Fyarro (nanoparticle albumin-bound rapamycin)

P1, N=12, Not yet recruiting, M.D. Anderson Cancer Center

Background: KRAS G12C inhibitors (G12Ci) are revolutionizing the therapeutic landscape of advanced NSCLC, but mechanisms of limited clinical efficacy observed in some patients (pts) merit continued exploration. Co-mutations in KEAP1 and STK11 and NRF2 signaling define a subgroup of KG12C NSCLC pts with markedly distinct outcomes upon treatment with ada. The mTORi and ada combination shows high efficacy for targeting KG12C NSCLC harboring KEAP1 and STK11 co-mutations. The clinical safety and efficacy of mTORi nab-sirolimus and ada will be determined in the ongoing KRYSTAL-19 trial (NCT05840510).

P2, N=29, Recruiting, Aadi Bioscience, Inc.

P1, N=28, Recruiting, Aadi Bioscience, Inc. | Trial completion date: Oct 2023 --> Apr 2025 | Trial primary completion date: Oct 2023 --> Apr 2025

Collaboration with leading NGS vendors will expedite 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.

Inactivating TSC1 and/or TSC2 alterations commonly occurred in GU cancers. A proportion of GU tumors have a low TMB and/or are microsatellite stable, suggesting that TSC1 and TSC2 inactivating alterations may be driver mutations rather than passenger mutations in those tumors. Therefore, patients with inactivating alterations in TSC1 or TSC2 may benefit from mTOR inhibition via nab-sirolimus.

In exploratory biomarker analyses of patients with perivascular epithelioid cell tumors treated with the mTOR inhibitor nab-sirolimus (AMPECT, NCT02494570), those with inactivating alterations in the tumor suppressor genes TSC1 or TSC2 (critical negative regulators of mTOR activity) had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations)...TSC1 and/or TSC2 alterations were commonly observed in GI cancers. These cancers were frequently microsatellite stable and of low TMB suggesting that these are actionable alterations that may be candidates for targeted therapy. This hypothesis is being tested in the PRECISION 1 (NCT05103358) trial which is open for enrollment or just-in-time clinical trial sites and available to patients with GI cancers harboring TSC1 or TSC2 alterations.

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.

P2, N=29, Recruiting, Aadi Bioscience, Inc. | Not yet recruiting --> Recruiting

The relationship between biomarkers and response outcomes is an exploratory endpoint. Current Trial Status: Open for enrollment.

Current Trial Status: Enrollment began in March 2022 and is expedited through collaboration with leading NGS providers. Patients with urothelial, endometrial, ovarian, and cervical cancers are expected to be enrolled based on the frequency of TSC1 and TSC2 inactivating alterations (Figure).

P1, N=33, Active, not recruiting, Children's Oncology Group | Trial completion date: Mar 2024 --> Sep 2024

No abstract available

P1/2, N=79, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting

Not applicable

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

P1/2, N=79, Not yet recruiting, Mirati Therapeutics Inc.

The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).

>aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) derived from analysis of TCGA and cBioPortal by Gulati et al. Data on file.

P1, N=33, Active, not recruiting, Children's Oncology Group | Trial completion date: Apr 2023 --> Mar 2024

This report details a multidisciplinary approach for the diagnosis and management of a highly aggressive, metastatic malignant PEComa in a young male patient. The basis for the treatment of malignant PEComas with the recently FDA-approved mTOR inhibitor, nab-sirolimus, is also reviewed. In summary, this case highlights the importance of molecular analysis, particularly TSC1/2 alterations, for both the definitive diagnosis of malignant PEComas and predicting their response to nab-sirolimus.

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.

