OP-1250 Plus Palbociclib Demonstrates Activity, Safety in HR+/HER2– Metastatic Breast Cancer

The combination of the oral complete estrogen receptor (ER) antagonist OP-1250 and palbociclib (Ibrance) produced a tolerable safety profile and elicited tumor responses and disease stabilization in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to data from the phase 1b/2 OP-1250-002 trial (NCT05266105) presented at the 2023 ESMO Breast Cancer Annual Congress.¹

Findings showed that no dose-limiting toxicities were observed during the dose-escalation portion of the trial. Most treatment-emergent adverse effects (TEAEs) were grade 1/2, and no dose-related increases in incidence or severity of TEAEs were reported. No patients discontinued treatment due to TEAEs.

Additionally, among treated patients (n = 29), 1 patient achieved a confirmed partial response (PR), and 4 patients experienced an unconfirmed PR. Nine patients had stable disease, including 4 who had stable disease for at least 24 weeks. The clinical benefit rate was 41.7% (n = 5/12). The longest duration of treatment was 56 weeks, and that patient was ongoing treatment at data cutoff. Treatment was ongoing in 17 patients (59%).

“The combination of OP-1250 at 30 to 120 mg with 125 mg of palbociclib was safe and well tolerated; no new safety signals were identified,” lead study author Arlene Chan, MD, a medical oncologist at the Hollywood Private Hospital, in Nedlands, Australia, and colleagues, wrote in a poster presentation of the data.

Although CDK4/6 inhibitors are standard of care in the first-line setting for patients with HR-positive advanced or metastatic breast cancer, resistance to these agents eventually develops, most commonly due to acquired ESR1 mutations.

OP-1250 is a complete ER antagonist and a selective ER degrade designed to block the AF1 and AF2 transcriptional activation domains of ER. In preclinical studies, it demonstrated activity in ESR1-mutant and ESR1–wild-type models.

In a phase 1/2 trial (NCT04505826) evaluating OP-1250 monotherapy, data showed that the agent had an acceptable safety profile and elicited objective tumor responses and stable disease in heavily pretreated patients with HR-positive, HER2-negative advanced or metastatic breast cancer.²

Previous findings from the OP-1250-002 trial established the recommended phase 2 dose (RP2D) of OP-1250 at 120 mg. The presentation at the 2023 ESMO Breast Cancer Annual Congress included updated data on combination’s pharmacokinetics (PK) profile, drug-to-drug interaction, safety, and antitumor activity.

The study is enrolling patients with HR-positive, HER2-negative advanced or metastatic breast cancer, irrespective of menopausal status, who have received no more than 1 prior endocrine therapy with or without a CDK4/6 inhibitor for locally advanced or metastatic disease. Additionally, 1 prior line of chemotherapy is allowed in the advanced or metastatic setting. Patients need to have evaluable disease per RECIST v1.1 criteria. The study plans to enroll 45 total patients.

In dose escalation, patients received OP-1250 at 30 mg, 60 mg, 90 mg, or 120 mg in combination with 125 mg of palbociclib once daily on days 1 to 21 of the 28-day cycle. In dose expansion, patients are receiving 120 mg of OP-1250 with 125 mg of palbociclib.

The primary end points of the dose escalation were to determine the maximum-tolerated dose and the RP2D, as well as evaluate safety, tolerability, and PK. Secondary end points included overall response rate (ORR) and clinical benefit rate. The primary end points of dose escalation are safety, tolerability, and PK at the RP2D. Secondary end points include ORR and clinical benefit rate.

As of the March 8, 2023, data cutoff, 29 patients had enrolled. The median age was 65 years (range, 46-76), and 97% were female. Seven percent of patients were premenopausal. Furthermore, 66% of patients had an ECOG performance status of 0, and 35% had a performance status of 1. Additionally, 79% of patients had measurable disease at baseline. Visceral disease of the liver, lung, peritoneum, pleura, and ascites was reported in 52% of patients. Furthermore, 7%, 69%, and 24% of patients had 0, 1, and 2 prior lines of therapy for advanced disease, respectively. Eighty-three percent of patients received 1 prior line of endocrine therapy.

Prior therapy for advanced disease included a CDK4/6 inhibitor (69%), aromatase inhibitor (72%), fulvestrant (Faslodex; 10%), and chemotherapy (21%). Additionally, 44% of evaluable patients (n = 8/18) had ESR1 mutations at baseline, based on circulating tumor DNA analysis.

Among the 12 patients to discontinue treatment, 10 were due to disease progression, 1 stopped due to physician decision, and 1 withdrew due to patient decision.

Across all doses of OP-1250, the most common TEAEs reported in at least 20% of patients included neutropenia (any grade, 66%; grade ≥3, 55%), nausea (48%; 0%), vomiting (28%; 0%), constipation (21%; 0%), diarrhea (21%; 0%), gastroesophageal reflux disease (21%; 0%), and thrombocytopenia (21%; 0%).

Specifically, 48% of patients (n = 14) had grade 3 neutropenia, and all instances occurred during the first treatment cycle. These AEs were assessed as related to palbociclib in all patients and possibly related to OP-1250 in 6 patients. Seven percent of patients (n = 2) had grade 4 neutropenia, and onset for both instances was week 4. One instance of grade 4 neutropenia was deemed related to palbociclib, and the other was related to palbociclib and possibly related to OP-1250. Six patients required dose reductions of palbociclib due to neutropenia, but no patients needed OP-1250 dose reductions due to the AE. All instances of neutropenia were reversible, and the timing was consistent with palbociclib-related neutropenia.

Five patients experienced serious AEs, including grade 2 malignant pleural effusion in 1 patient, grade 3 colitis in 1 patient, grade 4 neutropenia in 2 patients, and grade 3 multiple organ dysfunction syndrome in 1 patient. Outside of one instance of grade 4 neutropenia that was possibly related to OP-1250, the other 4 serious AEs were deemed unrelated to OP-1250.

Additionally, OP-1250 did not affect palbociclib at 125 mg, and the geometric parameters of palbociclib for each of the combination dose levels were recorded to be in geometric mean. Moreover, palbociclib did not affect the use of OP-1250, and steady state plasma levels showed minimal peak-to-trough variability.

References

1. Chan A, Dinh P, Day D, et al. A phase 1b/2 study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) with palbociclib in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer (MBC). Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 202P.
2. Hamilton E, Alemany C, Lin NU, et al. A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer. Cancer Res. 2021;81(suppl 4):OT-09-10. doi:10.1158/1538-7445.SABCS20-OT-09-10