Ci treated groups. Conclusions: The addition of a KRAS G12Ci to nab-sirolimus significantly reduced tumor volume and increased tumor drug levels, suggesting enhanced tumor targeting compared with everolimus plus KRAS G12Cis and correlating to improved antitumor activity and mTOR target suppression. Clinical dose-finding studies are needed to determine potential drug-drug interactions between nab-sirolimus and KRASis. Citation Format: Shihe Hou, Jorge Nieva, Maria Zalath, Neil Desai. Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6486.

Phase II Trial of nab-Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.nab-Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

Abstract B010: Response to treatment with nab-sirolimus among patients with primary uterine tumors: A subgroup analysis from AMPECT

Abstract Introduction/objective: AMPECT (NCT02494570) is a pivotal study of nab-sirolimus in patients with malignant perivascular epithelioid cell tumors (PEComa). Malignant PEComa is an aggressive, rare sarcoma for which cytotoxic chemotherapies provide limited patient benefit. Inactivation of TSC1 or TSC2 tumor suppressor genes, upstream of mTORC1, is commonly associated with malignant PEComa; these mutations occurred in 56% of patients in AMPECT. nab-Sirolimus is an mTOR inhibitor (mTORi) that utilizes albumin-bound nanoparticle technology to drive higher intratumoral drug levels and more complete pathway suppression than conventional mTORis. nab-Sirolimus is approved in the USA for the treatment of advanced or metastatic malignant PEComa based on the primary analysis results of the AMPECT trial, which showed a confirmed overall response rate (ORR) of 39%, regardless of mutation status. We describe outcomes of a subset of patients with primary uterine PEComa, representing 23% of efficacy-evaluable patients in AMPECT. Methods: AMPECT was an open-label, multicenter, phase 2 registration study in mTORi-naïve adult patients (≥18 years old) with a histologically confirmed diagnosis of malignant PEComa and Eastern Cooperative Oncology Group performance status score ≤1. Patients received nab-sirolimus 100 mg/m2 intravenously on days 1 and 8 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Key secondary endpoints included time to response, duration of response (DOR), and safety. Results: A total of 7 patients with uterine PEComa were treated with nab-sirolimus in AMPECT and were evaluable for both safety and efficacy. Mean ± SD age was 60.0 ± 13.4 years, and 71% (5/7) of patients were White. ORR was 43% (3/7 patients); all 3 were confirmed partial responses and were seen in patients with tumors with somatic inactivating alterations in TSC1 or TSC2. Two (29%) patients had best response of stable disease. For the 3 responders, time to response was 1.4, 1.4, and 1.5 months, and DOR was 5.6, 36.0+, and 39.7 months. All 7 patients had ≥1 treatment-related adverse event (TRAE; grade 3, 43%); no grade ≥4 or serious TRAEs occurred. Conclusions: Rates of response to treatment and safety findings in patients with primary uterine PEComa treated with nab-sirolimus in AMPECT were consistent with those previously reported in the overall patient population. Responses were rapid and durable. Notably, all responders had TSC1 or TSC2 alterations; however, there were too few patients in this subset to draw conclusions regarding efficacy in tumors without these alterations. nab-Sirolimus is being further evaluated in a tumor-agnostic trial of patients with TSC1 or TSC2 inactivating alterations (PRECISION I; NCT05103358). Citation Format: Vinod Ravi, Mark A. Dickson, Kristin Ganjoo, Li Ding, Anita N. Schmid, Norma A. Palma, Willis H. Navarro, Andrew J. Wagner. Response to treatment with nab-sirolimus among patients with primary uterine tumors: A subgroup analysis from AMPECT [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B010.

Abstract A018: A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer

Abstract Introduction/Objective: This trial in progress is designed to evaluate the anti-tumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative treatment options, particularly for advanced or recurrent EEC remain necessary. Dysregulation of mammalian target of rapamycin (mTOR) signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EC. nab-Sirolimus, a nanoparticle injectable form of mTORi, is approved in the USA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that nab-sirolimus in combination with letrozole may produce synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemo-based regimen, Eastern Cooperative Oncology Group performance status score 0 or 1, naïve to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. The relationship between biomarkers and response outcomes is an exploratory endpoint. Citation Format: Lauren E. Dockery, Anna Priebe, Linda Duska, Angela K. Green, Cara Mathews, Fernanda Musa, David O'Malley, Allison Puechl, Li Ding, Anita N. Schmid, Willis H. Navarro, Brian Slomovitz, Kathleen Moore. A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A018.

