Alpelisib
- Generic Name
- Alpelisib
- Brand Names
- Piqray 300 Mg Daily Dose, Vijoice 50 Mg 28 Day, Piqray
- Drug Type
- Small Molecule
- Chemical Formula
- C19H22F3N5O2S
- CAS Number
- 1217486-61-7
- Unique Ingredient Identifier
- 08W5N2C97Q
- Background
Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potent antitumor activity. It works by selectively inhibiting class I PI3K p110α , which is the catalytic subunit of PI3K, a lipid kinase that plays a role in various biological processes, including proliferation, survival, differentiation, and metabolism. Alpelisib was designed to target this enzyme that appears to be mutated at a rate of nearly 30% in human cancers, leading to hyperactivation.
There are several isoform-specific PI3K inhibitors that are under clinical development or currently approved, such as idelalisib used for chronic lymphocytic leukemia (CLL). Approved by the FDA in May 2019, alpelisib is the first approved PI3K inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer in combination with fulvestrant for postmenopausal women and male patients. To initiate alpelisib therapy, it is required that the presence of a PIK3CA mutation in the tissue and/or liquid biopsy sample collection should be confirmed via FDA-approved diagnostic tests. Alpelisib is marketed under the trade name Piqray and is available as oral tablets. Studies evaluating the therapeutic effectiveness of alpelisib in other cancers, such as ovarian cancer and colorectal cancer , are under ongoing investigations.
Alpelisib was granted FDA approval on 24 May 2019. In April 2022, the FDA granted the use of alpelisib in the treatment of PIK3CA-Related Overgrowth Spectrum (PROS) in adults and children who require systemic therapy.
- Indication
Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen.
Alpelisib is also used to treat adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
- Associated Conditions
- HR+, HER2-, Advanced Breast Cancer, PIK3CA-Related Overgrowth Spectrum (PROS), Metastatic HR + HER2 - breast cancer
Breakthrough Breast Cancer Drug Capivasertib Approved for NHS Use
• A groundbreaking twice-daily pill called capivasertib (Truqap) has been approved for NHS use, targeting hormone receptor-positive HER2-negative breast cancer by blocking cancer growth mechanisms.
• Clinical trials demonstrated the drug extends time before cancer progression by over four months when used alongside hormone therapy Fulvestrant, offering new hope for approximately 3,000 women annually.
• The treatment specifically benefits patients with PIK3CA, AKT1 or PTEN gene mutations, allowing many to maintain good quality of life with fewer debilitating side effects compared to other treatment regimens.
Datopotamab Deruxtecan's Role in HR+/HER2- Breast Cancer Treatment: Sequencing and Safety Considerations
• Datopotamab deruxtecan (Dato-DXd) is poised to become a standard treatment for metastatic hormone receptor-positive, HER2-negative breast cancer after prior systemic therapy.
• Optimal sequencing of antibody-drug conjugates (ADCs) like Dato-DXd, sacituzumab govitecan, and trastuzumab deruxtecan remains uncertain, especially considering overlapping toxicities.
• Real-world toxicity profiles suggest sacituzumab govitecan may cause more cytopenias and diarrhea, while Dato-DXd and trastuzumab deruxtecan are linked to interstitial lung disease.
• The lack of overall survival difference in the TROPION-Breast01 trial raises questions about efficacy issues or the impact of crossover between treatment arms.
Lilly to Acquire Scorpion Therapeutics' Mutant-Selective PI3Kα Inhibitor Program for $2.5 Billion
• Eli Lilly is set to acquire Scorpion Therapeutics' PI3Kα inhibitor program, including STX-478, currently in Phase I/II trials, for up to $2.5 billion.
• STX-478 is a novel, oral, mutant-selective PI3Kα inhibitor targeting breast cancer and advanced solid tumors, potentially offering improved tolerability.
• The acquisition expands Lilly's oncology pipeline, aiming to address the unmet need for effective and safe treatments for hormone-positive breast cancers with PI3Kα mutations.
• Scorpion Therapeutics will spin out a new entity focusing on precision medicines, with Lilly retaining a minority equity interest in the new company.
Novartis' Intrathecal Zolgensma Shows Positive Phase III Results for SMA Type 2
• Novartis' intrathecal onasemnogene abeparvovec (OAV101 IT) met its primary endpoint in the Phase III STEER study for SMA Type 2.
