Second Opinion: A Case-Based Exploration of Clinical Investigator Best Practices Related to the Use of PI3K/AKT/mTOR Inhibitors for HR-Positive Breast Cancer

Faculty

Sara A Hurvitz

MD, FACP

Fred Hutchinson Cancer Center, Seattle, Washington

Professor of Medicine, Smith Family Endowed Chair in Women’s Health, Senior Vice President, Clinical Research Division

UW Medicine, Seattle, Washington

Head, Division of Hematology/Oncology, Department of Medicine

Faculty

Komal Jhaveri

MD, FACP, FASCO

Memorial Sloan Kettering Cancer Center, New York, New York

Patricia and James Cayne Chair for Junior Faculty, Associate Attending Physician, Breast Medicine Service and Early Drug Development Service, Section Head, Endocrine Therapy Research Program

Weill Cornell College of Medicine, New York, New York

Associate Professor of Medicine

Faculty

Nicholas Turner

MD, PhD

The Royal Marsden and ICR NIHR Biomedical Research Centre, London, United Kingdom

Director

The Royal Marsden NHS Foundation Trust

Director of Clinical Research

The Institute of Cancer Research, London, United Kingdom

Professor of Molecular Oncology, Director of Clinical Research

Moderator

Hope S Rugo

MD

City of Hope Comprehensive Cancer Center, Duarte, California

Director, Women’s Cancers Program, Division Chief, Breast Medical Oncology, Professor, Department of Medical Oncology and Therapeutics Research

University of California, San Francisco

Professor Emeritus

Additional faculty to be announced.

Join us on Tuesday, December 8^th from 7:00 PM to 9:00 PM central time (8:00 PM to 10:00 PM eastern time).

Identification and Management of Newly Diagnosed Hormone-Receptor (HR)-Positive Metastatic Breast Cancer (mBC) Harboring a PIK3CA Mutation 

• Optimal methodology and timing of testing to identify PI3K/AKT/PTEN alterations in patients with HR-positive, HER2-negative mBC 
• Mechanistic similarities and differences between inavolisib and earlier-generation PI3K inhibitors such as alpelisib; implications for efficacy and tolerability 
• Design, eligibility criteria and key efficacy findings, including overall survival outcomes, from the Phase III INAVO120 study evaluating inavolisib in combination with palbociclib and fulvestrant as first-line therapy for patients with endocrine-resistant, PIK3CA-mutant, HR-positive, HER2-negative mBC 
• FDA approval of inavolisib/palbociclib/fulvestrant and current clinical role for newly diagnosed HR-positive, HER2-negative mBC with a PIK3CA mutation 
• Ongoing Phase III trials (INAVO123, CAPItello-292, VIKTORIA-2) evaluating PI3K/AKT/mTOR inhibitors as a component of first-line therapy for patients with HR-positive, HER2-negative mBC; estimated completion dates 

Current Management of Progressive HR-Positive mBC with a PI3K/AKT/PTEN Alteration 

• Mechanism of action of the AKT inhibitor capivasertib; implications for target selectivity and antitumor activity compared to the PI3K inhibitors inavolisib and alpelisib 
• Available efficacy findings, including final overall survival data, from the Phase III CAPItello-291 trial establishing the clinical benefit of capivasertib/fulvestrant for progressive HR-positive, HER2-negative mBC with PI3K/AKT/PTEN alterations 
• FDA approval of capivasertib and current clinical role opposite other evidence-based options 
• Mechanistic similarities and differences between the novel dual PI3K/mTOR inhibitor gedatolisib and currently approved PI3K/AKT/mTOR inhibitors; implications for antitumor activity and tolerability 
• Design, eligibility criteria and primary and secondary endpoints of the Phase III VIKTORIA-1 trial evaluating gedatolisib in combination with fulvestrant with or without palbociclib for patients with HR-positive, HER2-negative advanced breast cancer whose disease progressed on or after prior CDK4/6 inhibitor therapy and an aromatase inhibitor; FDA approval and optimal incorporation into clinical practice 
• Efficacy and safety findings from the PIK3CA-mutated cohort of VIKTORIA-1; anticipated full presentation of results and future role of gedatolisib-containing combination therapy 
• Other Phase III efforts investigating promising novel agents and strategies for HR-positive mBC harboring PI3K/AKT/PTEN alterations 

Optimal Approaches to the Management of Progressive PIK3CA Wild-Type, HR-Positive Disease 

• Historical outcomes with standard second-line regimens for HR-positive, HER2-negative mBC with no actionable alterations 
• Available data with and current role, if any, of CDK4/6 inhibitor continuation or rechallenge for patients with HR-positive, HER2-negative mBC progressing on first-line treatment with a CDK4/6 inhibitor and endocrine therapy 
• Rationale for the evaluation of gedatolisib-containing regimens for PIK3CA wild-type, progressive, HR-positive, HER2-negative mBC; specific regimens evaluated in VIKTORIA-1 for this patient subset 
• Recently published efficacy and safety findings from the PIK3CA wild-type cohort of VIKTORIA-1; comparative benefit of the triplet combination (gedatolisib with fulvestrant and palbociclib) and doublet combination (gedatolisib with fulvestrant) versus fulvestrant monotherapy 
• FDA approval of gedatolisib-containing combination therapy for pretreated HR-positive, HER2-negative mBC that is PIK3CA wild-type 