Abstract B011: Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract Introduction/objective: PRECISION I (NCT05103358) is an ongoing trial of nab-sirolimus in advanced cancers harboring pathogenic inactivating alterations in TSC1 or TSC2. TSC1 and TSC2 alterations have been observed in patients with various cancers, including the most common cancer of the female reproductive organs, endometrial cancer, where ~3% contain TSC1 and/or TSC2 alterations. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. In an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 64.3% (9/14) of patients with pathogenic inactivating TSC2 or TSC1 alterations had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers with TSC1 or TSC2 inactivating alterations. Patients with endometrial cancer are expected to be enrolled based on the frequency of TSC1 and TSC2 inactivating alterations. Methods: Eligible patients are ≥12 years old and mTORi-naïve, possess advanced or metastatic malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Trial Status: Enrollment began in March 2022 and is expedited through collaboration with leading NGS providers; ongoing study access is facilitated through a just-in-time approach to trial location activation. Citation Format: Debra L. Richardson, Gopa Iyer, Li Ding, Anita N. Schmid, Willis Navarro, David Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B011.

Phase 2 study of nab-sirolimus in patients with well-differentiated and advanced/metastatic neuroendocrine tumors of the gastrointestinal tract, lung, or pancreas.

TPS601 Background: Neuroendocrine tumors (NETs; ~2% of all malignancies) commonly arise from the gastrointestinal (GI) tract, pancreas, and lung, often presenting as metastatic disease. The PI3K/Akt/mTOR pathway is implicated in the pathogenesis and progression of NETs. Everolimus, an oral mTOR inhibitor (mTORi), is an option for treatment of NETs of the GI tract, lung, or pancreas but response rates observed in the RADIANT -3 and -4 studies were modest at 4–10%. nab-Sirolimus is a mTORi that utilizes nanoparticle technology to preferentially target tumors and is approved in the USA for malignant perivascular epithelioid cell tumor. In preclinical animal models, nab-sirolimus demonstrated higher intratumoral drug accumulation, improved target suppression, and stronger antitumor activity relative to equal weekly doses of sirolimus and everolimus, warranting further exploration of nab-sirolimus. This study will evaluate efficacy/safety of nab-sirolimus in patients with advanced/metastatic NETs. Methods: This phase 2, multicenter, open-label, single-arm study (NCT05997056) will enroll approximately 21 adults (≥18 years) with functional or non-functional, well-differentiated, locally advanced unresectable or metastatic NETs of the GI tract, lung, or pancreas who have received ≤2 prior lines of therapy, excluding somatostatin analogs (SSTa).Patients with functional NETS are eligible if they have been on a stable dose of SSTa for ≥12 weeks and had disease progression during SSTa treatment. Eligible patients must have ≥1 measurable target lesion (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), Eastern Cooperative Oncology Group performance status score 0 or 1, and adequate organ function/hematologic parameters.They are not permitted to have received prior mTORi, including nab-sirolimus, or to have tumors with known inactivating TSC1 or TSC2 alterations. Patients will receive nab-sirolimus 100 mg/m2 by intravenous infusion on days 1 and 8 of 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity, or until discontinuation based on investigator or patient discretion.The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints include duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of baseline molecular biomarkers with clinical outcomes. Analysis of study objectives will be descriptive. Study site activation is underway with the first patient on study anticipated for the 3rd quarter of 2023. Clinical trial information: NCT05997056 .

PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.

