izorlisib (MEN1611) / Roche, Menarini - LARVOL DELTA

SABINA: PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin (clinicaltrials.gov) - P2 | N=14 | Recruiting | Sponsor: MedSIR | Trial primary completion date: Jul 2025 ➔ Apr 2026

Monotherapy • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PIK3CA • PTEN

SABINA: PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin (clinicaltrials.gov) - P2 | N=14 | Recruiting | Sponsor: MedSIR | N=28 ➔ 14

Enrollment change • Metastases • Monotherapy • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PIK3CA • PTEN

B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=62 | Completed | Sponsor: Menarini Group | Active, not recruiting ➔ Completed

Metastases • Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov) - P1/2 | N=29 | Completed | Sponsor: Menarini Group | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Feb 2024 | Trial primary completion date: Jun 2024 ➔ Jan 2024

Metastases • Trial completion • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • PIK3CA • RAS

MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov) - P1/2 | N=29 | Active, not recruiting | Sponsor: Menarini Group | Trial completion date: Dec 2023 ➔ Jun 2024 | Trial primary completion date: Dec 2023 ➔ Jun 2024

Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • PIK3CA • RAS

The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway. (PubMed, Front Oncol) - "We demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo. Overall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PIK3CA

The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway (Front Oncol) - "We demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo."

Preclinical • Non Small Cell Lung Cancer

MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov) - P1/2 | N=29 | Active, not recruiting | Sponsor: Menarini Group | N=42 ➔ 29

Enrollment change • Metastases • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • PIK3CA • RAS

SABINA: PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin (clinicaltrials.gov) - P2 | N=28 | Recruiting | Sponsor: MedSIR | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Monotherapy • Breast Cancer • Oncology • Solid Tumor • PIK3CA • PTEN

B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=62 | Active, not recruiting | Sponsor: Menarini Group | Trial completion date: Jul 2022 ➔ Dec 2023 | Trial primary completion date: Jul 2022 ➔ Dec 2023

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (clinicaltrials.gov) - P1/2 | N=42 | Active, not recruiting | Sponsor: Menarini Group | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2023 ➔ Oct 2023 | Trial primary completion date: Jul 2023 ➔ Oct 2023

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • PIK3CA • RAS

The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models (AACR 2023) - "Overall, in all the tested in vivo models the combination of Elacestrant and MEN1611 was superior in comparison to the single agents by overcoming resistance to ER inhibition potentially driven by PI3K pathway activation in PIK3CA mutated tumors. The current data support the use of Elacestrant, the first oral SERD with positive phase III results in the EMERALD trial (Bidard et al.; JCO 2022), in combination with the PI3K inhibitor MEN1611, in ER+/HER2- mBC patients harboring PIK3CA mutations and who progressed to CDK4/6i plus ET."

Combination therapy • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

SABINA: PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin (clinicaltrials.gov) - P2 | N=28 | Not yet recruiting | Sponsor: MedSIR

Combination therapy • Metastases • Monotherapy • New P2 trial • Breast Cancer • Oncology • Solid Tumor • PIK3CA • PTEN

Emerging new treatments in HER2 positive breast cancer (SG-BCC 2023) - P1 | "Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026..."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Oncology • Solid Tumor • CDK4 • ER • HER-2 • KLRC1 • PD-L1 • PIK3CA

Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer. (PubMed, Breast Cancer Res Treat) - P1 | "The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335)."

Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

[VIRTUAL] MEN1611 in combination with cetuximab: Targeting PIK3CA mutations in RAS-wild-type patient-derived colorectal cancer xenografts (ESMO 2021) - P1/2 | "In conclusion, in the selected genetic setting, the combination of MEN1611 with cetuximab displayed higher activity compared to single agents showing a synergistic effect in cetuximab-resistant PDX models. These data support the ongoing C-Precise phase Ib/II study investigating anti-tumor activity and safety of MEN1611 in combination with cetuximab in PIK3CAmut/N-K-RASwt/BRAFwt mCRC patients (NCT04495621)."