Tolerability Considerations with PI3K/AKT/mTOR Inhibitors 

• Spectrum of common and agent-specific adverse events (AEs) documented with PI3K/AKT/mTOR inhibitors in mBC; comparative tolerability/toxicity profiles of the various agents 
• Pathophysiology of hyperglycemia associated with PI3K/AKT/mTOR inhibitors; incidence, severity and timing of hyperglycemia with the various agents 
• Optimal mitigation, monitoring and management protocols for PI3K/AKT/mTOR inhibitor-associated hyperglycemia 
• Frequency and severity of GI and cutaneous toxicities with PI3K/AKT/mTOR inhibitors; strategies to prevent and ameliorate these AEs 
• Impact on the tolerability of PI3K/AKT/mTOR inhibitors when administered in combination with endocrine therapy or CDK4/6 inhibitors; recommendations for monitoring and management of cytopenias with combination regimens 
• Relative and absolute contraindications to the use of and other practical considerations with PI3K/AKT/mTOR inhibitors for mBC 

Target Audience
This activity is intended for medical oncologists, breast surgeons, radiation oncologists and other healthcare professionals involved in the diagnosis and treatment of breast cancer.

Learning Objectives
Upon completion of this activity, participants should be able to

• Review available research findings documenting the correlation between the presence of various biomarkers (eg, PIK3CA/AKT1/PTEN alterations, ESR1 mutations) and response to specific therapies, and develop optimal testing algorithms for patients with hormone receptor (HR)-positive metastatic breast cancer (mBC). 
• Recognize the frequency of PI3K/AKT/PTEN alterations in individuals with HR-positive mBC, and employ evidence-based approaches designed to target these aberrations for appropriate patients with newly diagnosed and relapsed/refractory disease. 
• Understand the biological rationale for the development of agents targeting multiple components of the PI3K/AKT/mTOR pathway, and recognize available and emerging data with this strategy for patients with HR-positive, PIK3CA wild-type and PIK3CA-mutant mBC. 
• Appreciate the clinical and biological factors that guide the selection and sequencing of therapy for HR-positive mBC, and use this information to personalize treatment recommendations. 
• Recognize adverse events associated with available and investigational PI3K/AKT/mTOR inhibitors, and implement approaches to educate patients and manage complications. 
• Evaluate available research findings with and ongoing studies evaluating novel PI3K/AKT/mTOR inhibitor-based approaches, and consider the future role of these strategies. 

CE Credit
CME credit information will be given to each participant as part of the meeting course materials.

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FACULTY — The following faculty reported relevant financial relationships with ineligible entities:

Dr Hurvitz — Advisory Committees: Akari Therapeutics, BeOne, Boundless Bio, BriaCell, BridgeBio, Bristol Myers Squibb, Daiichi Sankyo Inc, Gilead Sciences Inc, Jazz Pharmaceuticals Inc, Lilly, Luminate, Mersana Therapeutics Inc, Novartis, Prelude Therapeutics, Roche Laboratories Inc; Consulting Agreements: ALX Oncology, Bayer HealthCare Pharmaceuticals, BeOne, Blueprint Medicines, Ellipses Pharma, EMBioSys, Genentech, a member of the Roche Group, Jazz Pharmaceuticals Inc, Myricx Bio; Contracted Research: AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Menarini Group, Novartis, Stemline Therapeutics Inc; Data and Safety Monitoring Boards/Committees: Atossa Therapeutics (paid to institution), Roche Laboratories Inc (paid to UW); Nonrelevant Financial Relationships: Alliance for Clinical Trials in Oncology Foundation, InClin, Quantum Leap Healthcare Collaborative, ROMTech (Stocks for orthopedic device for postop pts; not cancer related). Dr Jhaveri — Advisory Committees and Consulting Agreements: Arvinas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, BBOT, BeOne, Bicycle Therapeutics, Blueprint Medicines, ConcertAI, Daiichi Sankyo Inc, Eisai Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Halda Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Menarini Group, Merck, Mersana Therapeutics Inc, Natera Inc, Novartis, Olema Oncology, Pfizer Inc, Precede Biosciences, RayzeBio, Regor Therapeutics, Relay Therapeutics, Scorpion Therapeutics, Stemline Therapeutics Inc, Zymeworks Inc; Contracted Research: AstraZeneca Pharmaceuticals LP, BBOT, Bicycle Therapeutics, Blueprint Medicines, Eisai Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Merck, Novartis, Pfizer Inc, Puma Biotechnology Inc, RayzeBio, Scorpion Therapeutics, Zymeworks Inc; Nonrelevant Financial Relationships: Breast Cancer Research Foundation, Fred’s Team, Manhasset Women’s Coalition Against Breast Cancer, National Cancer Institute (BRIMM/UG3 CA239861 Award). Prof Turner — Consultant/Advisory: AstraZeneca Pharmaceuticals LP, Exact Sciences Corporation, Genentech, a member of the Roche Group, GSK, Guardant Health, Inivata, Lilly, Novartis, Pfizer Inc, Repare Therapeutics; Research Funding: AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Guardant Health, Inivata, Invitae, Labcorp, MSD, Natera Inc, Personalis, Pfizer Inc. Additional faculty to be announced.

MODERATOR
Dr Rugo — Consulting Agreements: BioNTech SE, Bristol Myers Squibb, Helsinn Therapeutics (US) Inc, Napo Pharmaceuticals; Contracted Research — Funding to City of Hope: ALX Oncology, Bicycle Therapeutics, Genentech, a member of the Roche Group, Mabwell Therapeutics Inc, Merck, NiKang Therapeutics, Pfizer Inc, Phoenix Molecular Designs, Relay Therapeutics, Stemline Therapeutics Inc; Contracted Research — Funding to UCSF: Ambrx, AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Lilly, Merck, Novartis, Pfizer Inc, Stemline Therapeutics Inc. 

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Supporters
This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Celcuity, and Genentech, a member of the Roche Group.

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