P53 Antagonist Shows Early Activity in Advanced Liposarcoma

CHICAGO — Almost 90% of patients with metastatic liposarcoma achieved disease control with an investigational drug targeting p53 suppression, according to an early study reported at the American Society of Clinical Oncology (ASCO) annual meeting.

The results showed that 24 of 32 patients with de-differentiated liposarcoma and MDM2 amplification had stable disease and four other patients had partial responses for a disease control rate of 87.5% in response to BI 907828, an MDM2-p53 antagonist. Additionally, all 15 patients with well-differentiated liposarcoma (normally a surgically managed disease) had disease control, including four partial responses.

In a safety cohort of 48 patients, the most common grade 3/4 treatment-related adverse events (TRAE) were neutropenia (n=10 patients), thrombocytopenia (n=9), anemia (n=5), and nausea (n=3), reported Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York City.

P53 is inactivated by missense mutations in more than half of all cancers, facilitating evasion of cell-cycle arrest and apoptosis. Overexpression of MDM2 protein is a potential inactivator of p53. Additionally, MDM2 amplification occurs across all tumor types, suggesting amplification/copy number gain is another potential mechanism by which MDM2 inactivates p53, said Gounder.

Standard of care for advanced sarcomas includes chemotherapy, tyrosine kinase inhibitors, trabectedin, and eribulin, all of which are associated with low response rates and a median overall survival of 11-20 months. In particular, systemic therapy for de-differentiated liposarcoma has limited activity, said Gounder.

Orally available BI 907828 demonstrated antitumor activity in de-differentiated liposarcoma xenografts, providing support for a phase I trial in patients with advanced solid tumors. The first 96 patients enrolled included 49 patients with advanced liposarcoma. The dose-expansion phase continues, and enrollment has begun in a phase II/III randomized comparison against doxorubicin as initial therapy for de-differentiated liposarcoma.

Antibody-Drug Conjugate Active in mCRPC

Almost half of patients with metastatic castration-resistant prostate cancer (mCRPC) had a PSA response when treated with an antibody-drug conjugate (ADC) targeting CD46 antigen, a phase I study showed.

Fourteen of 31 (45%) evaluable patients had at least a 50% reduction in baseline PSA level, and 10 of 21 (48%) patients evaluable for objective response had some degree of tumor regression, including four partial responses. Median duration of response exceeded 14 weeks and range of duration exceeded 31 weeks, reported Rahul Aggarwal, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

The ADC FOR56 consists of a fully human antibody linked with monomethyl auristatin E and targets a tumor-selective epitope of CD46, which is highly expressed in mCRPC. The epitope is accessible on tumor cells but appears to be less accessible or not fully formed on normal cells, said Aggarwal. Internalization is tumor selective.

Preclinical studies showed that FOR56 had substantial antitumor activity, providing support for a first-in-human dose-escalation study in mCRPC with expansion cohort. Eligible patients had progressive mCRPC, prior treatment with at least one androgen signaling inhibitor, and no prior taxane treatment for mCRPC.

Study population consisted of 33 patients in the dose-escalation phase and 10 in the dose-expansion phase. Among all 43 patients, the most common (≥20%) TRAEs included neutropenia, infusion-related reaction, neuropathy, diarrhea, fatigue, nausea, decreased appetite, and alopecia. Grade 3/4 neutropenia occurred in 23 patients but no other grade 3/4 TRAEs occurred in more than two patients.

Aggarwal said the CD46-targeting antibody might provide a platform for additional drug development, including combinations with androgen receptor-targeted treatment, bispecific T-cell engagers, and targeted radioligand therapy.

Targeting Mutant p53

A third of advanced tumors associated with the “hot spot” p53 Y220C mutation responded to a small-molecule mutation corrector, which achieved disease control in more than 60% of a small cohort.

Among 31 patients who received the highest doses of PC14586, eight had partial responses (two unconfirmed) and 11 others had stable disease. Across all dose cohorts, 23 of 41 patients achieved disease control, reported Ecaterina E. Dumbrava, MD, of the MD Anderson Cancer Center in Houston. Reduction in target lesion size occurred in multiple tumor types, including partial responses in prostate, ovarian, breast, endometrial, pancreatic, and small-cell lung cancer.

TRAEs were generally grade 1/2. At the highest dose levels, the most common grade 3 TRAEs were increased ALT and anemia; one patient had grade 4 immune thrombocytopenia.

TP53 mutations are the most common genomic events in human cancer, including 10 so-called “hot spot” mutations that account for about 30% of all TP53 mutations. The p53 Y220C hot-spot mutation occurs in about 1% of all solid tumors and has a destabilizing effect on p53 protein. PC14586 stabilizes p53 Y220C mutant protein to restore p53 transcription and tumor-suppressor function, said Dumbrava.

Enrollment in the trial will continue at dose levels lower than the maximum tolerated dose to help determine the recommended phase II dosing.