MEN1611

P1, N=62, Completed, Menarini Group | Active, not recruiting --> Completed

P1/2, N=29, Completed, Menarini Group | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Feb 2024 | Trial primary completion date: Jun 2024 --> Jan 2024

P1/2, N=29, Active, not recruiting, Menarini Group | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

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.

P1/2, N=29, Active, not recruiting, Menarini Group | N=42 --> 29

P2, N=28, Recruiting, MedSIR | Not yet recruiting --> Recruiting

P1, N=62, Active, not recruiting, Menarini Group | Trial completion date: Jul 2022 --> Dec 2023 | Trial primary completion date: Jul 2022 --> Dec 2023

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).

P1/2, N=42, Active, not recruiting, Menarini Group | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Oct 2023 | Trial primary completion date: Jul 2023 --> Oct 2023

P2, N=28, Not yet recruiting, MedSIR

"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."

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.

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 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.

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.

P1, N=62, Active, not recruiting, Menarini Group | Recruiting --> Active, not recruiting

Thus, PI3K/AKT/mTOR pathway activation contributes to Ptch1/Tis21 MB development and to high frequency tumorigenesis, observed when the Tis21 gene is down-regulated. MEN1611 could provide a promising therapy for MB, especially for patient with down-regulation of Btg2 (human ortholog of the murine Tis21 gene), which is frequently deregulated in Shh-type MBs.

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).

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.

P1, N=48, Recruiting, Menarini Group | Trial completion date: Jul 2020 --> Jul 2022 | Trial primary completion date: Jul 2020 --> Jul 2022

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).

P1/2, N=42, Recruiting, Menarini Group | Not yet recruiting --> Recruiting

P1/2, N=42, Not yet recruiting, Menarini Group

Funding: Menarini Ricerche S.p.A. Clinical trial identification: NCT03767335.