Inavolisib

RLY-2608, an oral, mutant-selective PI3Kα allosteric inhibitor, addresses off-target toxicities of current modulators, currently in Ph. I for HR+/HER2- breast cancer treatment.

MSKCC advanced cancer treatments in 2024 include new surgical techniques, vaccines, drugs enhancing radiation, and diagnostic tools. The FDA approved 11 drugs based on MSK's pivotal clinical trials, covering new uses for existing drugs, effective drug combinations, engineered cell therapies, and novel targeted therapies. Key developments include a KRAS vaccine for pancreatic and colorectal cancer, combination drug-radiation treatment for basal cell carcinoma, noninvasive E-nose for lung cancer detection, improved transplant success with partially matched donors, exercise impact on prostate cancer biomarkers, new imaging for lung and prostate cancers, TIL therapy for non-small cell lung cancer, robotic neurosurgery for spinal tumors, avoiding surgery for HPV throat cancer with innovative radiation, imlunestrant for ER+, HER2- advanced breast cancer, mRNA vaccine for pancreatic cancer, and immunotherapy for rectal cancer. FDA approvals included tepotinib for METex14 lung cancer, CAR T treatment for mantle cell lymphoma, selpercatinib for RET-linked thyroid cancer, repotrectinib for NTRK fusion cancers, adagrasib with cetuximab for KRAS-G12C colorectal cancer, afamitresgene autoleucel for synovial sarcoma, vorasidenib for IDH glioma, inavolisib with fulvestrant and palbociclib for breast cancer, revumenib for KMT2A leukemia, zanidatamab for HER2 biliary tract cancer, and zenocutuzumab for NRG1 fusion pancreatic and lung cancers.

FDA approved inavolisib with palbociclib and fulvestrant for HR+/HER2- metastatic breast cancer with PIK3CA mutation in Oct 2024, highlighting progress in precision medicine.

At the 2024 San Antonio Breast Cancer Symposium, experts discussed FDA approvals for ribociclib and inavolisib in HR+/HER2- BC, emphasizing treatment optimization, clinical trial design, and addressing ovarian/reproductive toxicities. Ribociclib's approval was based on NATALEE trial data showing improved invasive disease-free survival (iDFS) with safety concerns. Inavolisib, targeting PIK3CA mutations, showed improved progression-free survival (PFS) with post-marketing commitments for further evaluation. The session highlighted the need for comprehensive data analysis and monitoring of fertility impacts.

Recent advancements in sequencing targeted therapies are reshaping HR-positive, HER2-negative metastatic breast cancer management, emphasizing the critical role of NGS in personalizing treatment decisions. Key factors include considering CDK 4/6 inhibitors, biomarker assessment, and sequencing new therapies like inavolisib and capivasertib. Trials such as SOLAR-1, INAVO120, and CAPItello-291 highlight improved progression-free survival and tolerable adverse effects. NGS is crucial for identifying PIK3CA/AKT mutations to determine optimal frontline and second-line treatments.

The 2024 NCCN Breast Cancer guidelines update includes ribociclib plus an aromatase inhibitor as a preferred regimen for HR-positive, HER2-negative early breast cancer. Ribociclib is the only category 1 CDK4/6 inhibitor for first-line treatment in combination with an AI. The guidelines also add adjuvant ribociclib for premenopausal patients with HR-positive, HER2-negative disease, and revise other treatment pathways. The FDA approval of adjuvant ribociclib may apply to a wider population than abemaciclib, with ribociclib given at 400 mg for 3 years, compared to abemaciclib's 2 years.

The INAVO120 trial shows that adding the PI3Kα inhibitor inavolisib to standard endocrine plus CDK4/6 inhibitor therapy for PIK3CA-mutant HR+, HER2- breast cancer increases efficacy, with progression-free survival as the primary endpoint.

Inavolisib, a PI3Kα isoform-selective kinase inhibitor and monovalent degrader of mutant p110α, selectively depletes mutant p110α in cancer cells with active RTK signaling. It received FDA approval in October 2024 for use with palbociclib and fulvestrant in treating endocrine-resistant, PIK3CA-mutated, HR+/HER2- breast cancer.

FDA approvals in October 2024 include nivolumab for resectable NSCLC, inavolisib triplet for PIK3CA-mutated HR+/HER2– advanced breast cancer, Optune Lua for metastatic NSCLC, zolbetuximab plus chemotherapy for CLDN18.2+ gastric or GEJ adenocarcinoma, and asciminib for newly diagnosed Ph+ chronic-phase CML. Other approvals include Cologuard Plus for average-risk CRC and Ion Torrent Oncomine Dx Target Test for vorasidenib.

PredicineCARE™ enabled accurate identification of PIK3CA-mutated metastatic breast cancer patients in China, contributing to FDA approval of Inavolisib in the U.S.