High Response Rates in Platinum-Resistant Ovarian Cancer With Immunotherapy Agents

SAN JUAN, Puerto Rico — Two inhibitors of the same immune checkpoint family produced high response rates and evidence of durability in preliminary studies of advanced gynecologic cancers.

Patients with platinum-resistant ovarian cancer (PROC) had dose-dependent objective response rates as high as 62% with the antibody-drug conjugate (ADC) mocertatug rezetecan targeting B7-H4, and response rates topped out at 67% for two small cohorts of patients with advanced endometrial cancer. The B7-H3 inhibitor SYS6043 achieved disease control in 80-90% of patients with advanced ovarian, endometrial, or cervical cancer.

Both therapies exhibited “manageable” safety profiles, according to reports at the Society of Gynecologic Oncology (SGO) meeting.

The BEHOLD-1 trial of mocertatug rezetecan confirmed the near-universal expression of B7-H4 by gynecologic cancers, as 95% of patients with PROC and endometrial cancers demonstrated varying levels of expression, said Ana Oaknin, MD, PhD, of Hospital Universitario Puerta de Hierro Majadahonda in Spain. Across three dose levels, objective responses occurred in 31-62% of 103 efficacy-evaluable patients with previously treated PROC and in 9% and 67% of 23 patients with advanced endometrial cancer who received either of two dose levels.

Grade ≥3 treatment-related adverse events (TRAEs) also were dose-related, including 28 of 44 evaluable patients with PROC treated with the highest dose (5.8 mg/kg) and 13 of 24 patients with advanced endometrial cancer treated with 4.8 mg/kg. The most common any-grade TRAEs were gastrointestinal in nature, most of which were low grade. The most common grade ≥3 TRAEs were neutropenia and anemia.

Four patients (two each with PROC and endometrial cancer) discontinued treatment because of TRAEs. No fatal TRAEs occurred in any cohort.

On the basis of the results, two global phase III trials will continue evaluation of the 5.8 mg/kg dose of mocertatug rezetecan, one each in PROC and advanced endometrial cancer.

B7-H3 also is overexpressed in a wide range of solid tumors and often correlates with poor prognosis. The ADC SYS6043 has demonstrated potent antitumor activity against multiple tumor cell lines that express B7-H3, said Jing Zuo, MD, of Peking Union Medical College in Beijing.

Zuo reported initial findings from a multicenter, first-in-human trial of SYS6043 in advanced ovarian (n=73), cervical (n=47), or endometrial (N=22) cancer. The safety analysis showed grade ≥3 TRAEs in 38% of patients, including 34.3% of 70 patients treated with the recommended phase II dose (RP2D). One fatal TRAE occurred and two patients discontinued treatment because of TRAEs. Hematologic TRAEs were most common, as about half patients treated with the RP2D developed anemia, decreased white blood cells, and decreased neutrophils (all grades).

In 70 efficacy-evaluable patients with ovarian cancer, 32 (45.7%) achieved partial responses and 30 (42.9%) had stable disease, resulting in a disease control rate (DCR) of 88.6%. Responses occurred in B7-H3-positive and negative tumors, said Zuo. The highest response rate occurred in B7-H3-positive high-grade serous ovarian cancers, with a DCR of 90.7%, including partial responses in 24 of 43 (55.8%) patients. Median PFS was 8.3 months.

The DCR in 21 efficacy-evaluable endometrial cancers was 81.0%, including partial responses in seven patients. Median PFS was 8.0 months. In 39 evaluable patients with cervical cancer, 14 achieved partial responses and 18 had stable disease, resulting in a DCR of 82.1%. Median PFS was 5.8 months.

Activity in TP53-Mutated Ovarian Cancer

The p53 reactivator rezatapopt led to objective responses in 32 of 72 (44.4%) evaluable patients with previously treated ovarian cancer, and another 23 (31.9%) patients had stable disease, reported Alison M. Schram, MD, of Memorial Sloan Kettering Cancer Center in New York City. The cohort had a median response duration of 8.2 months.

Response rates were similar in subgroups of patients with platinum-resistant (45.5%) and platinum-refractory (44.0%) disease, prior bevacizumab treatment (43.9%), prior exposure to a PARP inhibitor (52.6%), and folate receptor-alpha positive (50.0%) and negative disease (41.9%). Some degree of tumor shrinkage occurred in 53 of 63 evaluable patients.

Single-agent rezatapopt was generally well tolerated, as most adverse events (AEs) were grade 1 or 2, said Schram. The most common AEs of any grade were nausea (41.8%, no grade 3/4); fatigue (25.5%); increased blood creatinine (22.0%); increased alanine aminotransferase and aspartate aminotransferase, anemia (18.4% each); and vomiting (17.0%). Four patients discontinued treatment because of AEs.

TP53 Y220C is a key “hotspot” missense mutation occurring in about 3.1% of all ovarian cancers and 3.6% of high-grade serous ovarian cancers. Rezatapopt stabilizes mutated p53 Y220C protein to restore p53 tumor suppressor function, Schram noted.

The pivotal phase II PYNNACLE trial evaluated rezatapopt in a basket trial that included a cohort of patients with heavily pretreated ovarian cancer. More than half of the patients had received four or more prior therapies for ovarian cancer. Indicative of rezatapopt’s on-target activity, 52 of 55 evaluable patients had a reduction in TP53 Y220C variant allele frequency, reaching 50% or greater in 85% of the patients.

Perfect Response Rate in Gestational Trophoblastic Neoplasia

Adding two novel agents to chemotherapy led to complete responses in all 34 patients who completed treatment for gestational trophoblastic neoplasia (GTN) in a prospective, single-arm, phase II trial conducted in China.

The only patient who did not achieve a complete response with camrelizumab, apatinib (also known as rivoceranib), and chemotherapy did not complete treatment but had a partial response when lost to follow-up, reported Fang Jiang, MD, PhD, of Peking Union Medical College.

After a median follow-up of 2 years, median PFS had yet to be reached. PFS at 1, 2, and 3 years was 97%, 84%, and 84%, respectively. Four patients relapsed, three of whom responded to salvage chemotherapy plus surgery. No patient has died to date.

The chemotherapy-containing induction phase of treatment led to high rates of grade 3/4 hematologic toxicity, including neutropenia (91.4%), leukopenia (77.1%), anemia (40.0%), and thrombocytopenia (71.4%). During maintenance therapy with camrelizumab and apatinib, grade 3/4 toxicity was uncommon (four of 34 patients).

The rationale for the regimen included recognition that GTN frequently responds to chemotherapy, but relapse and resistance remain major challenges, said Jiang. A prior study of the anti-PD1 antibody camrelizumab and the VEGF receptor inhibitor apatinib showed complete responses in 50% of patients. Data from a retrospective cohort study suggested that PD-1 inhibition plus chemotherapy might improve efficacy versus anti-PD-1 therapy alone.

Earlier this year, Elevar Therapeutics announced the FDA had accepted for integrated review a resubmitted New Drug Application (NDA) for rivoceranib and camrelizumab (submitted by Hengrui Pharma) for unresectable hepatocellular carcinoma. The FDA had responded to the initial NDA with a Complete Response Letter seeking additional information.