Steering the Treatment of Gynecologic Cancers With Biomarkers

Over the past 10 years, PARP inhibitors, immunotherapy and antibody drug conjugates have changed the treatment landscape of gynecologic cancers, providing options for patients beyond chemotherapy, an expert said.

Dr. Kari E. Hacker, assistant professor in the division of gynecologic oncology at NYU Langone in New York, discussed the newer treatment options for gynecologic cancers during the CURE® Educated Patient® Gynecologic Cancers Summit.

Most of the recent FDA approvals for treating patients with gynecologic malignancies are based on biomarkers. In ovarian cancer, germline genetic testing (patient’s blood or saliva) or somatic profiling (next-generation sequencing of a patient’s tumor) can focus on several biomarkers. For example, it can identify BRCA and homologous recombination deficiency — which occurs in approximately 50% of patients with ovarian cancers and can be treated with PARP inhibitors — and Lynch syndrome, which is a mismatch repair deficiency.

Endometrial cancer also has several biomarkers that can be acted upon. Through simplified testing, proteins like p53 and mismatch repair proteins can be identified, in addition to a mutation in POLE. HER2 and other biomarkers can also be seen in patients with endometrial cancer.

“The different molecular subheads have different prognoses in endometrial cancer,” Hacker said during the presentation.

These can also help identify what class of drugs may work best for patients. Several new classes of anti-cancer drugs may be used beyond chemotherapy, including PARP inhibitors for ovarian and endometrial cancer; immunotherapy/checkpoint inhibitors for endometrial cancer and cervical cancer; and antibody drug conjugates for ovarian cancer, cervical cancer and for three or more HER2 tumors.

PARP Inhibitors

PARP inhibitors are a class of drug in the form of oral medications that are taken one to two times daily for approximately two to three years.

Currently, there are two PARP inhibitors approved by the FDA for patients. Zejula (niraparib) was approved for the treatment of patients with newly diagnosed ovarian cancer whose disease responded to chemotherapy. Patients can receive Zejula for up to three years after completing chemotherapy.

Lynparza (olaparib) is also approved for patients who completed and responded to chemotherapy, but it is specifically approved as a single agent in patients with a BRCA mutation. Of note, this has also been approved for patients who are homologous recombination deficient in combination with Avastin (bevacizumab). Lynparza can also be used to treat patients with a BRCA mutation with a recurrence and had a response to platinum-based chemotherapy only at the time of first recurrence.

Immunotherapy

When discussing immunotherapy in the treatment of gynecologic malignancies, cancer teams mostly focus on checkpoint inhibitors. Hacker explained that with T cells, which recognize either cancer cells or infected cells, it can recognize a specific complex on those cells. There is also a safety mechanism in place called PD1 or PD-L1 that, when engaged, does not kill cells.

Hacker added, “Tumor cells have become really smart, and unfortunately, they have upregulated or increased expression of PD-L1 on the surface in order to avoid immune cell killing. And checkpoint inhibitors prevent that interaction from occurring, and so [they] allow those T cells that recognize tumor cells to kill the tumor cell.”

Two checkpoint inhibitors have been FDA-approved for endometrial cancer: Keytruda (pembrolizumab) and Jemperli (dostarlimab). In particular, they have been approved for the treatment of recurrent deficient DNA mismatch repair (DMMR; cells with mutations in certain genes involved in correcting errors with DNA is copied in a cell) or microsatellite instability-high (MSI-H; cancer cells with a high number of mutations within microsatellites, which hinders the ability to correct mistakes that occur when DNA is copied in the cell) endometrial cancer.

Hacker noted that with Keytruda, approximately 50% of patients respond with progression-free survival (the time when a patient with cancer lives with the disease without worsening) of 13 months. With Jemperli, approximately 45% of patients responded, most of which were sustained responses.