• The STEER trial demonstrated a statistically significant increase in motor function, as measured by HFMSE scores, in treatment-naïve patients.
• OAV101 IT showed a favorable safety profile, with adverse events similar to the control arm, potentially expanding treatment options for SMA.
• Novartis plans to submit the data to regulatory agencies in 2025, seeking approval to broaden the availability of this one-time gene therapy.
Olema Oncology Secures $250M Funding and Novartis Partnership for Phase 3 Breast Cancer Trial
• Olema Oncology has secured a $250 million private placement to advance its clinical programs, including the Phase 3 OPERA-02 trial.
• A collaboration with Novartis will provide ribociclib for the OPERA-02 trial, evaluating palazestrant in combination for ER+/HER2- metastatic breast cancer.
• The OPERA-02 trial is expected to begin in mid-2025, with approximately 1,000 patients, and Olema retains global commercial rights to palazestrant.
• Olema's funding supports multiple clinical milestones, including OPERA-01 Phase 3 data in 2026 and OP-3136 Phase 1/2 data, strengthening its development pipeline.
Kura Oncology and Kyowa Kirin Partner to Advance Ziftomenib for Acute Leukemias
• Kura Oncology secures a $330 million upfront payment through a collaboration with Kyowa Kirin to develop and commercialize ziftomenib for acute leukemias.
• Ziftomenib, a menin inhibitor, targets leukemias driven by KMT2A gene mutations and is expected to have an FDA submission in 2025 for advanced AML.
• The collaboration includes plans to investigate ziftomenib as an earlier line of therapy, in combination with other drugs, and as a post-transplant maintenance treatment.
• Kura Oncology is also developing tipifarnib for head and neck squamous cell carcinomas, with data from a Phase 1/2 study expected in the first half of next year.
FDA Approves Caris Life Sciences' MI Cancer Seek as Companion Diagnostic
• The FDA has approved MI Cancer Seek, a comprehensive companion diagnostic test by Caris Life Sciences, for both adult and pediatric cancer patients.
• MI Cancer Seek utilizes simultaneous whole exome and whole transcriptome sequencing to identify patients who may benefit from targeted therapies.
• This approval includes one pan-cancer and five tumor-specific indications, covering numerous FDA-approved therapies, enhancing precision medicine.
• The test aims to provide a comprehensive molecular blueprint, saving tissue and time by combining DNA and RNA analysis in a single process.
FDA Approves Caris Life Sciences' MI Cancer Seek as Companion Diagnostic
• Caris Life Sciences' MI Cancer Seek receives FDA approval as a companion diagnostic for targeted cancer therapies, benefiting both adult and pediatric patients.
• MI Cancer Seek is the first assay to simultaneously use Whole Exome Sequencing (WES) and Whole Transcriptome Sequencing (WTS) with FDA-approved companion diagnostic indications.
• The diagnostic tool identifies single nucleotide variants, microsatellite instability, and tumor mutational burden in solid tumors to guide treatment decisions.
• The FDA's approval underscores Caris' commitment to advancing precision medicine and providing clinicians with advanced tools for personalized cancer treatment strategies.
FDA Approves MI Cancer Seek as Companion Diagnostic for Targeted Therapy Across Tumor Types
• The FDA has approved MI Cancer Seek as a companion diagnostic to identify cancer patients who may benefit from targeted therapy, covering both adult and pediatric populations.
• MI Cancer Seek is the first FDA-approved assay that combines whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) for molecular profiling of solid tumors.
• The diagnostic can detect single nucleotide variants, insertions, deletions, microsatellite instability (MSI), and tumor mutational burden (TMB) across multiple cancer types.
• MI Cancer Seek holds companion diagnostic indications in breast, colorectal, melanoma, non-small cell lung, and endometrial cancers, guiding treatment decisions with targeted therapies.
FDA Approves Caris Life Sciences' MI Cancer Seek as Companion Diagnostic
• The FDA has approved Caris Life Sciences' MI Cancer Seek as a companion diagnostic to identify cancer patients who may benefit from targeted therapies.
• MI Cancer Seek is the first assay to use simultaneous Whole Exome Sequencing (WES) and Whole Transcriptome Sequencing (WTS) with CDx indications.
• The diagnostic test is available for both adult and pediatric patients (ages 1-22) with previously diagnosed solid tumors.
