Immunotherapy Drug Keytruda Could Be Effective for Aggressive Cervical Cancer Regardless of PD-L1 Protein Expression, Study Shows: Expanding Use of Trailblazing Drug

PD-L1 is a protein found on cancer cells, and determining the level of PD-L1 helps doctors determine if immunotherapy would be effective in controlling the cancer. Some medicines may not work if there is a small level of PD-L1.

But a recent study shows that this Keytruda treatment option could be effective for patients regardless of their PD-L1 expression, potentially opening the door for the drug to help a wider range of patients.

Lead author Dr. Bradley Monk, medical director of Gynecologic Oncology Research at US Oncology and professor on the clinical scholar track at the University of Arizona College of Medicine, encapsulates the monumental impact of his practice-changing study: "We can improve longevity in young women suffering from this terrible disease by more than a year."

This treatment combo “is now [becoming] the standard of care as a result of this." Dr. Monk,  also the medical director of gynecologic oncology research at the US Oncology Network, said in a press briefing.

This data, from the KEYNOTE-826 trial, is being presented at the 2023 American Society of Clinical Oncology's (ASCO) Annual Meeting, the largest cancer conference in the world.

Dr. Merry Markham, a medical oncologist at the University of Florida Health, said in a press release that this study solidifies this treatment combo “as the front-line standard of care for this disease.”

But more than that, she said, “Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population.”

WATCH: Understanding Clinical Trials and What They Mean

Cervical Cancer: What Is It And How Many People Does It Impact?

Cervical cancer is a tumor that starts within the cervix, which is the conduit between the vagina and the uterus.

An overwhelming risk factor for this cancer is Human Papilloma Virus (HPV) infection, which is sexually transmitted and incredibly common in the sexually active population.

More than half of sexually active people will be infected with HPV during their lifetimes. Women between 35 and 44 years old are most at risk for this disease.

Ways to prevent or catch cervical cancer in a timely manner include HPV vaccinations and regular cancer screenings, such as pap smears. According to the US Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG), women aged 21 to 29 should have a pap smear every three years.

This exam can be paired with HPV testing as well. Women between 30 and 65 can continue with pap smears every three years, HPV testing every five years, or pap smears with HPV co-testing every five years.

RELATED: Most People Will Get This Virus. But Fewer People Know It Can Cause Cancer: Concerning New Evidence About HPV

"It’s the fourth-most common cause of cancer worldwide," says Dr. Monk.

In 2023, more than 13,000 women will be diagnosed with cervical cancer in the United States, of which around 4,000 will die from the disease. However, the rates of this cancer within the U.S. have steadily declined for many decades, in part due to cancer screenings, which have steadily increased during this time.

How Many Cases Of Cervical Cancer Are Recurrent Or Metastatic?

Cervical cancer is usually confined to the cervix at the time of diagnosis. However, between 15-61% of women will develop persistent, recurrent, or metastatic disease within two years of their initial diagnosis and treatment.

Persistent disease occurs in patients who continue to harbor cancer despite treatment. Recurrent disease refers to cervical cancer that returns within some discrete area of the pelvis. It is potentially curable through surgery or radiation.

Metastatic disease, on the other hand, is incurable. The five-year survival rate for women with metastatic disease is only 17%, according to the American Cancer Society.

These numbers underscore the great need for new, innovative, and effective treatments for recurrent and metastatic disease. Pembrolizumab, combined with chemotherapy, is a potential way to address this need.

RELATED: Report Finds that Black Women Are 1.5 Times More Likely to Die from Cervical Cancer Than White Women; How Can We Close the Gap?

How Does Pembrolizumab Work?

Pembrolizumab is an immunotherapy medication. In other words, it primes the patient's own immune system in the fight against their cancer.

"Because [cervical cancer] is a virus-related cancer, immunotherapy should work [well]. Immunotherapy is very effective in all sorts of cancers, but for virally induced cancers, it [is especially] effective," says Dr. Monk,

Cancers oftentimes learn to evade detection by the immune system by hijacking the PD-1 (Programmed Death Receptor-1) and PD-L1 (Programmed Death Ligand-1) pathways. PD-1 is a protein on the surface of immune cells. PD-L1 is a protein on the tumor cells and can bind to PD-1 and prevent the immune system from killing the cancer cell.

Pembrolizumab interrupts this process by binding to PD-1, allowing the immune cells to exterminate the cancer.

In other words, Keytruda “stimulates the immune system to [correctly] recognize the cancer as foreign," expressed Dr. Monk.