Keytruda has also been approved by the FDA for use in combination with Lenvima (lenvatinib) for recurrent MMR-proficient endometrial cancers. Of these tumors, nearly 40% responded to treatment.

Several advancements have been recently made regarding immunotherapy for endometrial cancer, Hacker said. For instance, Keytruda and Jemperli were shown to be effective in the treatment of metastatic and recurrent endometrial cancer when combined with chemotherapy. Keytruda was also approved by the FDA to treat cervical cancer, particularly for CPS/PD1-positive recurrent disease as a single agent. Metastatic and recurrent PD1-positive cervical cancer may also be treated by FDA-approved Keytruda either with or without Avastin.

Lastly, Keytruda was also recently FDA-approved to treat locally advanced cervical cancer in combination with chemotherapy and radiation.

“So, patients who have a new diagnosis of cervical cancer that has spread outside of the cervix, within the pelvis, but not outside of the pelvis, are eligible for treatment with chemotherapy and radiation,” Hacker explained.

She added that many patients treated with checkpoint inhibitors experience side effects. This includes inflammation, which is an autoimmune reaction, that occurs in nearly all organs in a patient’s body.

“The most common sites of inflammation, which happens probably in about 15% to 20% of patients, depending on the specific checkpoint inhibitor, are inflammation in the skin, so rashes, inflammation in the GI tract. A lot of patients can get diarrhea,” Hacker said. “And then the other most common site of inflammation is actually in the thyroid. So the thyroid can either become overactive or underactive when patients are on these drugs. Less common but potentially severe sites of inflammation include the kidney, the heart, the brain. These are things that we need to constantly be monitoring patients for throughout treatment.”

Antibody-Drug Conjugates

Antibody-drug conjugates are a fairly new class of drugs for gynecologic malignancies, with the first FDA approval occurring in 2021. The function of these therapies is to deliver highly effective chemotherapy directly to the tumor, with the goal of highly active treatments with minimal off-target effects.

“The other thing that's unique about antibody-drug conjugates is that as those [cancer] cells die, they can release some of that chemotherapy into the local tumor or the neighboring tumor, and you can get killing of adjacent cells that may not express the protein that you see on the surface of the cancer cells that you targeted,” Hacker said.

Elahere (mirvetuximab soravtansine) was approved by the FDA for the treatment of platinum-resistant ovarian cancer. In the trial that supported its approval, approximately 30% of patients responded to treatment with Elahere, and 50% had disease control (the disease responded, or it was stable) for more than 12 weeks. The duration of response was a median of seven months,

“It showed that patients with platinum-resistant ovarian cancer, who have high levels of folate alpha receptor, which is what Elahere targets, respond better and live longer when they receive Elahere compared to chemotherapy,” Hacker explained.

Another antibody-drug conjugate approved for recurrent or metastatic cervical cancer is Tivdak (tisotumab vedotin), which can be used as a second-line therapy. Treatment with Tivdak produced a 24% response rate and a disease control rate as high as 72%. In addition, disease control greater than six months was observed in 62% of patients.

Enhertu (trastuzumab deruxtecan), an antibody-drug conjugate, targets HER2, a protein found on several different cancers. Response rates with Enhertu were as high as 85%, with a duration of response of 11.3 months.

There are several side effects associated with antibody-drug conjugates. For example, Elahere and Tivdak are linked with some ocular toxicities like conjunctivitis (pink eye) and keratitis (inflammation of the eye itself) potentially leading to blurred vision.

“Based on these toxicities, patients need to see an ophthalmologist before they start treatment,” Hacker said. “And then they also need special eye care protocols with eye drops on the day of treatment and then following treatment as well.”

Enhertu has a potential side effect associated with it known as pneumonitis, or inflammation of the lungs.

“Patients need to continually be monitored for symptoms of that,” she added. “And you want to make sure that when [patients] get their CT scans to monitor disease response, that the radiologist is also keeping an eye out for signs of inflammation in the lungs.”

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