Itovebi (inavolisib) / Roche - LARVOL DELTA

Itovebi: Regulatory submissions in US/EU for 1L HER2+ PIK3CA-mutant metastatic breast cancer in combination with Phesgo in 2027 (Roche) - Q1 2025 Results: Regulatory submissions in US/EU for 1L ES PIK3CA-mut. HR+ HER2- advanced breast cancer (in combination with letrozole) in 2028 and beyond

EMA filing • FDA filing • Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology

Comparative analysis of PIK3CA mutation detection methods in the first-in-human phase 1/1b study of inavolisib. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Biomarker • P1 data • Breast Cancer • Oncology • Solid Tumor • PIK3CA

Phase I/Ib study of inavolisib (INAVO) alone and in combination with endocrine therapy ± palbociclib (PALBO) in patients (pts) with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced/metastatic breast cancer (HR+, HER2– LA/mBC): Analysis of hyperglycemia (HG) in prediabetic/obese pts. (ASCO 2025) - P1 | "Clinical Trial Registration Number: NCT03006172 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Combination therapy • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Obesity • Oncology • Solid Tumor • HER-2 • PIK3CA

INAVO120: Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). (ASCO 2025) - P2/3 | "Clinical Trial Registration Number: NCT04191499 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Phase Ib study of inavolisib (INAVO) + weekly paclitaxel (wP) in patients (pts) with locally advanced/metastatic (LA/m) incurable solid tumors: Safety, pharmacokinetics (PK), and preliminary antitumor activity. (ASCO 2025) - "Clinical Trial Registration Number: ISRCTN45319897 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P1 data • PK/PD data • Oncology • Solid Tumor

Palbociclib in the Evolving Landscape of HR+ mBC Treatment : Real-World Data and Future Directions (GBCC 2025) - "Young-PEARL, the first study comparing CDK4/6 inhibitor plus ET and cytotoxic chemotherapy capecitabine focused on premenopausal women with HR+/HER2− mBC, reported that palbociclib plus exemestane and ovarian suppression significantly prolonged PFS compared with capecitabine...The INAVO120 trial demonstrated superior PFS when inavolisib was added to palbociclib and fulvestrant in patients with PIK3CA-mutated HR+/HER2− mBC. The AFT-38 PATINA trial showed that adding palbociclib to maintenance endocrine and first line trastuzumab and pertuzumab significantly extended PFS in patients with HR+/HER2+ mBC. Moreover, palbociclib is also being studied in combination with other PI3K/AKT pathway inhibitors, such as gedatolisib and capivasertib, or selective estrogen receptor degraders(SERDs) in order to explore potential synergistic effects in overcoming treatment resistance in HR+/HER2− mBC. Taken together, these findings suggest that palbociclib’s role in the treatment landscape..."

Clinical • Real-world • Real-world evidence • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

ET-Based Combinations and Novel Agents in HR+/HER2- Advanced Breast Cancer (GBCC 2025) - "Tumors with alterations in the PIK3CA/AKT/PTEN pathway may be offered a pathway inhibitor such as capivasertib or alpelisib, and patients with high risk recurrence of HR+ disease with a PIK3CA mutation may benefit from early introduction of a first-line inavolisib triplet...The oral SERD elacestrant is approved as monotherapy in pretreated patients with tumors harboring an ESR1 mutation. Additional oral SERDs, including imlunestrant, camizestrant, and giredestrant, have demonstrated activity and are in registrational trials. An additional maneuver in the pretreated space includes continuation of a CDK4/6 inhibitor after prior CDK4/6 inhibitor, with activity seen from switching to abemaciclib or ribociclib from a prior agent, and novel CDK inhibitors are in trials as a next generation approach. The mTOR inhibitor everolimus remains an option for pretreated patients as well, particularly when actionable mutations are not present. The continued introduction of novel agents..."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor (AACR 2025) - P1, P1/2 | "Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. TY-2291 is a potent kinase inhibitor of mutant PI3Kα with high selectivity over WT PI3Kα. In in vitro antiproliferative test, TY-2291 showed better antiproliferative activity against multiple PI3Kα mutant cells than LOXO-783, STX-478, and RLY-2608. In the mouse HCC1954 CDX model, TY-2291 showed potent tumor-inhibitory activity and excellent tolerance."

Breast Cancer • Colon Cancer • Colorectal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • HER-2 • PIK3CA

GSC002639, a brain penetrating and mutant-selective PI3Kα inhibitor, exhibits potent mono- and combination therapy against PI3CA mutant tumors (AACR 2025) - "Our study also revealed a notable observation: In an HR-positive and HER2-negative PI3Kα H1047X CDX model, the combination of GSC002639 with Fulvestrant exhibited greater efficacy than the combinations of either Alpelisib or Inavolisib with Fulvestrant. In this report, we present the identification and characterization of GSC002639, a selective inhibitor targeting the PI3Kα H1047X mutation. GSC002639 demonstrates high specificity, the ability to cross the blood-brain barrier, and robust in vivo efficacy, while avoiding the insulin elevation. The promising pharmacokinetic and toxicological profiles of GSC002639 suggest its potential as a safe and effective cancer therapy."