A Landmark Study Demonstrates The Effectiveness of Pembrolizumab For Cervical Cancer

Researchers from 19 countries, including the U.S., recruited 617 patients with persistent, recurrent, or metastatic cervical cancer between 2018 and 2020. These patients were not eligible for curative surgery or radiation and had not received any chemotherapy.

The patients were divided into two groups. One group received pembrolizumab and a chemotherapy drug (cisplatin or carboplatin) and with or without bevacizumab. The other group received a placebo combined with chemo and with or without bevacizumab (placebo group).

They also quantified the levels of PD-L1 in the patients’ tumors using the combined positive score (CPS). This score ranges between 0-100, with 0 signaling no PD-L1 expression and 100 denoting the maximum level of PD-L1 expression. This score is used to identify patients who are suitable to receive pembrolizumab.

The Incredible Results

The researchers analyzed overall survival (OS) and progression-free survival (PFS). OS, the ultimate measure of a treatment's efficacy, is defined as the length of time patients are alive after their initial diagnosis of cancer. PFS represents the time a patient is alive without a worsening of their disease.

For those with a PD-L1 CPS ≥ 1 (90% of the patients), OS was 28.6 months for the pembrolizumab group and 16.5 months for the placebo group. Patients with PD-L1 CPS scores ≥ 10 had an overall survival of 29.6 months for those in the pembrolizumab group versus 17.4 for those in the placebo group.

This translates into an OS of 26.4 months for the pembrolizumab and 16.8 months for the placebo group for patients with any CPS score.

In terms of percentages, pembrolizumab and chemotherapy reduced the risk of death by:

• 40% in those with PD-L1 CPS ≥ 1
• 42% in those with CPS ≥ 10
• 37% in those with any CPS score

Dr. Monk summarizes these results, concluding that "in the 90% of patients that expressed PD-L1 [CPS ≥ 1] when pembrolizumab was added to chemotherapy with or without bevacizumab, there was a 40% difference in survival… So, at any given point along the curve, there’s a 40% likely chance that the patient will be alive."

He continues, "If you add the 10% that did not have the biomarker [CPS < 1] … the [OS] difference is 9.6 months [26.4 months vs. 16.8 months]. This is clinically relevant [and] statistically significant."

Furthermore, the pembrolizumab group experienced a PFS of 10.4 months while the placebo group had a PFS of 8.2 months.

There Are Side Effects To This Treatment

Although pembrolizumab and chemotherapy with or without bevacizumab is highly effective, it does carry side effects. In the study, the pembrolizumab group experienced more serious side effects than the placebo group.

The most common side effects associated with pembrolizumab include:

• Tiredness and fatigue
• Muscle and joint pain
• Stomachache
• Fever
• Vomiting
• Nausea
• Diarrhea
• Headaches
• Low red blood cell counts, termed anemia
• Low white blood cell levels

WATCH: Managing the Side Effects of Immunotherapy

Serious side effects can also occur and are usually related to the immune system targeting normal body tissues. This can lead to:

• Rashes that may be itchy
• Painful mouth sores and ulcers
• Lung Problems, including shortness of breath and chest pain.
• Liver issues, such as jaundice, dark urine, and right-sided abdominal pain.
• Hormonal imbalances, leading to mood swings, hair loss, feeling cold, feeling thirstier, and weight loss or weight gain, among others.
• Kidney issues, which can lead to kidney failure in extreme cases.

Please note that this is not an exhaustive list. Other side effects can also occur. Should you experience any side effects while taking the medication, notify your physician immediately.

It Is A Significant Step Forward

Persistent, recurrent, or metastatic cervical cancer presents a significant challenge for oncologists. With five-year survival rates as low as 17% with the current standard-of-care treatments, such as chemotherapy with or without bevacizumab, there is a pressing need for better, more effective treatments.

Merck's workhorse pembrolizumab has left an indelible mark on the treatment of 16 types of cancers. Now, in combination with chemotherapy with or without bevacizumab, it is improving the outlook for patients with persistent, recurrent, or metastatic cervical cancer.

By reducing the risk of death by 37%-42%, depending on the levels of PD-L1 expression within the tumors, it now offers hope to patients who have had limited options so far.

Questions to Ask Your Doctor

If you are battling aggressive cervical cancer and are wondering about your options, here are some questions you may consider asking your doctor to help start the conversation:

• What type of cervical cancer do I have?
• Does my tumor express the PD-L1 protein? What test is available to check?
• How far has my cervical cancer spread?
• Am I eligible to receive Keytruda as treatment?
• How does Keytruda differ from what I’ve already received?
• Are there ways to manage side effects of the treatment?

Learn more about SurvivorNet's rigorous medical review process.

---