TPS585 Background: SEER data report that US patients with advanced gastrointestinal (GI) cancers have a poor prognosis as indicated by low 5-year survival rates in patients with colorectal (15.6%), liver (3.5%), and other GI cancers, highlighting the need for more efficacious treatments. Dysregulation of the mTOR pathway contributes to tumor growth and disease progression in many cancers, including GI cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of mTOR activity whose inactivation can lead to tumor cell growth. Inactivating TSC1 and TSC2 alterations have been observed in GI cancers with a combined frequency of up to 6.5% in hepatocellular carcinoma, 1.7% in colorectal adenocarcinoma and gastrointestinal stromal tumors, and 1.6% in cholangiocarcinoma. nab-Sirolimus, approved in the US for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. The trial is open to patients with GI cancers with inactivating alterations in TSC1 or TSC2. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors harboring TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) of tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors is expediting the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .

Clinicopathological features of primary malignant perivascular epithelioid cell tumors of ureter: Histologic-radiologic correlation

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor that is mainly seen in middle-aged women. PEComa originating in the ureter is extremely rare it is unclear whether they display typical clinical and radiographic features seen elsewhere. Herein, we report findings from 2 cases of primary PEComa of the ureter that we classified as malignant. Case 1: A 45-year-old woman was admitted to the hospital with intermittent distension in her waist. After appropriate imaging, the right ureter and right kidney were excised under general anesthesia. The tumor measured 1.4 cm. Microscopically, the tumor displayed infiltrative growth, >2 mitoses per 10 high power fields (HPF), necrosis, and lympho-vascular invasion. Case 2: A 30-year-old woman was admitted to the hospital due to hematuria 20 days duration. The left ureter and left kidney were ultimately excised under general anesthesia. The tumor measured 2 cm. Microscopically, the tumor showed infiltrative growth and >2 mitoses/10 HPF. Our cases were diagnosed as malignant PEComa. No disease recurrence was observed in either of the two patients during the postoperative follow-up period. Malignant primary ureteral PEComa is very rare. The clinical manifestations are not specific, and it is usually misdiagnosed as a malignant neoplasm on imaging. Therefore, its diagnosis requires pathological examination and immunohistochemical analysis of the sampled or resected tumor. Treatment requires a complete surgical resection and regular clinical follow-up.

Italian report of expanded access for nab-sirolimus in patients with malignant perivascular epithelioid cell tumor (PEComa).

e23541 Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment in Europe, while the mechanistic target of rapamycin (mTOR) inhibitor nab-sirolimus has been approved in US. In Europe, an expanded access program is available for patients with advanced or metastatic PEComa. Methods: We retrospectively collected data of patients with advanced/metastatic PEComa treated at our institution from December 2020 through 3rd February 2023 with nab-sirolimus. Nab-sirolimus was administered as an intravenous infusion over 30 minutes at a dosage of 100 mg/m2 on days 1 and 8 of each 21-day cycle. Results: At the time of this analysis, 10 patients were treated with nab-sirolimus and 8 are evaluable for response. Of them, 4 patients received nab-sirolimus as their first mTOR inhibitor therapy, while 4 had already received another mTOR inhibitor, being discontinued for PD. Amongst patients not pretreated with mTOR inhibitors, 2/4 had a PR as their best response, 1/4 obtained SD and 1/4 obtained PD. Amongst patients pretreated with another mTOR inhibitor, all but 1 obtained PD as their best response and 1/4 had SD. The majority of nab-sirolimus-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade 4 treatment-related adverse events were observed. Amongst the 10 patients treated with nab-sirolimus, tumor profiling is available for 6 patients, being ongoing for the other 4. Conclusions: nab-Sirolimus is active in patients with malignant PEComa. Activity is mainly confined to those not already treated with other mTOR inhibitors.

Rare perivascular epithelial cell tumor of the colon 18F-FDG PET/CT imaging: A case report.

