ONCT-216 Shows Encouraging Efficacy, Safety in Relapsed/Refractory Ewing Sarcoma

James Breitmeyer, MD, PhD

The targeted small molecule inhibitor of the E26 transformation-specific family of oncoproteins, ONCT-216 (formerly TK216), produced notable response and disease control rates when delivered at the recommended phase 2 dose (RP2D) to heavily pretreated patients with Ewing sarcoma, according to updated interim findings from a phase 1/2 trial (NCT02657005).^1,2

Results, which were presented during the 2021 Connective Tissue Oncology Society Virtual Annual Meeting, demonstrated that among the 37 patients who received ONCT-216 at the RP2D, the agent induced an overall response rate (ORR) of 8.1%, with a complete response (CR) rate of 5.4% and a partial response (PR) rate of 2.7%. Additionally, 32.4% of patients achieved stable disease and 59.5% experienced progressive disease.

The disease control rate (DCR) was 40.5% with the agent, with a median duration of response (DOR) of 14.7 months (range, 1.1-28.6). The 6-month progression-free survival (PFS) rate was 12.0% (95% CI, 3.9%-25.0%).

Among all 60 patients who received treatment, the ORR with the agent was 5.0%, and this included a CR rate of 3.3% and a PR rate of 1.7%. Moreover, 23.3% of patients achieved stable disease and 71.7% experienced disease progression. The DCR in this population was 28.3%, and the DOR was 14.7 months (range, 1.1-28.6). The PFS rate at 6 months was 7.2% (95% CI, 2.4%-15.8%).

“We remain encouraged by the 2 CRs to ONCT-216 in heavily pretreated patients with relapsed or refractory Ewing sarcoma, including 1 patient who had a durable CR for 24 months on treatment, and remains with no evidence of disease off of all treatments for several months,” James Breitmeyer, MD, PhD, president and chief executive officer of Oncternal Therapeutics, Inc., stated in a press release. “We believe that an intensified dosing schedule, which we are investigating in a new study cohort that is now enrolling, holds promise to address the significant unmet needs for patients suffering from this devastating disease.”

Fusions of the EWS gene and 1 of 5 different ETS transcription factors, such as EWS-FLI1, serve as dominant drivers of Ewing sarcoma. For oncogenic function, binding of EWS-FLI1 to RNA helicase A is critical. ONCT-216 was designed to bind ETS proteins, disturb protein-protein interactions, hinder transcription factor function, and result in the death of these cancer cells.

The phase 1/2 study was designed to establish the initial safety and efficacy of ONCT-216 as a monotherapy and in combination with vincristine in patients with Ewing sarcoma. To be eligible for enrollment, patients needed to have metastatic disease, be at least 8 years of age, and have received 5 or fewer prior systemic therapies.

The phase 1 portion of the trial, parts 1 and 2, has been completed, and the primary dose-limiting toxicity observed with the agent was neutropenia. The maximum tolerated dose for 7-day infusion was established to be 220 mg/m2 daily. Part 3 of the phase 2 portion of the trial enrolled 44 patients, who received the RP2D of the agent, which was 200 mg/m2 daily for a continuous 14-day infection. Vincristine was given at doses ranging from 0.75 mg/m2 to 1.5 mg/m2 on day 1 of each treatment cycle. Part 4 of the trial is now enrolling and will be evaluating ONCT-216 as a monotherapy, at a dose of 175 mg/m2 for 28 days in up to 21 evaluable patients.

The median age among all patients was 26.5 years (range, 11.0-77.0), 63.5% were male, 96.5% had an ECOG performance status of 0 or 1, and the median time from diagnosis to study start was 3.2 years (range, 0.4-18.0). The median number of prior systemic therapies received was 3.0 (range, 1.0-9.0); 78.4% of patients previously underwent surgery, and 81.1% had prior radiotherapy.

Moreover, the majority of patients (98.6%) had metastases at the time of study entry; 9.5% had them in the bone only, 45.9% had them in the lung only, 13.5% had them in the bone and lung only, and 29.7% had then in another location.

Additional data from the trial indicated that among 37 evaluable patients who were heavily pretreated and who had received treatment with ONCT-216 with or without vincristine at the RP2D, a durable treatment effect was observed.

Case Discussions

One patient who was 19 years of age presented with Ewing sarcoma of the clavicle and multiple pulmonary metastases. The patient had a tumor that harbored a EWAR1-FLI1 fusion, previously received ifosfamide/etoposide plus cyclophosphamide, doxorubicin, and vincristine (VDC/IE); underwent surgical resection; and received radiotherapy at 50.4 Gy.

The patient relapsed 1.5 years following initial diagnosis. Multiple recurrences were treatment with whole lung radiation, irinotecan/temozolomide, bevacizumab (Avastin), and pazopanib (Votrient). The patient also had multiple progressing lung metastases at the time of study entry.

This patient was administered ONCT-216 at a daily dose of 200 mg/m2 for 14 to 28 days. Following cycle 2 of treatment without vincristine, the patient experienced regression of all target lesions. At cycle 6, a residual non-target lung lesion was resected. The patient received ONCT-216 plus vincristine for over 2 years on the study, completed treatment, and had no evidence of disease.

Another patient who was 51 years of age presented with Ewing sarcoma of the kidney and several pulmonary metastases. This patient’s tumor harbored a EWSR1 translocation, received prior treatment with VDC/IE, high-dose ifosfamide, and underwent surgical resection. The patient relapsed 1.6 years after they were initially diagnosed. This patient also had multiple progressing lung metastases at the time of study entry.

The patient received ONCT-216 at a daily dose of 200 mg/m2 for 14 cycles plus vincristine at a dose of 0.75 mg/m2 on day 1. At cycle 2, the patient 90% of target lesions regressed; all target lesions regressed by cycle 6. The patient continues to receive treatment with ONCT-216 for longer than 20 months and has not shown evidence of disease. The patient has not received vincristine since month 3.7.

ONCT-216 with or without vincristine was found to have a tolerably toxicity profile. Among all patients who received treatment, 100% experienced an all-grade, treatment-emergent adverse effect; 33.3% were grade 1 or 2 in severity, and 66.7% were grade 3 or higher.

The most common toxicities included anemia (grade 1 or 2, 20.8%; grade 3 or higher, 29.2%), neutropenia (12.5% and 37.5%, respectively), leukopenia (9.7% and 31.9%), fatigue (36.1% and 4.2%), pyrexia (37.5% and 0.0%), alopecia (31.9% and 0.0%), nausea (31.9% and 0.0%), headache (23.6% and 1.4%), thrombocytopenia (11.1% and 11.1%), and constipation (19.4% and 1.4%).

“Myelosuppression is the primary safety observation, which is transient, reversible, and responsive to growth factors,” study author Ravin Ratan, MD, of the University of Texas MD Anderson Cancer Center, said during the presentation on the data.

References

1. Ludwig JA, Federman NC, Anderson PM, et al. TK216 for Ewing sarcoma- interim phase 1/2 results. Presented at: 2021 Connective Tissue Oncology Society Virtual Annual Meeting; November 10-13, 2021; virtual. https://bit.ly/3DQ8Hou
2. Oncternal Therapeutics presented updated interim phase 1/2 clinical trial data for ONCT-216 in patients with relapsed/refractory Ewing sarcoma at CTOS 2021 Virtual Annual Meeting. News release. Oncternal Therapeutics, Inc.; November 15, 2021. Accessed November 23, 2021. https://bit.ly/3FY3ATV