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Novel Strategies Show Winning Potential in Ovarian Cancer

— High response rates in small studies of immuno-oncology combination, neoadjuvant olaparib

Ƶ MedicalToday

TAMPA, Fla. -- Adding a T-cell primer to a PD-1 inhibitor led to objective responses in a third of patients with recurrent platinum-refractory/resistant ovarian cancer enrolled in a small preliminary study.

Eight of 24 patients had objective responses, including one complete response, to the investigational combination of botensilimab and balstilimab. Two-thirds of the patients derived clinical benefit, and a majority had some degree of tumor reduction.

Grade 3/4 toxicity, primarily gastrointestinal, occurred in 10 of the 24 patients, but the overall safety profile was manageable, reported Bruno Bockorny, MD, of Beth Israel Deaconess Hospital in Boston, at the Society of Gynecologic Oncology (SGO) meeting.

"Botensilimab is a multi-functional CTLA-4 antibody with the ability to enhance T-cell priming, memory formation in the APCs [antigen-presenting cells], and suppression of the immunosuppressive T-regulatory cells," said Bockorny. "This combination has demonstrated deep and durable responses in a heavily pretreated population of platinum-resistant/refractory ovarian cancer. The safety profile is manageable and [toxicity] resolves with treatment."

The ongoing phase Ia/b trial continues to accrue patients with ovarian and endometrial cancer, he added.

A second small trial of a novel treatment strategy showed that 100% of patients had optimal surgical debulking following neoadjuvant olaparib (Lynparza) for newly diagnosed BRCA-mutant ovarian cancer, reported Shannon Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Priming the Immune System

Botensilimab was designed specifically to extend the reach of immunotherapy to patients with immunologically "cold" and immuno-oncology-refractory tumors, said Bockorny. The immune-priming effects have been demonstrated in studies involving more than 300 patients. Balstilimab has demonstrated safety and efficacy similar to approved anti-PD-1 monoclonal antibodies in studies involving more than 750 patients.

Bockorny reported findings from the first-in-human study of the combined therapies. Eligible patients had metastatic platinum-resistant/refractory ovarian cancer, a condition for which immunotherapy has had limited success. Previous treatment with immuno-oncology drugs was allowed, including crossover from single-agent botensilimab.

The 24 patients included in data analysis had received a median of four prior lines of therapy, including bevacizumab (Avastin) in 19 cases. Five patients had prior exposure to immuno-oncology treatment. Nineteen of the patients had high-grade serous ovarian cancer. Two patients had BRCA-mutated disease, and seven tested positive for PD-L1 expression. All patients had microsatellite-stable tumors.

The results showed one complete response, seven partial responses, and eight patients with stable disease, resulting in a disease control rate of 67%. Median duration of response had yet to be reached after a brief median follow-up of 6.9 months, but several patients had responses lasting 48 weeks or longer.

With regard to safety, 11 of 24 patients had immune-related diarrhea/colitis, which reached grade 3 severity in five patients. Other common all-grade treatment-related adverse events were nausea (33%), vomiting (17%), fatigue (38%), pyrexia (25%), rash (33%), pruritus (33%), and arthralgia (21%). No treatment-related pneumonitis, hypophysitis, or myocarditis occurred, and there were no treatment-related deaths.

"The combination of botensilimab and balstilimab in platinum-resistant ovarian cancer shows promise for a substantial improvement in efficacy compared to existing therapies, which typically only yield single-digit response rates," Bockorny said in a . "The remarkable efficacy and manageable tolerability profile of this combination suggest a transformative potential for ovarian cancer patients."

Neoadjuvant PARP Inhibition

PARP inhibitors, led by olaparib, the first approved agent in the class, have reached front-line status as maintenance therapy for ovarian cancer, having the greatest impact on tumors with biomarkers, Westin noted in the introduction to the study data. Among various trials exploring the potential for earlier use of PARP inhibitors, a study assessed the impact of single-agent PARP inhibition in the time window between laparoscopic assessment and tumor-reductive surgery for newly diagnosed ovarian cancer.

"After only 7 to 10 days of PARP inhibitor therapy, we saw clear target engagement in matched-pair tumor sites," said Westin. "Further, we saw an intriguing fall in CA-125 levels."

The findings were consistent with those seen in an of neoadjuvant PARP inhibition in BRCA-mutant breast cancer, which showed an 88% reduction in tumor volume after 2 months of treatment.

The study of neoadjuvant olaparib in ovarian cancer involved patients with newly diagnosed BRCA1/2, RAD51C/D, or PALB2-mutant, high-grade serous tumors. Eligible patients received olaparib for two 28-day cycles. If response assessment showed the tumors amenable to surgery, patients went directly to surgery. If the assessment showed the tumor was not amenable to surgery, patients received chemotherapy, followed by tumor adaptive surgery, if possible.

Genetic testing for 51 patients revealed the presence of a mutation in 20. One patient each had RAD51C and PALB2 mutations, and the rest had BRCA mutations. Subsequently, 15 patients received neoadjuvant olaparib, followed immediately by surgery in 13 cases, and interval surgery after chemotherapy in one case.

Among 13 patients with measurable disease, seven (53.8%) had partial responses and six had stable disease. Of the 14 patients who underwent debulking surgery, 12 had no residual gross disease after surgery and the remaining two had less than 1 cm of residual disease.

Consistent with the prior window-of-opportunity study, 14 of 15 patients who received neoadjuvant olaparib had at least a 25% reduction in the CA-125 cancer biomarker. The median decrease from baseline was 81%, and three-fourths of patients had a 75% decrease.

After a median follow-up of 11.7 months, the 12-month progression-free survival rate was 81%.

The most common adverse events (AEs) were abdominal pain (five patients), constipation (four), and anemia (three). Grade 3/4 AEs consisted of the three cases of anemia.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The botensilimab-balstilimab study was supported by Agenus.

Bockorny disclosed relationships with Blueprint Medicines, BiolineRx, Agenus, and NanoView Biosciences.

The olaparib study was sponsored by the University of Texas MD Anderson Cancer Center in collaboration with the NCI.

Westin disclosed relationships with AstraZeneca, Avenge Bio, Bayer, Clovis Oncology, GlaxoSmithKline, Mereo, Novartis, Roche/Genentech, Zentalis, Caris, Eisai, EQRx, ImmunoGen, Lilly, Merck, Mersana, NGM Bio, Nuvectis, Seagen, and Vincerx.

Primary Source

Society of Gynecologic Oncology

Bockorny B, et al "Botensilimab, a novel innate/adaptive immune activator, plus balstilimab anti-PD1 in patients with recurrent platinum refractory/resistant ovarian cancer" SGO 2023; Plenary presentation.

Secondary Source

Society of Gynecologic Oncology

Westin S, et al "NOW: Neoadjuvant Olaparib Window trial in newly diagnosed BRCA-mutant ovarian cancer" SGO 2023; Plenary presentation.