LY4170156 was well tolerated and generated promising efficacy data in patients with recurrent, platinum- resistant high-grade serous ovarian cancer.
The antibody-drug conjugate (ADC) LY4170156 was well tolerated and demonstrated promising antitumor activity in patients with recurrent, platinum-resistant high-grade serous ovarian cancer (HGSOC), according to data from a phase 1 study (NCT06400472) presented at the
Findings showed that no patients with recurrent, platinum-resistant HGSOC and other select metastatic and advanced solid tumors who were treated with LY4170156 at any dose level (n = 105) experienced grade 3 or higher treatment-related ocular toxicities, neuropathy, or alopecia. Nausea was the most common treatment-emergent adverse effect (TEAE) across all dosage levels, occurring in 64% of patients at any grade. Fatigue, anemia, and vomiting were the next most common TEAEs, occurring at rates of 53%, 39%, and 36% in all patients. Moreover, grade 3 or higher anemia, nausea, fatigue, and vomiting were observed in 25%, 3%, 2%, and 2% of patients, respectively.
Grade 4 neutropenia was observed in 8% of patients, and 2% experienced febrile neutropenia. Fifty patients are in ongoing treatment; 12 patients discontinued treatment due to adverse effects, and 26% of all patients had dose reductions due to TEAEs.
Regarding efficacy, patients who were efficacy evaluable (n = 104) achieved an overall response rate (ORR) of 50% (n = 52), including 4 patients with complete responses (CRs) and 48 with partial responses (PRs). Additionally, patients achieved a disease control rate (DCR) of 78% (n = 81). Out of patients who responded, 73% (n = 38) are still in ongoing treatment, and 14 have discontinued treatment, 6 of which were due to progressive disease.
“LY4170156 was well tolerated among patients with platinum-resistant ovarian cancer [PROC] with promising clinical activity across all folate receptor alpha [FRα] expression levels and regardless of prior mirvetuximab soravtansine-gynx [Elahere] treatment,” lead study author Isabelle Ray-Coquard, MD, PhD, said in a presentation of the data.
Ray-Coquard is an oncologist at Centre Léon Bérard and a professor of medicine at Université Claude Bernard Lyon I in Lyon, France.
Investigators sought to explore FRα-specific ADCs, such as LY4170156, in recurrent, platinum-resistant HGSOC, given the success of other FRα-specific ADCs in different types of ovarian cancer.
The first-in-human, open-label, randomized trial enrolled patients who were at least 18 years of age and diagnosed with PROC in addition to other select metastatic and advanced solid tumors. Patients also needed to have an ECOG performance status of 0 or 1, and those who had progressed on prior mirvetuximab soravtansine remained eligible.
Patients who had known or suspected uncontrolled central nervous system metastases, a history of carcinomatous meningitis, active uncontrolled infections, evidence of corneal keratopathy, a history of corneal transplant, or significant cardiovascular disease were not included in the study.
The study used an mTPI-2 dose-escalation design across the following dose levels: 2 mg/kg (n = 35), 3 mg/kg (n = 17), 4 mg/kg (n = 39), and 6 mg/kg (n = 14). All patients received intravenous LY4170156 once every 3-week cycle.
The primary end points of the study were safety, pharmacokinetics, determination of the recommended phase 2 dose, and antitumor activity per RECIST 1.1 criteria.
Baseline characteristics revealed that patients had a median age of 63 years (range, 40-89) and that most were White (65%; n = 68). Over half the patients had an ECOG performance status of 1 (64%; n = 67) vs 0 (36%; n = 38). Regarding histology, nearly all patients had serous histology (92%; n = 97), followed by endometrioid (3%; n = 3), carcinosarcoma (1%; n = 1), and other histologies (4%; n = 4). Most patients had less than 75% FRα expression at 2+ and/or 3+ intensity per immunohistochemistry (IHC) testing (51%; n = 54), while slightly fewer had 75% or higher FRα expression at 2+ and/or 3+ intensity per central IHC testing (44%; n = 46). Patients had received a median of 5 prior systemic regimens (range, 1-11), and 96% (n = 101) had platinum-resistant disease.
Safety data at each dose level followed similar trends to those found in all patients, with nausea being the most common TEAE at each dose level, occurring at rates of 60%, 47%, 69%, and 79% in the 2 mg/kg, 3 mg/kg, 4 mg/kg, and 6 mg/kg cohorts, respectively. Fatigue was the next most common TEAE at each dose level, with rates of 60%, 41%, 46%, and 71%, respectively. However, TEAEs such as anemia were more common at the higher dose levels of 3 mg/kg (41%), 4 mg/kg (44%), and 6 mg/kg (71%) than at the lowest dose level of 2 mg/kg (20%). Additionally, TEAEs such as abdominal pain were more common at 2 mg/kg (43%) vs 3 mg/kg (6%), 4 mg/kg (23%), and 6 mg/kg (14%). No patients who received LY4170156 at 2 mg/kg required a dose reduction due to TEAEs, whereas 24%, 36%, and 64% of patients did at the other respective dose levels.
Response rates were also evaluated by level of FRα expression and comprised patients with up to 24% FRα expression (n = 25), expression that ranged from 25% to 49% (n = 12), expression that ranged from 50% to 74% (n = 16), expression that was 75% or higher (n = 46), and patients with pending FRα information (n = 5). ORRs of 40% (n = 10), 50% (n = 6), 50% (n = 8), 54% (n = 25), and 60% (n = 3) were achieved for each subgroup, respectively. PRs were achieved by 10, 6, 7, 22, and 3 patients in each FRα expression subgroup, respectively. One patient achieved a CR in the 50% to 74% FRα expression subgroup, as did 3 patients in the 75% or higher FRα expression subgroup; no patients achieved such a response in the other subgroups. DCRs occurred at respective rates of 68% (n = 17), 83% (n = 10), 81% (n = 13), 83% (n = 38), and 60% (n = 3) for each subgroup.
The two-part phase 3 FRAmework-01 study (NCT07213804) will evaluate the efficacy of LY4170156 monotherapy in patients with PROC and in combination with bevacizumab (Avastin) in patients with platinum-sensitive ovarian cancer.3 The multicenter study is currently recruiting patients and is expected to be completed in August 2031.