Neoplasms with perivascular epithelioid cell differentiation (PEComas) are mesenchymal tumors that rarely occur in the colon. Here, we report the occurrence of a malignant PEcoma in the colon using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). A 55-year-old woman was admitted to the hospital with abdominal pain for 10 days and a self-induced abdominal mass for 3 days. 18F-FDG PET/CT imaging showed a large hypermetabolic nodule and mass in the right mid-upper abdomen with heterogeneous density and a further increase in metabolism on the delayed scan. PEComa of the colon. Tumor resection was performed. The patient is well after 2 months of treatment, pending further follow-up. Malignant perivascular epithelioid cell tumors originating in the colon are extremely rare, and our report suggests that PEComa should be considered as a differential diagnosis for 18F-FDG gastrointestinal malignancies. Additionally, 18F-FDG PET/CT may play a key role in the staging and extent of lesions in intestinal malignancies.

Abstract LB288: Biomarker analysis from AMPECT correlating response to nab-sirolimus with TSC1 and TSC2 inactivating alterations

Abstract nab-Sirolimus is an mTOR inhibitor (mTORi) approved in the US for the treatment of adult patients with locally advanced, unresectable, or metastatic malignant perivascular epithelioid cell tumor (PEComa) based on clinical efficacy and safety data from the phase 2, multicenter, open-label AMPECT trial (NCT02494570). TSC1 and TSC2 are tumor suppressor genes and key upstream regulators of mTOR complex 1 (mTORC1); inactivating alterations (loss-of-function mutations or deletions) in these genes lead to mTORC1 hyperactivation, which may contribute to tumor formation. Phosphorylation of S6 ribosomal protein (pS6) is a reliable surrogate for mTORC1 activity. Here we present the results of an exploratory biomarker analysis performed on samples from patients enrolled in the AMPECT study. Targeted exome next-generation sequencing (NGS) using a 500-gene OncoPanel test (Center for Advanced Molecular Diagnostics, Brigham and Women’s Hospital, Boston, MA) assessed mutations, copy number changes, and translocation events. pS6 was assessed by immunohistochemistry (IHC). Twenty-five patients had tissue sufficient for NGS, 56% (14/25) had either TSC1 (N=5, 20%) or TSC2 (N=9, 36%) mutations: TSC1, 1 frameshift, 2 splice site, 1 missense, and 1 nonsense mutation; TSC2, 1 nonsense, 7 frameshift, and 1 homozygous deletion. In this dataset, TSC1 and TSC2 inactivating alterations were mutually exclusive. Patients with TSC1 or TSC2 inactivating alterations achieved a clinically meaningful benefit: 64.3% (9/14) objective overall responses (including complete and partial responses) and median (95% CI) duration of response (DOR) of 45.7 (5.6, not reached [NR]) months, progression-free survival (PFS) of 41.2 (5.5, NR) months, and overall survival (OS) of NR (31.6, NR) months. Mutations in TP53, RB1, and ATRX were also common (48%, 24%, and 20%, respectively). Of tissue samples evaluable for IHC (N=25), responses occurred in 58.8% (10 of 17) of patients with pS6 positive tumors versus 0% (0 of 8) with pS6 negative tumors; absent pS6 staining was negatively associated with response to nab-sirolimus (P=0.008, Fisher’s exact). Median DOR for pS6 positive responders was 39.7 (5.6, NR) months. In pS6 positive vs pS6 negative patients, the median PFS was 24.4 (2.8, 53.1) vs 5.5 (2.8, NR) months, and OS was 53.1 (18.0, NR) vs 37.0 (16.6, NR) months. A variety of pathogenic inactivating alterations were observed in TSC1 and TSC2 genes, though TSC2 mutations were most commonly frameshift mutations; no recurring mutations were observed. A tumor-agnostic study (PRECISION 1: NCT05103358) is now recruiting patients with pathogenic inactivating TSC1 or TSC2 alterations to further examine these biomarker findings. Citation Format: Lee D. Cranmer, Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen N. Ganjoo, Brian A. Van Tine, Rashmi Chugh, Erlinda M. Gordon, David J. Kwiatkowski, Jason L. Hornick, Heng Du, Li Ding, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Mark A. Dickson. Biomarker analysis from AMPECT correlating response to nab-sirolimus with TSC1 and TSC2 inactivating alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB288.