Clinical • Combination therapy • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • PIK3CA

Characterization of the mechanism of action and efficacy of MEN1611 (PA799), a novel PI3K inhibitor, in breast cancer preclinical models (ESMO 2019) - P1; "MEN1611 acts synergistically when combined with trastuzumab in several HER2-positive PIK3CA-mutated breast cancer cell lines and patient-derived xenograft models. Overall, these preclinical data support the progression in the development of MEN1611 in breast cancer and pave the way to the B-Precise-01 clinical study, a multicentre phase Ib study. Clinical trial identification: NCT03767335. Legal entity responsible for the study: Menarini Ricerche S.p.A."

Preclinical

[VIRTUAL] Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer (AACR 2021) - P1 | "Moreover, efficacy evaluation showed significant tumor-regression activity in the BID group of animals compared to the QD (79% versus 43% respectively). Although further studies are needed to evaluate time-dependent drug exposure in tumor and plasma samples, these preliminary findings support the BID clinical schedule of MEN1611 in the B-PRECISE-01 clinical trial (NCT03767335)."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

MEN1611, a PI3K inhibitor, combined with trastuzumab ± fulvestrant for HER2+/PIK3CA mutant advanced or metastatic breast cancer: updated safety and efficacy results from the ongoing phase 1b study (B-PRECISE-01) (SABCS 2022) - "Median metastatic regimens 4; 71.0% had prior pertuzumab and 91.9% had prior T- DM1. Updated results from B-PRECISE-01 demonstrated that MEN1611 combined with trastuzumab ± fulvestrant continued to show a manageable safety profile with encouraging anti-tumor activity and duration of response in heavily pre-treated patients with HER2+/PIK3CA-mutated advanced or metastatic breast cancer."

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Model-based prediction of effective target exposure for MEN1611 in combination with trastuzumab in HER2-positive advanced or metastatic breast cancer patients. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "A slightly lower exposure (i.e., 25% lower) was found for the 3-weekly s.c. schedule. This important outcome confirmed the adequacy of the therapeutic dose administered in the ongoing phase 1b B-PRECISE-01 study in patients with HER2+ PI3KCA mutated advanced/metastatic BC."

Combination therapy • Journal • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

B-PRECISE-01: MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=62 | Active, not recruiting | Sponsor: Menarini Group | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

[VIRTUAL] MEN1611, a PI3K inhibitor, combined with trastuzumab (T) ± fulvestrant (F) for HER2+/PIK3CA mutant (mut) advanced or metastatic (a/m) breast cancer (BC): Safety and efficacy results from the ongoing phase Ib study (B-PRECISE-01) (ESMO 2021) - P1 | "Median metastatic regimes 4; 57.1% had prior pertuzumab and 73.8% had prior T-DM1. MEN combined with T ± F shows a manageable safety profile with encouraging duration of antitumoral activity in heavily pre-treated pts with HER2+/PIK3CAmut a/m BC. Recruitment for CE is open."

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

B-PRECISE-01 Study:A Phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer. (ASCO 2019) - P1; "The enrollment began in July 2018 at European sites and US sites will shortly participate; up to date the first dose cohort level has been achieved. Clinical trial information: NCT03767335"

P1 data

[VIRTUAL] Results of the phase Ib dose escalation study of MEN1611, a PI3K inhibitor, combined with trastuzumab (T) ± fulvestrant (F) for HER2+/PIK3CA mutant (mut) advanced or metastatic (a/m) breast cancer (BC) (ESMO 2020) - P1 | "Funding: Menarini Ricerche S.p.A. Clinical trial identification: NCT03767335."

P1 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

[VIRTUAL] C-PRECISE-01 study: A phase Ib/II trial of MEN1611, a PI3K inhibitor, and cetuximab in patients with PIK3CA mutated metastatic colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens (ESMO-GI 2020) - "Legal entity responsible for the study Menarini Ricerche S.p.A. Funding The trial is supported by Menarini Ricerche S.p.A."

Clinical • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • PIK3CA