Approximately 14,000 American women are expected to be diagnosed with invasive cervical cancer in 2021, and more than 4,000 are expected to succumb to the disease.
Agenus Chief Medical Officer Dr. Steven O’Day/Courtesy of Agenus Inc.
While increased screening and the Human papillomavirus (HPV) vaccine has vastly reduced the threat of cervical cancer, it is still cutting down American women in the prime of their lives, and in developing countries, it remains a major killer.
As is the case with many tumors, cervical cancer is highly curable when caught early. It is primarily when these tumors metastasize that tragedy strikes. Approximately 14,000 American women are expected to be diagnosed with invasive cervical cancer in 2021, and more than 4,000 are expected to succumb to the disease.
During the past decade, the U.S. Food and Drug Administration (FDA) has approved two new drugs in the space. In 2014, the agency signed off on Genentech (Roche’s) Avastin® (bevacizumab) plus chemotherapy for women with persistent, recurrent or metastatic cervical cancer. This was followed in 2018 by Merck’s Keytruda® for recurrent or metastatic PD-L1 positive tumors.
According to Dr. Robert L. Coleman, chief scientific officer for US oncology research at the US Oncology Network, these drugs won’t be alone for long.
“It’s going to be a banner year,” Coleman stated. He highlighted, among others, Sanofi and Regeneron Pharmaceuticals’ PD-1 checkpoint inhibitor Libtayo® (cemiplimab), tisotumab vedotin, an investigational antibody-drug conjugate (ADC) being developed by Seagen and Genmab and balstilimab, an anti-PD-1 monoclonal antibody being developed by Agenus Inc. All three could potentially be approved in 2021.
In February, Seagen and Genmab submitted a Biologics License Application (BLA) to the FDA for tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The submission was based on the results of a pivotal phase II trial, in which Seagen Chief Medical Officer Dr. Roger Dansey said the drug “induced clinically meaningful and durable responses.”
Meanwhile, Libtayo performed so well in its phase III trial, the Independent Data Monitoring Committee (IDMC) recommended the trial be halted early. Compared to patients receiving chemotherapy alone, those receiving Libtayo demonstrated a 31% reduced risk of death, and a median 12 months survival compared to 8.5 months for the chemotherapy group.
After detailing a modern history of the space that saw the adoption of platinum-based chemotherapy in the late 1980s and 1990s, followed by the 2014 Avastin approval, Coleman’s optimism was palpable.
“In one year, we’ve got immunotherapy, new ADCs and new strategies in combination. For us in this field, incrementally we’re making almost no progress, then to have all this happen in one year, we’re excited,” he said.
On June 17, the FDA accepted Agenus’ BLA and granted priority review for the submission. It anticipates a Prescription Drug User Fee Act (PDUFA) date of December 16.
T cells, one of the immune system’s primary defenses against disease, hit a wall when cancer is progressing throughout the body. This state of exhaustion is represented by the PD-1 receptor.
“PD-1 inhibitors are human antibodies that block that exhaustion marker. By blocking that marker, it makes the T cell come back to life as an active T cell that can attack cancer,” explained Agenus Chief Medical Officer Dr. Steven O’Day.
Agenus presented preliminary data at the 2020 European Society for Medical Oncology (ESMO) congress showing that Balstilimab monotherapy resulted in a 14% objective response rate (ORR) among 160 patients in a phase II trial with a median duration of response (DOR) of 15.4 months.
O’Day noted the significance of this duration in a disease state that has an average survival time of 6 to 9 months.
Balstilimab is also being tested in combination with Agenus’s zalifrelimab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody. CTLA-4 is a negative regulator of immune activation. In the combination trial, an ORR of 22% was achieved among 143 patients.
Agenus hopes to be celebrating an approval for the monotherapy by the end of 2021.
Then, there is Akeso Biopharma, which is developing a bi-specific antibody that incorporates both CTLA-4 and PD-1 on the same molecule. The drug was granted Fast Track designation for recurrent and metastatic cervical cancer by the FDA in August 2020.
While acknowledging that there is still work to be done, Coleman is high on the potential of immunotherapy in this space.
“Immunotherapy has the unusual principle of being able to educate the system,” he said. “If the immune system has been educated against the specific tumor antigens, and they reoccur in cells that get transformed, then the body can handle that without actually needing treatment. So, I think what is most promising is to develop lasting tumor-specific immunity. Then you would have the best opportunity for long-term disease control.”
Adoptive cell therapy, which aims to empower tumor-infiltrating lymphocytes, or TILs, is providing hope for more than incremental improvement in advanced cervical cancer. After surgery to resect a metastatic tumor, powerful immune cells that are attacking the tumor are grown to large numbers, then returned to the patient to fight the cancer.
Early work in this space was done at the National Institutes of Health (NIH) by Dr. Christian S. Hinrichs, who in 2012 led a first-in-human trial targeting cancers caused by the HPV virus, including cervical cancer. Hinrichs treated nine patients with a single infusion of TILs selected when possible for human papillomavirus (HPV) E6 and E7 reactivity. For three patients, the results were life-giving.
“Three of those patients had objective responses. Two of them had their cancers completely go away. They had widespread metastatic cancer and it all disappeared from their CAT scans. No further treatment was given, with all of them for many years. Now both are more than eight years out, and the cancer has not come back,” said Hinrichs, who is now chief of the section of cancer immunotherapy and co-director of the Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence at Rutgers Cancer Institute.
Hinrichs acknowledged that this approach too is not without its limitations.
“One of them is that you have to do surgery just to initiate treatment, and that generally also means that there is some time required to generate the cells for therapy,” he said, adding that because the treatment is governed by what the extracted cells were targeting, there is limited control.
In order to overcome these challenges, Hinrichs has moved on to next-generation approaches based on the genetic engineering of T cells.
“Instead of using chimeric antigen receptors [CARs], which can only target antigens on the surface of a cell, we are using T cell receptors [TCRs]. TCRs can target proteins from anywhere in the cell. The cell has a way of processing them into pieces and then ‘showing’ the pieces to T cells, which ‘see’ the pieces through their TCRs,” he explained.
Hinrichs was able to identify a TCR that permits T cells that are gene-engineered to express it to avidly target the HPV-16 E7 oncoprotein, which is expressed by HPV-associated cancers. In a trial of 12 patients with metastatic HPV-16+ cancers, with a TCR targeting this HPV-16 E7 oncoprotein, Hinrichs saw ORRs in six of the 12 patients, including 4 out of 8 patients with anti-PD-1 refractory disease.
“These responses were remarkable. Many of the patients who responded had many of their tumors completely disappear. It’s an unprecedented level of clinical activity and response for highly refractory, metastatic, HPV-associated cancers, albeit in a small patient sample,” he said.
Clearly seeing the potential of this approach, many companies are running with TIL-based therapies targeting a variety of cancers. One of these is Iovance Biotherapeutics, which is conducting pivotal trials with its TIL-based candidate, lifileucel (LN-145), for which it is conducting pivotal phase II trials in both melanoma and cervical cancer. Iovance received the FDA’s Fast Track designation for cervical cancer in February 2019.
In early data from the cervical cancer trial, lifileucel demonstrated a 44% ORR among 27 patients, with three achieving complete responses, and 9 receiving partial responses.
Therapeutic approaches to invasive tumors such as these clearly take some time to perfect. The important thing is, as Coleman noted: “Fortunately, because we’ve had some wins in cervix cancer now, companies are starting to re-enter the space.”
