FDA Approves Pembrolizumab for PD-L1-Positive Ovarian Cancer

There have been some new treatments approved for patients with aggressive ovarian cancer. For those fighting a tough to treat form of ovarian cancer, there is some much needed hope as researchers and clinicians continue to work tirelessly to find effective treatment options for women with platinum-resistant ovarian cancer.

Why it matters

Two experimental therapies for ovarian cancer have been approved by the Food and Drug Administration, offering new promise to the hundreds of thousands of women worldwide who get the disease. Ovarian cancer is typically detected late in life, and is usually treated with chemotherapy, which, in most cases, stops working in a year or two as the cancer transforms into an untreatable, advanced stage. The two approved drugs target two specific proteins found in some ovarian cancer tumors, and are intended for patients with these difficult-to-treat cases of cancer. The two drugs are an early example of the kind of more personalized cancer treatments scientists hope to develop.

This review discusses evidence for pembrolizumab (PMB) and pembrolizumab co-formulated with berahyaluronidase alfa (pMBA) given with paclitaxel with or without bevacizumab. This review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative. Project Orbis enables concurrent oncology drug development, submission, and review with international regulatory partners. Collaborating regulatory agencies for this review included the Therapeutic Goods Administration in Australia, Health Canada and the Swissmedic in Switzerland.

New Approval

The FDA granted accelerated approval to pembrolizumab and pembrolizuzmab co-formulated with berahyaluronidase alfa (pmph) Plus paclitaxel, with or without bevacizumab for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, including patients who have received prior therapy. Patients with newly diagnosed advanced ovarian cancer and a positive PD-L1 expression status (Combined Positive Score \[CPS\] ≥1) also are eligible for treatment with the combination. The approvals were based, in part, on overall response rate data from the multicenter, open-label, randomized, active-controlled, Phase 3 KEYNOTE-B96 (ENGOT-ov65) trial, which were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.

Ovarian cancer is considered Platinum-Resistant when the cancer does not respond to platinum-based therapy (chemotherapy) or does not improve or worsen within 6 months of completing platinum-based chemotherapy. Treatment for recurrence differs from treatment for initial diagnosis of Platinum-Resistant ovarian cancer. Patients with Platinum-Resistant ovarian cancer or recurrent ovarian cancer may also be candidates for clinical trials.

KEYNOTE-B96

KEYNOTE-B96 (NCT05116189) is a multicenter, randomized, double-blind, placebo-controlled investigation involving 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and 1 or 2 prior lines of systemic therapy for ovarian cancer. Patients must have received platinum-based chemotherapy for ovarian cancer and have demonstrated disease progression within 6 months of the last dose of platinum-based chemotherapy. Patients will be randomly assigned at screening to one of two treatment regimens: pembrolizumab (200 mg) plus paclitaxel (175 mg/m(2)) with or without bevacizumab (15 mg/kg) or placebo plus paclitaxel with or without bevacizumab.

The major efficacy outcome was progression-free survival (PFS) assessed by investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The KEYNOTE-B96 clinical trial was conducted to evaluate pembrolizumab (KEYTRUDA) plus paclitaxel, with or without bevacizumab, in patients with platinum-resistant recurrent ovarian cancer. In the trial, patients with PD-L1-positive tumors (CPS ≥1), experienced improved progression-free survival (PFS) and overall survival (OS). Pembrolizumab plus paclitaxel with or without bevacizumab demonstrated a statistically significant increase in PFS (28% reduced risk of disease progression or death; median 8.3 months). Pembrolizumab plus paclitaxel with or without bevacizumab also demonstrated a statistically significant increase in overall survival (24% reduced risk of death; median 18.2 months). The trial included 643 patients with platinum-resistant recurrent ovarian cancer, and PD-L1-positive tumors (CPS ≥1) were present in 72% of patients. Patients received prior bevacizumab in 46% of cases, and received bevacizumab in 73% of cases in the trial. The mean platinum-free interval was 2 months (range 0-5 months). Less than 3 months in 47%.

Adverse Reactions

More serious side effects. The following are serious adverse reactions that were observed more often than in the control group in patients receiving KEYTRUDA and paclitaxel with or without bevacizumab (some deaths were also reported): pneumonia (6%), urinary tract infection (3%), adrenal insufficiency (2%), hyponatremia (2%), and conditions related to COVID-19 (2%). The following were associated with decreases in neutrophil count: decreased neutrophil count (2%). The following were associated with thromboembolic events: pulmonary embolism (2%). The following were gastrointestinal in nature: abdominal pain (2%), anemia (2%), colitis (2%), diarrhea (2%), and febrile neutropenia (2%). The following were general and spirit (other) in nature

Fatal adverse reactions reported with pembrolizumab and paclitaxel with or without bevacizumab in patients with various types of cancer: Death, general medicinal dangers, oncology, other. Fatal adverse reactions were observed in 3.9% of patients and included assisted suicide, death, intestinal perforation, and others occurring in frequency in <1% of patients and include: sepsis and cardio-respiratory arrest due to serious COVID-19; life threatening

Approved Indications

The efficacy and safety of pembrolizumab/berahyaluronidase alfa-pmph for intended use were evaluated based on clinical study results including efficacy, safety, and pharmacokinetics data from previous pembrolizumab studies and intra- and inter- study comparisons of pharmacokinetics, efficacy and safety with pembrolizumab.