Abstract 5484: Synergistic antitumor activity of nab-sirolimus in combination with KRAS inhibitors (KRASis) sotorasib and adagrasib in KRAS G12C NSCLC and bladder cancer xenografts

Abstract KRAS is frequently mutated in non-small cell lung cancer (NSCLC) and other tumor types, with KRAS G12C mutation representing ~12% of patients with NSCLC. Sotorasib (sot) is approved and adagrasib (ada) is under review for the treatment of KRAS G12C NSCLC. Mutations in KRAS may lead to mTORC1 activation, and mTOR may contribute to adaptive resistance to KRASis. nab-Sirolimus (nab-S) is a novel albumin-bound nanoparticle form of the mTOR inhibitor sirolimus approved for the treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumors. This study investigated the antitumor activity of nab-s in combination with KRASis in KRAS G12C NSCLC and bladder xenograft models. Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutant NCI-H2030 and NCI-H2122 NSCLC and KRAS G12C and PTEN-null UMUC3 bladder cancer were treated for 6 weeks with nab-s IV at 15 mg/kg/wk, sot or ada (for NCI-H2122 and UMUC3) orally at 30 mg/kg/d alone or in combination. Tumor samples were harvested for analysis of tumor drug levels and biomarkers. In all 3 models tested, single-agent (SA) nab-s or KRASis overall showed modest tumor growth suppression. In contrast, nab-s in combination with either sot or ada showed greater tumor growth inhibition and a higher meaningful tumor regression rate vs SA (Table). There was no significant difference in antitumor activity between combinations of nab-s with either sot or ada. High trough intertumoral sirolimus levels were observed in groups treated with nab-s alone or in combination with KRASis, indicating sustained presence of sirolimus in the tumor. nab-S in combination with either sot or ada showed synergistic antitumor activity compared to the SA. A multicenter, single-arm, open-label Phase 1/2 clinical study is planned to determine the recommended Phase 2 dose, safety, tolerability, and efficacy for the combination of ada and nab-s in patients with KRAS G12C tumors. Changes in TGI and Tumor Regression Tumor Model Combination Treatment TGI vs Single Agent (%) P Value vs Single Agent for Tumor Growth Curve (ANOVA) Tumor Regression Over 30% P Value vs Single Agents for Rate of Tumor Regression Over 30% (Chi-Square) vs nab-S vs KRASi vs nab-S vs KRASi NCI-H2030 nab-S + Sotorasib 129 111 0.01 0.001 3/6 0.03 NCI-H2122 nab-S + Sotorasib 112 106 0.001 <0.001 8/10 <0.001 nab-S + Adagrasib 101 100 0.001 <0.001 4/10 0.03 UMUC3 nab-S + Sotorasib 107 105 <0.001 <0.001 6/6 <0.001 nab-S + Adagrasib 107 107 <0.001 0.04 6/6 0.001 ANOVA, analysis of variance; KRASi, KRAS inhibitor; nab-s, nab-sirolimus; TGI, tumor growth inhibition. Citation Format: Shihe Hou, Andrew Kwon, Jorge Nieva, Neil Desai. Synergistic antitumor activity of nab-sirolimus in combination with KRAS inhibitors (KRASis) sotorasib and adagrasib in KRAS G12C NSCLC and bladder cancer xenografts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5484.

Perivascular malignant epithelioid cell tumor (PEComa) of the uterus:

Perivascular epithelioid cell tumors, called PEComas, have a mesenchymal origin with immunoreactivity for melanocytic and smooth muscle markers. Its incidence in the form of uterine involvement is rare, between 1 and 2 cases per million inhabitants, affecting mainly women in their fifth decade of life. The present study was elaborated according to the rules of the CARE case report. The patient's medical record was analyzed, and who authorized access to it and signed the Free and Informed Consent Form, together with those involved in this work. This patient underwent treatment and medical follow-up with the supervisor of this work. Therefore, this study aimed to describe a rare clinical case report of uterine malignant perivascular epithelioid cell tumor (PEComa). Although the literature on this subject is scarce and there are no consistent criteria for diagnosis and treatment, our case in question presented aspects of unfavorable evolution (a large number of cytological atypia and high mitotic index) characterizing a PEComa with uncertain malignant potential, requiring a treatment adjuvant after surgery. The patient evolved well after the surgery and adjuvant treatment, undergoing quarterly follow-ups at the oncology and gynecology outpatient clinic, with a physical examination and nuclear magnetic resonance of the pelvis for control purposes.

