Evolving standards of care: new treatments for cervical cancer

Pharma giant Pfizer’s Tivdak was approved by U.S. regulators for the treatment of cervical cancer last month. As current standards of care include surgery, radiation, and chemotherapy,  new drugs broaden treatment options, and extend to more patient groups.

Tivdak wins FDA approval for the treatment of cervical cancer

The go-ahead from the U.S. Food and Drug Administration (FDA) came after the antibody drug conjugate showed overall survival (OS) benefit in patients who had previously been treated for cervical cancer. A 30% reduction in the risk of death compared to chemotherapy was also observed. 

Tivdak contains a monoclonal antibody directed against the cell surface protein TF1, a microtubule disruptor – a microtubule is a structure in cells that supports cell shape but plays a role in cancer growth – and a linker molecule that connects the monoclonal antibody and the drug. A first in cervical cancer research as it targets the Tissue Factor (TF) prevalent in these cancers, the drug awaits clearance from the European Medicines Agency (EMA), which is most likely to happen by the end of this year or early next year.

As cervical cancer is the fourth most common cancer in women globally with around 660,000 new cases and 350,000 deaths recorded in 2022, according to the World Health Organization (WHO), there is a burgeoning need for more medicines to address all stages of the disease.

Changing standards of care for cervical cancer

The number one cause of cervical cancer is human papillomavirus (HPV). Persistent HPV infection can result in the growth of abnormal cells, which become cancer in the cervix, the region that connects the uterus to the vagina. Nearly 85% of cervical cancers are linked to HPV-related tumors. HPV vaccines work well to prevent more than 90% of cancers caused by the infection.

“There is no question that the standard of care, surgery and chemoradiation, have improved the outcomes of early and late-stage cervical cancer but, the approval of the HPV vaccine has had a major positive impact in the prevention of cervical cancer since most cases are related to this infection. For instance, in the U.S. since 2006, the rate of HPV infections has decreased by 86% in teens and 70% in older women,” said Francisco Contreras, chief oncologist at Oasis of Hope Hospital in Mexico.

However, the absence of a global vaccination movement affects the rate of prevention across the world.

“Fortunately, the incidence and death rate from cervical cancer is low in developed countries. For instance, in the U.S., about 14,000 new cases are diagnosed every year and around 4,500 will succumb to this disease,” said Contreras. “Cervical cancer is a major problem in underdeveloped countries where about 600,000 cases are diagnosed every year, and the challenge is the lack of resources that impede effective screening to detect it early where surgery, the gold standard of care, offers patients a more than 90% cure rate.”

But in countries like Mexico where Contreras practices, most patients with early-stage cervical cancer are treated with open and laparoscopic surgery, the latter of which is minimally invasive.

“For women in advanced stages, we have developed less expensive but effective therapies to help women in low-income communities such as high dose vitamin C, ozone therapy, hyperthermia, and low dose chemotherapy,” said Contreras.

Vitamin C in high doses contributes to cancer cell destruction, and so does hyperthermia (thermal therapy). Ozone therapy is said to inhibit cells that aid in cancer cell growth but its safety has been questioned, and it has not been approved by the FDA.

Keytruda combination therapy more effective than standard-of-care CRT

Like Tivdak’s success in the clinic, multinational biopharma Merck’s immunotherapy drug Keytruda has also made headlines. Keytruda (pembrolizumab) is designed to block the PD-1 pathway and prevent cancer cells from hiding. Following its U.S. approval to treat patients with stage 3 and 4A cervical cancer in combination with chemoradiotherapy (CRT) in January, a study found that a regimen with Keytruda and CRT was more effective than CRT alone. 

The comparative study with CRT is the first phase 3 trial of its kind to show “a statistically significant and clinically meaningful improvement in overall survival” over the latter, according to Gursel Aktan, vice president of global clinical development at Merck Research Laboratories. These results could potentially turn regulators’ heads towards approval for a range of cancers and a broader population. 

Moreover, as Tivdak and Keytruda look to beat CRT, which is currently regarded as the standard of care in the U.S., these clinical results could push these drugs to the forefront of cervical cancer treatment.

Can Squibb’s Opdivo deliver better long-term results for cervical cancer?

Another contender in the running for “better long-term results” is Bristol-Myers Squibb’s Opdivo, according to Contreras. Along with Japanese multinational Ono Pharmaceutical, the pharma giant funded a phase 1/2 open-label trial with 176 patients across 10 countries. The drug was first approved nearly a decade ago for advanced skin cancer, and since then, it has been cleared to treat lung cancer, liver cancer, and kidney cancer, among others.

Like Keytruda, it is a checkpoint inhibitor that blocks the PD-1 pathway. The clinical trial tested Opdivo (nivolumab) as a monotherapy as well as in combination with ipilimumab, a monoclonal antibody sold under the brand name Yervoy. A 26% objective response rate was observed in the monotherapy group consisting of 19 patients, with a complete response in four patients, based on results published two months ago. But the median response duration was not reached.

In the combination therapy group, there was a 31% objective response rate out of 45 patients. The median progression-free survival was 3.8 months, and median overall survival was 15.2 months.

The most common side effects were diarrhea, hepatic cytolysis – a condition that affects the liver – low sodium in the blood, and lung inflammation. There was also a treatment-related death caused by immune-mediated colitis, an adverse event linked to immune checkpoint inhibitors that affects the digestive system.

The researchers involved in the trial stated that both the nivolumab monotherapy and the combination therapy with ipilimumab “showed promise” as a treatment for cervical cancer. Randomized controlled trials are warranted to verify the drug’s clinical benefit. 

Can gene editing treat cervical cancer?

As immunotherapy shakes up research and development (R&D) in cervical cancer, gene editing offers a promising approach, and scientists in Japan have proven this in a preclinical study. 

It involves a treatment method using rejuvenated cytotoxic T lymphocytes (rejTs), which was discovered a few years ago. rejTs are immune cells derived from stem cells of a patient. These cells can be engineered to target antigens expressed in cervical cancer cells. However, the process is both time-consuming and expensive, so taking cells from another individual (allogeneic cells) seemed to be the best bet. But even this poses problems, the major one being a patient’s body rejecting the cells. 

To address this, researchers at the Juntendo University, School of Medicine in Japan, have integrated gene editing technology. They modified the T cells with the help of a CRISPR/Cas9 ‘scarless’ gene editing technique. First, a protein that prompts cells to identify foreign cells was deleted. This helped the T cells evade detection.

Next, CRISPR/Cas9 was tasked with turning down the expression of two antigens that would otherwise provoke an attack on the engineered cells. This allowed the engineered T cells to do their job with more ease. 

The scientists found that because the rejTs did not trigger attacks from immune cells, they were able to damage cancer cells. The rejTs significantly reduced tumor sizes in mice with cervical cancer cells compared to the control group. 

As these engineered rejTs are set to enter the clinic this year to confirm whether it is a viable option to treat patients, regulatory nods for Tivdak and Keytruda are encouraging for the cervical cancer community. As these drugs continue clinical development to target wider patient populations, standards of care seem to be changing for the better.

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