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. $$table_{D2CC43B4-19F7-4EEF-B479-9D4337036322}$$Changes in TGI and Tumor RegressionTumor ModelCombination TreatmentTGI 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-Svs KRASivs nab-Svs KRASiNCI-H2030nab-S + Sotorasib1291110.010.0013/60.03NCI-H2122nab-S + Sotorasib1121060.001<0.0018/10<0.001nab-S + Adagrasib1011000.001<0.0014/100.03UMUC3nab-S + Sotorasib107105<0.001<0.0016/6<0.001nab-S + Adagrasib107107<0.0010.046/60.001ANOVA, analysis of variance; KRASi, KRAS inhibitor; nab-s, nab-sirolimus; TGI, tumor growth inhibition.

aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons). 1L, first-line.

No abstract available

Sponsored by Aadi Bioscience. This presentation will include an overview of nab-sirolimus mechanism of action and AMPECT data, an introduction to TSC1/2 alterations and discussion of frequency across tumor types and an overview of the ongoing tumor agnostic RECISION1 study in patients with TSC1/2 inactivating alterations.

>All gastrointestinal tumors (bolded) with known incidence of TSC1/TSC2, and tumor types with combined incidence of TSC1/TSC2 alterations of >2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact; this includes frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons).

>All gastrointestinal tumors (bolded) with known incidence of TSC1/TSC2, and tumor types with combined incidence of TSC1/TSC2 alterations of >2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact; this includes frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons).

For instance, advanced/metastatic basal cell carcinomas can be treated with Hedgehog inhibitors (vismodegib and sonidegib) targeting the smoothened (SMO) or patched 1 (PTCH1) gene alterations that are a hallmark of these cancers and activate the Hedgehog pathway. Advanced/metastatic basal and cutaneous squamous cell cancers often have a high tumor mutational burden (which predicts immunotherapy response); immune checkpoint blockade with cemiplimab, a programmed cell death protein 1 (PD1) inhibitor, is now approved for these malignancies...In the realm of rare neoplasms, PEComas-which can originate in the skin, albeit uncommonly-have tuberous sclerosis complex 1 (TSC1)/tuberous sclerosis complex 2 (TSC2) gene alterations, which activate mammalian target of rapamycin (mTOR) signaling, and can be suppressed by nab-sirolimus, now approved for this condition. In summary, precision dermatologic techniques/strategies are an important emerging approach for evaluation and management of skin disorders and cutaneous neoplasms, and may serve as a paradigm for the application of precision medicine beyond dermatology.

Trial in progress: there are no available results at the time of submission.

Trial in progress abstract

Combining mTOR inhibition with KRAS G12C inhibition improves response against tumors in vivo. nab-Sirolimus showed greater potency compared to everolimus and is the preferred agent for further clinical development using this strategy.

P1, N=33, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2025 --> Apr 2023

Genomic alterations in malignant PEComas frequently involve TSC1 and TSC2 genes (mTOR activators), as well as TFE3 fusions. In November 2021, the FDA approved nab-sirolimus (mTOR inhibitor) for PEComas.

"Aadi Bioscience, Inc...announced partnerships with prominent next generation sequencing (NGS) providers and leaders in genomic testing and profiling, including Foundation Medicine, Tempus and others. We expect these collaborations to expedite patient identification for the ongoing PRECISION 1 trial of nab-sirolimus in patients harboring tumors with inactivating alterations in TSC1 or TSC2 genes....'We expect to report preliminary data from this trial in the first half of next year.'"

P1, N=44, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2021 --> Dec 2025 | Trial primary completion date: Dec 2021 --> Mar 2022

P2, N=120, Recruiting, Aadi, LLC | Not yet recruiting --> Recruiting | N=180 --> 120

nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

P1/2, N=34, Completed, Sarcoma Oncology Research Center, LLC | Recruiting --> Completed | Trial completion date: Apr 2022 --> Dec 2021

All patients were previously treated with either sirolimus, everolimus or temsirolimus. nab-Sirolimus was active with manageable toxicities in patients with malignant PEComa with prior mTORi treatment and achieved clinical benefit including partial responses. This was particularly evident in patients with alterations in their TSC1 or TSC2 genes.