163 (PB043) - KRAS G12C mutated NSCLC and bladder cancer xenografts treated with sotorasib and adagrasib in combination with mTOR inhibitors show improved antitumor activity of nab-sirolimus vs everolimus

Background: KRAS is frequently mutated in non-small cell lung cancer (NSCLC) and other tumor types, with KRAS G12C mutation representing ∼9% of NSCLC patients. mTOR pathway is often activated in patients with KRAS mutation and contributes to adaptive resistance to KRAS inhibitors. A combination of mTOR and KRAS inhibitors may mitigate resistance. nab-Sirolimus is a novel albumin-bound nanoparticle form of mTOR inhibitor sirolimus and is approved for the treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Retroperitoneal malignant perivascular epithelioid cell tumor: a rare case report and literature review

Background: Perivasuclar epithelioid cell tumor (PEComa) is a rare group of mesenchymal tumors with unique histological and immunophenotypes. Retroperitoneal PEComa is extremely rare and almost benign lesion. Herein, we will present a case from China, focusing on histological and immunohistochemical characteristics of the tumor, follow-up and long-term outcome and the related literature review.

Nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program.

11574 Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare and aggressive sarcoma. nab-Sirolimus is an albumin-bound intravenous (IV) mTOR inhibitor (mTORi) approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The AMPECT trial (NCT02494570) was the first prospective study in advanced malignant PEComa. In exploratory biomarker analyses, TSC1 or TSC2 alterations were associated with response. We report data from the final analysis of AMPECT patients, who were naïve to mTORi, and in patients with malignant PEComa with prior mTORi exposure treated with nab-sirolimus in an expanded access program (EAP) (NCT03817515). Methods: In AMPECT, patients with malignant PEComa naïve to mTORi received nab-sirolimus (100 mg/m2 IV days 1 and 8 of every 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Other endpoints included duration of response (DOR) and disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) at ≥12 weeks. In the EAP, patients with malignant PEComa and prior mTORi exposure received the same dose of nab-sirolimus as in AMPECT. Responses and DCR were evaluated post hoc via electronic medical record review. Genetic profiling, including TSC1 or TSC2 status, was assessed in both protocols, but no specific mutation criteria were required for enrollment. Results: Data include 47 total efficacy-evaluable patients, 31 in AMPECT and 16 with malignant PEComa and prior mTORi exposure treated in the EAP from July 2019–July 2021. Prior mTORi on the EAP included sirolimus, everolimus, temsirolimus, or sapanisertib; 12 patients had exposure to 1 prior mTORi and 4 to ≥2 prior mTORi, and 50% had had progressive disease as best response on mTORi. In AMPECT, ORR was 39% (12/31 patients), and DCR was 71%. Median DOR was not reached after 3 years of follow-up. On the EAP, 4/16 patients (25%) achieved PR (DOR range: 1.3+–25.2+ months, 3 ongoing), and 8/16 (50%) had SD as best response; the DCR was 63% (10/16). Of patients with known TSC1 or TSC2 inactivating alterations in the combined datasets (n = 23), 57% had a response (AMPECT, 64%; EAP, 44%). There were no Grade 4 or 5 treatment-related adverse events on either protocol Conclusions: nab-Sirolimus provided durable responses in mTORi-naïve patients with malignant PEComa and clinical benefit in an expanded access protocol for patients with malignant PEComa with prior mTORi therapy. Although AMPECT and the EAP cannot be directly compared, response rates showed similar trends regardless of prior mTORi exposure and in patients with TSC1 or TSC2 alterations. Based on the emerging biomarker results, a tissue-agnostic study in patients with TSC1 and TSC2 alterations has been initiated (NCT05103358). Clinical trial information: NCT02494570, NCT03817515.

Distinct oncogenic signatures in malignant PEComa and leiomyosarcoma identified by integrative RNA-seq and H3K27ac ChIP-seq analysis.