• MI Cancer Seek can detect SNVs, indels, MSI, TMB, and CNAs, providing a comprehensive molecular profile for precision medicine.
Caris Life Sciences' MI Cancer Seek Receives FDA Approval as Companion Diagnostic
• Caris Life Sciences' MI Cancer Seek receives FDA approval as a companion diagnostic for targeted cancer therapies, benefiting both adult and pediatric patients.
• MI Cancer Seek is the first assay to simultaneously use Whole Exome Sequencing (WES) and Whole Transcriptome Sequencing (WTS) with FDA-approved CDx indications.
• The diagnostic tool identifies single nucleotide variants, insertions, deletions, microsatellite instability, and tumor mutational burden in solid tumors.
• MI Cancer Seek supports treatment decisions across multiple cancers, including breast, colorectal, melanoma, non-small cell lung cancer, and endometrial carcinoma.
RLY-2608 Plus Fulvestrant Shows Promise in PI3Kα-Mutated, HR+/HER2- Breast Cancer
• RLY-2608 combined with fulvestrant demonstrates clinically meaningful progression-free survival in heavily pretreated patients with PI3Kα-mutated, HR+/HER2- breast cancer.
• Patients without PTEN or AKT co-mutations achieved a median PFS of 9.2 months at the recommended phase 2 dose (RP2D) of RLY-2608 plus fulvestrant.
• The overall response rate was 33% in patients with measurable disease, with tumor reductions observed in 73% of patients, and the combination was generally well-tolerated.
• RLY-2608 shows a favorable safety profile, with lower rates of hyperglycemia, diarrhea, and rash compared to other PI3K inhibitors like alpelisib and capivasertib.
Roche's Itovebi Approved for Breast Cancer; Turnstone Biologics Restructures
• The FDA approved Roche's Itovebi, inavolisib, for HR-positive, HER2-negative breast cancer with PIK3CA mutation, to be used with Pfizer’s Ibrance and endocrine therapy.
• Turnstone Biologics is restructuring, laying off 60% of its workforce to focus on a Phase 1 cancer cell therapy program for solid tumors, with updates expected next year.
• Pfizer's Talzenna combined with Xtandi showed prolonged survival in advanced prostate cancer patients, regardless of genetic alterations, seeking expanded use.
• Gritstone bio filed for bankruptcy after disappointing vaccine study results; Denali Therapeutics' multiple sclerosis drug, oditrasertib, failed in Phase 2 trial.
Novel Anti-Estrogen Therapies Expand Options for Advanced ER+ Breast Cancer
• Novel anti-estrogen therapies are poised to expand treatment options for patients with estrogen receptor (ER)-positive advanced breast cancer after CDK4/6 inhibitor therapy.
• The phase 3 INAVO120 trial showed that inavolisib, combined with palbociclib and fulvestrant, significantly improved progression-free survival in patients with PIK3CA-mutated advanced breast cancer.
• Updated INAVO120 findings presented at ASCO 2024 demonstrated a longer time to next-line treatment with the inavolisib combination compared to palbociclib and fulvestrant alone.
• Researchers are focusing on identifying specific subgroups of patients who may benefit most from certain therapies or combinations, bringing a more personalized approach.
Kisqali and Itovebi Secure FDA Approval for Advanced Breast Cancer Treatment
• Ribociclib (Kisqali) gains FDA approval in combination with aromatase inhibitors for adjuvant treatment of HR+/HER2- early breast cancer, reducing recurrence risk.
• Inavolisib (Itovebi) receives FDA approval when combined with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer.
• The approvals offer new treatment options for a broader range of breast cancer patients, addressing unmet needs and improving care approaches.
Relay Therapeutics' RLY-2608 Shows Promise in PI3Kα-Mutated Breast Cancer
• Relay Therapeutics' RLY-2608, combined with fulvestrant, demonstrated a median progression-free survival of 9.2 months in pre-treated patients.
• The ReDiscover trial data supports advancing RLY-2608 into a pivotal Phase 2 study in 2025 for metastatic breast cancer.
• RLY-2608 exhibited a favorable tolerability profile, with few patients discontinuing treatment due to adverse events.
• Relay Therapeutics plans to present updated data on lirafugratinib at the AACR-NCI-EORTC conference in October 2024.
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