Pembrolizumab is a human monoclonal IgG4 kappa antibody that binds to PD-1 (programmed death receptor-1) expressed on activated T-cells. By binding to PD-1, Pembrolizumab releases T-cells from inhibitory ligands, PD-L1/L2, enabling them to kill cancer cells. The interaction of PD-1 with its ligands, PD-L1/PD-L2, is an important immune checkpoint pathway that prevents lymphocytes from attacking normal cells. Tumors with high expression of PD-L1 can be distinguished from normal cells and targeted using pembrolizumab. The resulting release of T-cells from suppression and enhanced killing of cancer cells, are believed to be responsible for the therapeutic effects observed with pembrolizumab. Common side effects seen with pembrolizumab include headache, back pain, arthralgia, rash or itching, decreased weight, decreased appetite, diarrhea and severe stomach pain, nausea, and irregular heart rhythm.

Berahyaluronidase alfa permits co-administration of berahyaluronidase alfa and pembrolizumab as a subcutaneous injection. This formulation change allows the administration of pembrolizumab to no longer require extended infusion time. Patients and their caregivers, as well as healthcare professionals, will no longer require a port for this treatment. In addition, administration of pembrolizumab will ensure that all patients receive the full benefits of this medication.

Who it affects

Women with platinum-resistant ovarian cancer who test positive for the presence of PD-L1 may now have a second bite at the cherry with a number of new treatments emerging for the disease.

All of these cancers are classified as ovarian epithelial cancers, fallopian tube cancers or primary peritoneal cancers. They are diseases in which malignant cells form in the tissue covering the ovary or lining the fallopian tube or peritoneum.

What is primary peritoneal cancer and where is the peritoneum? The peritoneum is a membrane that covers and lines the abdominal cavity and the surfaces of the organs in the cavity. Primary peritoneal cancer is cancer that originates in the lining of the peritoneum (Peh-ri-TAH-nee-um) and has not spread to that area from anywhere else in the body. It is sometimes confused with ovarian cancer. Cancer can originate in an ovary and then spread to the lining of the peritoneum. The fallopian tubes are two narrow channels, one leading from each ovary to the uterus. In some cases the cancer that originates from the distal end of the fallopian tube can also involve the ovary.

The ovaries are two small, oval-shaped organs that produce a woman’s eggs and hormones. The hormones then travel to many parts of the body and affect such things as the growth and maintenance of the female reproductive structures and the secondary sex characteristics, which include the breasts and distribution of fat. The ovaries are located on each side of the uterus, a hollow, pear-shaped organ that is where a fetus develops during pregnancy. The ovaries are about the size of almonds. After puberty, the ovaries release an egg about once a month in a process called ovulation. When a woman reaches the end of her childbearing years, the ovaries stop producing eggs, marking the end of the menstrual cycle. This time in a woman’s life is called menopause. Ovarian cancer, however, begins with the cells of the ovaries or the fallopian tubes. These abnormal cells then multiply rapidly out of control and form a tumor.

Ovarian Cancer

Ovarian cancer is not the most common type of cancer arising from the female reproductive organs, but it is not rare either. Women with a prior family history of ovarian cancer are at increased risk for this disease.

Ovarian cancer is cancer of the ovaries. It is uncommon. The National Cancer Institute estimates that 10.3 cases of ovarian cancer will be diagnosed per 100,000 women per year. It is the eighth most common cancer worldwide, accounting for 4% of cancer cases in women. It is the eighth most common cause of cancer death in women as well, responsible for 4% of cancer deaths. An estimated 21,010 cases of ovarian cancer will be diagnosed this year in the United States, and an estimated 12,450 women will die of the disease. While standard platinum-based chemotherapy can induce durable remission in approximately 80% of women with ovarian cancer, most will suffer relapse within six months of completion of first-line therapy. Indeed, more than 80% of women with ovarian cancer will ultimately experience recurrence of or progression of disease on current standard therapies. Despite this, prognosis and treatment for such patients is very poor and entirely prohibited by current legislation.

This research will benefit patients, and their families and carers. It will also benefit healthcare professionals, such as oncologists and nurses, who care for people with this illness and their carers. It should also benefit families and support networks of people with this illness and their carers by helping to support their emotional and psychological well-being.

What changes

• Healthcare professionals may need to update their treatment protocols and training to incorporate these new therapeutic options effectively.
• Current treatment options for patients with ovarian cancer include surgery, chemotherapy, and targeted therapy.
• Radiation therapy and immunotherapy, like pembrolizumab, are new types of treatment options that are being tested in clinical trials. Patients who have undergone previous treatment with recurrent cancer, such as platinum-resistant ovarian cancer patients, are largely eligible for clinical trial enrollment.
• Patients will have additional choices when it comes to managing their condition, which may help to alleviate feelings of helplessness and anxiety around treatment.
• This development could lead to increased research interest and funding in innovative therapies for other hard-to-treat cancers.

References

1. https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis
2. https://clinicaltrials.gov/study/NCT05116189
3. https://clinicaltrials.gov/study/NCT05722015
4. https://www.ncbi.nlm.nih.gov/books/NBK546616/
5. https://pubmed.ncbi.nlm.nih.gov/40957773/
6. https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq
7. https://seer.cancer.gov/statfacts/html/ovary.html
8. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-paclitaxel-platinum-resistant-epithelial-ovarian-fallopian-tube-or