Combination therapy • Breast Cancer • Colorectal Cancer • Endometrial Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Targeting mechanisms of adaptive resistance to the PI3Kαmutant selective inhibitor RLY-2608 in HR+/PIK3CA mutant breast cancer (AACR 2025) - "Alpelisib and inavolisib are currently FDA approved for treatment of PIK3CA-mutant breast cancers, although neither is selective for mutant PIK3CA...To identify the ERBB RTKs causing this adaptation, we tested the TKIs erlotinib, neratinib, and tucatinib, and the HER3 antibodies patritumab and zenocutuzumab, each in combination with RLY-2608...Other upregulated Hallmark pathways in both cell lines included Myogenesis, Hypoxia, and KRAS signaling down. These findings suggest that, in addition to RTK activation, adaptive resistance to RLY-2608 may involve metabolic reprogramming, increased oxidative stress, and hypoxia signaling, highlighting the need for combination strategies to overcome resistance and enhance treatment efficacy."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • KRAS • PIK3CA

ETX-636, a novel allosteric pan-mutant-selective PI3Kα dual inhibitor and degrader with best-in-class potential (AACR 2025) - "Orthosteric ATP-competitive inhibitors, alpelisib and inavolisib, which inhibit both Wild-type (WT) and mutant PI3Kα, are approved in combination regimens for treating PIK3CA-mutant, HR+/HER2-, advanced or metastatic BrCA...In addition to greater biochemical selectivity for mutant PI3Kα over WT PI3Kα, ETX-636 has stronger target binding affinity, better on-target potency in biochemical and cellular pharmacodynamic assays, and demonstrates superior anti-tumor activity in vivo when compared to other allosteric, pan-mutant-selective PI3Kα inhibitors (i.e. RLY-2608 and STX-478)...In an ER-positive, HER2-negative, PI3Kα-mutant BrCA xenograft, ETX-636 is efficacious as a single agent and shows synergistic activity with fulvestrant, inducing tumor regression while being well-tolerated...In addition, based on pharmacokinetic, pharmacodynamic, efficacy, and toxicology studies, predicted human efficacious doses of ETX-636 are not projected to cause hyperglycemia. The preclinical..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • HER-2 • PIK3CA

Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids (AACR 2025) - "As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS...In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy."

Oncology • Solid Tumor • KRAS • PIK3CA

INAVO123: Phase III study of first-line (1L) inavolisib/placebo + a CDK4/6 inhibitor + letrozole (INAVO/PBO + CDK4/6i + LET) in participants (pts) with PIK3CA-mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2-), endocrine-sensitive advanced breast cancer (aBC) (ESMO-BC 2025) - No abstract available

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Inavolisib plus letrozole or fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer (GO39374): An open-label, multicentre, dose-escalation and dose-expansion phase 1/1b study. (PubMed, Eur J Cancer) - "Inavolisib plus ET demonstrated a manageable safety profile and encouraging preliminary anti-tumour activity in patients with PIK3CA-mutated, HR-positive, HER2-negative LA/mBC, including those in the post-CDK4/6i setting."

Journal • P1 data • Breast Cancer • Dental Disorders • Diabetes • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Stomatitis • HER-2 • PIK3CA

MORPHEUS BC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer (clinicaltrials.gov) - P1/2 | N=510 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Apr 2026 ➔ Nov 2027

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

MORPHEUS BC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer (clinicaltrials.gov) - P1/2 | N=316 | Recruiting | Sponsor: Hoffmann-La Roche | N=510 ➔ 316

Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids. (PubMed, SLAS Discov) - "Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib."

Journal • Oncology • KRAS

Health Canada authorizes Itovebi (inavolisib film-coated tablets), a targeted treatment for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation (Canada Newswire) - "Hoffmann-La Roche Limited (Roche Canada) today announced that Health Canada has granted authorization for Itovebi (inavolisib film-coated tablets) in combination with palbociclib and fulvestrant, for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, following recurrence on or after completing adjuvant endocrine treatment....Health Canada's authorization of Itovebi is based on results of the pivotal Phase III INAVO120 study, which showed that the Itovebi-based treatment reduced the risk of disease worsening or death by 57% compared with palbociclib and fulvestrant alone in the first-line metastatic setting, demonstrating a statistically significant benefit."

Canada approval • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

INAVO122: A Study to Evaluate the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P3 | N=230 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jan 2028 ➔ Dec 2032

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

GO42144: A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Mar 2025 ➔ Feb 2026

Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=542 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2029 ➔ Nov 2028

Trial completion date • Colorectal Cancer • Oncology • Solid Tumor

CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells. (PubMed, Cancer Metab) - "Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CD36 • PIK3CA • PTEN • SCARB1 • SCD

Itovebi: First-patient-in of P3 INAVO123 trial (NCT06790693) for 1L endocrine-sensitive PIK3CA-mutated HR+/HER2-, advanced breast cancer in Q1 2025 (Roche) - FY 2024 Results

Trial initiation date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology

INAVO121: A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy (clinicaltrials.gov) - P3 | N=400 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

Itovebi: Regulatory approval in EU for 1L PIK3CA-mut HR+ breast cancer (in combination with palbociclib and fulvestrant) in H1 2025 (Roche) - Q4 2024 Results: Regulatory submissions in US/EU for post CDKi HR+ PIK3CA-mutant breast cancer in combination with fulvestrant in 2026

EMA approval • EMA filing • FDA filing • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology