[Translation] A Study of LOXO-783 as Monotherapy and in Combination with Other Anticancer Therapies in Patients with Advanced Breast Cancer and Other Solid Tumors with PIK3CA H1047R Mutations

主要目的：确定在PIK3CA H1047R突变的晚期乳腺癌和其他实体瘤患者中 LOXO-783单药治疗和与其他抗癌疗法联合治疗的LOXO-783的MTD/RP2D

[Translation]

Primary Objective: To determine the MTD/RP2D of LOXO-783 as monotherapy and in combination with other anticancer therapies in patients with advanced breast cancer and other solid tumors harboring the PIK3CA H1047R mutation

Start Date27 Nov 2023

Sponsor / Collaborator

Eli Lilly Suzhou Pharmaceutical Co. Ltd.

[+2]

ISRCTN11595117 / RecruitingPhase 1

A Phase I/Ib study evaluating single-agent inavolisib and inavolisib plus atezolizumab in PIK3CA-mutated cancers

Start Date31 May 2022

Sponsor / Collaborator-

NCT04344795 / Active, not recruitingPhase 1

Phase 1a/1b Open Label Dose-escalation and Expansion Study of TPST-1495 as a Single Agent and in Combination With Pembrolizumab in Subjects With Solid Tumors

This is a first-in-human Phase 1a/1b, multicenter, open-label, dose-escalation, dose and schedule optimization, and expansion study of TPST-1495 as a single agent and in combination with pembrolizumab to determine its maximum tolerated dose (MTD) and or recommended Phase 2 dose (RP2D), safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity in subjects with advanced solid tumors. Subjects with all histologic types of solid tumors are eligible for the escalation and dose-finding portions of the study. However, the preferred tumor types for enrollment are colorectal cancer (CRC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), urothelial cancer, endometrial cancer, and gastroesophageal junction (GEJ) or gastric adenocarcinoma. Enrollment in the expansion cohorts is limited to the following tumor types: endometrial, SCCHN, CRC, and a basket cohort in subjects selected for an activating mutation in PIK3Ca.

Start Date06 May 2020

Sponsor / Collaborator

TempestTx, Inc.

100 Clinical Results associated with PIK3CA H1047R mutant Solid Tumors

100 Translational Medicine associated with PIK3CA H1047R mutant Solid Tumors

0 Patents (Medical) associated with PIK3CA H1047R mutant Solid Tumors

Literatures (Medical) associated with PIK3CA H1047R mutant Solid Tumors

01 Jan 2022·Cancer Discovery

RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy

Article

Author: Hanan, Emily J. ; Heffron, Timothy P. ; Malek, Shiva ; Song, Kyung W. ; Hong, Rebecca ; Hafner, Marc ; Friedman, Lori S. ; Guan, Jane ; Nannini, Michelle A. ; Plise, Emile G. ; Edgar, Kyle A. ; Staben, Steven T. ; Cheong, Jonathan ; Stawiski, Eric ; Oeh, Jason ; Wallin, Jeffrey J. ; Salphati, Laurent ; Phu, Lilian ; Sampath, Deepak ; Dey, Anwesha ; Olivero, Alan G. ; Lewis Phillips, Gail D. ; Merchant, Mark ; Kirkpatrick, Donald S. ; Forrest, William F. ; Schmidt, Stephen ; Endres, Nicholas

AbstractPIK3CA is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.Significance:The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in PIK3CA-mutant tumors.See related commentary by Vanhaesebroeck et al., p. 20.This article is highlighted in the In This Issue feature, p. 1

01 Feb 2021·Annals of OncologyQ1 · MEDICINE

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial

Q1 · MEDICINE

Article

Author: Krop, I E ; Hsu, J Y ; Schimmoller, F ; De Laurentiis, M ; Cui, N ; Im, Y-H ; Dent, S ; Harbeck, N ; Sousa, S ; He, J ; Cortés, J ; Jacot, W ; Wilson, T R ; Drullinsky, P ; Diéras, V

BACKGROUNDThe phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer.PATIENTS AND METHODSPostmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life.RESULTSThe PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm.CONCLUSIONSANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

01 Dec 2018·Clinical Cancer ResearchQ1 · MEDICINE

Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma

Q1 · MEDICINE

Article

Author: Moghal, Nadeem ; Shepherd, Frances A. ; Li, Ming ; Tam, Shirley ; Tsao, Ming-Sound ; Shi, Ruoshi ; Raghavan, Vibha ; Pham, Nhu-An ; Cabanero, Michael

AbstractPurpose:Lung squamous cell carcinoma (LUSC) is a major subtype of non–small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single-agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed.Experimental Design:PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds.Results:Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways.Conclusions:PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA-mutant LUSC.

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