The OP-1250 is fast-track designated by the FDA for patients with ER+/HER2-metastatic breast cancer

Female breast cancer is the world's most common cancer, with 2.
3 million women developing breast cancer in 2020, including 685,000 deaths
.
The number of female breast cancer incidence and death in China ranks first
in the world.

Depending on the type of pathology, the corresponding treatment plan for breast cancer is also different
.
Among them, ER+/HER2- breast cancer is a common type
of breast cancer.

Endocrine therapy is the preferred therapy for ER+/HER2-breast cancer patients, and the only CERAN/SERD drug fulvestrant currently has the disadvantages of inconvenient administration (intramuscular injection), insufficient drug exposure (unable to achieve the maximum effective exposure), and poor efficacy of ESR1 mutations, and poor compliance, and the urgent need for a new generation of drugs
.

Recently, the US FDA granted the new anti-cancer drug OP-1250 fast-track designation for the treatment of ER-positive, HER2-negative patients with metastatic breast cancer (mBC).

These patients progressed
after prior endocrine therapy (at least one therapy combined with a CDK4/6 inhibitor).

OP-1250 is an oral small molecule drug with both complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) activities, which can effectively and completely inhibit the activity of ER (AF1 and AF2 transcriptional activation domains), block ER-driven transcriptional activity, inhibit ER-driven breast cancer cell growth, and induce ER degradation
.

To continue evaluating OP-1250's potential in hormone receptor (HR)-positive, HER2-negative MBCs, two clinical trials of the drug are ongoing
.

(1) OP-1250 is being studied as a single drug in a Phase 1/2 clinical trial (NCT04505826);

(2) Treatment of patients with recurrent, locally advanced or metastatic ER-positive, HER2-negative breast cancer in combination with Ibrance in
a phase 1b trial (NCT35266105).

Phase 1/2 trial refers to the maximum tolerated dose of OP-1250 under study, and Phase 1b is designed to determine the incidence of dose-limiting toxicity, characteristics and incidence of adverse events and serious adverse events, and plasma levels
of OP-1250 and Ibrance.

Published clinical trial data

Of the 24 patients with evaluable efficacy, 3 experienced partial remission and up to 100% reduction
in target lesion volume.

Among all doses, the objective response rate (ORR) was 8% and the clinical benefit rate (CBR) was 29%.

Within the recommended phase II dose range, the ORR is 17% and the CBR is 46%.

As of the data cut-off, 32% of patients are still receiving treatment, and efficacy data are still improving
.

The open-label, multicenter phase 1/2 study enrolled a total of 68 patients
diagnosed with recurrent, locally advanced, or metastatic ER-positive HER2-negative breast cancer.
The researchers assigned patients to receive either 60 mg or 120 mg orally OP-1250
once daily.

A total of 69% of patients received 2 or more prior treatments, 32% received prior chemotherapy, 96% received CDK4/6 inhibitors, and 65% received fulvestrant (Faslodex).

Circulating tumor DNA was evaluated in 46 patients, 59% of whom had an activated ESR1 mutation
at baseline.

The primary endpoint of the study was to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D)
for OP-1250 monotherapy.

If a patient has an ECOG fitness status of 0 or 1, they are eligible to participate in the study
.
Other inclusion criteria included no endocrine therapy more than 2 weeks prior to the first dose, as well as prior treatment with fulvestrant, chemotherapy, antibody therapy, or investigational therapy 4 weeks or less prior to the first dose of OP-1250, and adequate liver and kidney function
.

Based on high oral bioavailability and dose-proportional exposure, OP-1250 has demonstrated good pharmacokinetics
in studies.
In addition, the overall pharmacokinetics, tolerability, and efficacy of OP-1250 supported the selection of 120 mg per day of RP2D, exceeding the target efficacy threshold
for preclinical models.

Dose-limiting toxicity
was not observed in patients treated with OP-1250, regardless of dose level.
The most common treatment-related adverse reactions (TRAEs) occurring in 15% or more of patients included nausea (42%), fatigue (25%), and vomiting (15%)
.
One patient presents with grade 3 neutropenia with disease progression
.
In addition, in the 120 mg cohort, 3 patients developed grade 4 neutropenia, although these events are uncommon and are controllable and reversible
.
Of these patients, 1 patient confirmed a response after interrupting the 1-week dose before restarting 60 mg of therapy with no further neutropenia
.
In addition, 2 other patients discontinued treatment
after neutrophil recovery.

Presented
at the 34th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium in Barcelona, Spain.
In 2 dose groups, the study reported 6 partial responses (PRs)
per RECIST criterion in 57 evaluable patients with measurable lesions and at least 1 in-treatment tumor assessment.
Of these responses, 4 have been confirmed and 2 need to be confirmed
by subsequent scans.
A total of 41% of patients experienced a reduction in target lesions and demonstrated antitumor activity
at both doses of wild-type and mutant ER.

"The results we present today from the single-agent dose expansion study further validate our belief
that OP-1250 has the potential to be the endocrine therapy of choice for [ER-positive] breast cancer.
" OP-1250 has a compelling CERAN/SERD profile because it is well tolerated, enables high drug exposure, and shows encouraging efficacy in wild-type and ESR1-mutant tumors," said
Sean P.
Bohen, M.
D.
, President and CEO of Olema Oncology.
"Our mission is to change the treatment landscape for breast cancer and develop therapies
that have the potential to improve outcomes for women with cancer.
" We believe in the potential of OP-1250 and we look forward to launching our first pivotal Phase 3 trial
by the middle of next year.
" ”

Resources:

Olema Oncology announces complete ER antagonist OP-1250 continues to demonstrate robust activity in phase 1/2 clinical trial.
News release.
Olema Oncology.
October 26, 2022.
Accessed October 28, 2022.
http://bit.
ly/3TLm3u3