11552 Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make their diagnostic distinction challenging. We aimed to characterize the transcriptional and epigenetic landscape of PEComa and LMS to identify distinguishing features. Methods: We performed whole transcriptome RNA-sequencing on 19 PEComas and compared their gene expression profile to 259 sarcomas from The Cancer Genome Atlas (TCGA) including 104 LMS. ChIP-sequencing for H3K27ac, a histone modification associated with activation of nearby genes/open chromatin, was conducted on 9 malignant PEComas and 12 LMS and were compared with publicly available data from 4 other sarcoma subtypes (chordoma; osteosarcoma; undifferentiated pleomorphic sarcoma; rhabdomyosarcoma; n = 29 tumors). Results: Genome-wide epigenetic and transcriptional analyses revealed overlapping patterns between PEComa and LMS, which were distinct from other sarcomas. However, we also identified a set of highly expressed and epigenetically distinct transcripts which may represent diagnostic?biomarkers: e.g., DAPL1, MLANA, SULT1C2, GPR143, and CHI3L1 for PEComa; and MYOCD, WDFC2, DES, MYH11, and CNN1 for LMS; each of which showed >17x fold higher expression for each tumor entity by DESeq2 (FDR<0.0001). Gene Set Enrichment Analyses (GSEA) demonstrated enrichment in the KEGG Lysosome pathway for PEComa (FDR=0.11), whereas myogenesis and smooth muscle contraction pathways were enriched in LMS (FDR=0.09). Integrative transcriptomic and epigenetic analyses revealed a unique set of master core transcription factors for each tumor type including among others MYOCD for LMS; MITF for PEComa, which require further functional investigation. Twelve selected genes including new as well as known and standard diagnostic markers (e.g., DAPL1, MLANA, GPR143, PNL2, CHI3L1, DES, MYH11, ER, CD68, PU.1, pS6 and CNN1) were validated by immunohistochemistry (IHC) in multiple sections from PEComa and LMS (n = 26). The combination of three melanocytic markers (HMB45, MLANA, PNL2) and pS6 can distinguish LMS from PEComas (**** p<0.0001). IHC for CD68 and PU.1 macrophage markers did not show any difference regarding the degree of immune infiltration in PEComa vs. LMS. Conclusions: Our studies revealed novel epigenetic signatures translating into lysosomal and melanocytic proteins for PEComa and myogenic proteins for LMS, which may serve as useful diagnostic biomarkers in the distinction of these two sarcoma subtypes.

Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a common malignancy threatening human health, and existing diagnostic and therapeutic techniques are facing great challenges. In the last decade or so, nanotechnology has been developed and improved for tumor diagnosis and treatment. For example, nano-intravenous injections have been approved for malignant perivascular epithelioid cell tumors. This article provides a comprehensive review of the applications of nanotechnology in HCC in recent years: (I) in radiological imaging, magnetic resonance imaging (MRI), fluorescence imaging (FMI) and multimodality imaging. (II) For diagnostic applications in HCC serum markers. (III) As embolic agents in transarterial chemoembolization (TACE) or directly as therapeutic drugs. (IV) For application in photothermal therapy and photodynamic therapy. (V) As carriers of chemotherapeutic drugs, targeted drugs, and natural plant drugs. (VI) For application in gene and immunotherapy. Compared with the traditional methods for diagnosis and treatment of HCC, nanoparticles have high sensitivity, reduce drug toxicity and have a long duration of action, and can also be combined with photothermal and photodynamic multimodal combination therapy. These summaries provide insights for the further development of nanotechnology applications in HCC.

Malignant gastrointestinal neuroectodermal tumor: Cytologic, histologic, immunohistochemical, and molecular pitfalls

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare malignant primary gastrointestinal mesenchymal tumor which can be diagnosed via fine-needle aspiration (FNA) cytology. In the context of FNA, the diagnosis requires a cell block and the use of significant resources including immunohistochemical stains and molecular testing. The differential diagnosis of GNET includes clear cell sarcoma (CCS), gastrointestinal stromal tumor (GIST), gastric schwannoma, metastatic melanoma, malignant perivascular epithelioid cell tumor (PEComa) and granular cell tumor, among others. Here we describe a case which was initially diagnosed as malignant granular cell tumor by FNA which was later revised to GNET following the finding of an EWSR1-ATF1 fusion gene rearrangement.

A STRANGE CAUSE OF A PULMONARY NODULE

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Perivascular epithelioid cell tumors (PEComas) are part of an uncommon group of mesenchymal tumors with histological and immunohistochemical markers for myogenic and melanocytic tissue. Its prevalence is very low, accounting for approximately 100 reported cases in the literature with 20 % of them exhibiting lung metastasis. Nonspecific gynecologic symptoms appear to be the most common manifestation. The majority of these cases are classified as non-malignant, thus making our case very atypical. Given that these tumors are extremely rare, there are no specific therapeutic guidelines in the literature. Some experts recommend tumoral resection and adjuvant chemotherapy or radiotherapy in malignant cases. CASE PRESENTATION: We describe a 62-year-old nulligravid female with no known past medical history who came to the emergency room with suprapubic discomfort of one-day evolution. An abdominopelvic computed tomography (CT) revealed a large pelvic mass of 27 cm x 19 cm x 22 cm with heterogeneous density and calcifications, ascites, as well as bibasilar pulmonary nodules. A subsequent chest CT scan showed the presence of multiple bilateral nodular lesions, the largest one measuring 3.6cm x 2.6 cm. Histological sampling was obtained via CT guided biopsy from lung and uterus which came back positive for HMB45, CD10, and for desmin consistent with a metastatic malignant PEComa of gynecologic origin. The patient underwent pelvic mass surgical resection and at the moment is receiving mTOR inhibitors. DISCUSSION: This extremely rare type of tumor is immunoreactive for smooth muscle and melanocytic markers. Its behavior is marked by invasion of the vessel wall and smooth muscle. While some PEComas occur in patients with tuberous sclerosis, it’s lack of association often leads to an inverse relation of malignant potential. Proposed guidelines for classification of PEComas divide them into benign, uncertain malignant potential and malignant. In view of the low prevalence of PEComas, treatment options are limited and prognostic factors are uncertain. Several case studies have discussed the benefit of mTOR inhibitors, chemotherapy, and radiotherapy. Initial therapy with mTOR inhibitors seems to be the best approach while disease progression allows. CONCLUSIONS: PEComas are an extremely rare type of sarcoma very rarely showing metastasis. Typical symptoms can be nonspecific and diverse given organ involvement. PEComa must be kept in the differential diagnosis of gynecological tumors despite its low prevalence. All PEComas exhibit both melanocytic (HMB45, Melan-A, tyrosinase, microphthalmia transcription factor) and myoid (desmin, smooth muscle actin, muscle-specific actin, caldesmon, calponin) markers. Treatment strategies include tumor resection and a combination of mTOR inhibitors, chemotherapy or radiation. Lung nodularities may represent metastasis and in appropriate setting may lead to diagnosis. Reference #1: Henry B Armah; Anil V Parwani. Malignant perivascular epithelioid cell tumor (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literatura. Diagnostic Pathology 2, Article number: 45 (2007) Reference #2: Valentina Natella; et al. A huge malignant perivascular epithelioid cell tumor (PEComa) of the uterine cervix and vagina. Pathology - Research and Practice, Volume 210, Issue 3 (2014) Reference #3: Óscar Cuevas Herreros;Lilian Escobar Lezcano; Manuel Rodriguez Blaco; Vicente Artigas Raventós. PEComa, un raro tumor de células epiteliodes. Cirugia Española.Vol 93. Num. 7. 65-67 (2015) DISCLOSURES: no disclosure on file for Rosangela Fernandez-Medero; No relevant relationships by Juan Garcia-Puebla, source=Web Response No relevant relationships by Ricardo Hernandez, source=Web Response No relevant relationships by Kimberly Padilla Rodriguez, source=Web Response no disclosure on file for Ileana Rivera Burgos; No relevant relationships by Gabriela Torres, source=Web Response No relevant relationships by Marina Torres Torres, source=Web Response