Libtayo (cemiplimab-rwlc) became the first PD-1 therapy to score a phase III win in cervical cancer, a pleasing development not only for investors in Regeneron Pharmaceuticals Inc. and partner Sanofi SA but for patients with the stubborn disease.

The World Health Organization has said that, with a comprehensive approach to prevent, screen and treat the disease, cervical cancer could be “eliminated as a public health problem within a generation,” but for now it’s still the fourth most common tumor type in women, bearing only a 66% five-year survival rate. About 14,000 new cases surface in the U.S. every year. The indication is hotly pursued in late-stage clinical work by a handful of biopharma players, with approved therapies such as Libtayo seeking to expand their labels as new compounds near fruition.

Thanks to positive results, Tarrytown, N.Y.-based Regeneron and Sanofi, of Paris, stopped early the phase III trial comparing Libtayo to chemotherapy in advanced cervical cancer. Libtayo reduced the risk of death by 31% compared to chemotherapy in a 590-participant bid that enrolled patients regardless of PD-L1 status. Oppenheimer analyst Hartaj Singh called the results “fascinating, and it just continues its steady stream of data where Libtayo really seems to be probably one of the best PD-1s.” Singh spoke March 16 during his firm’s health care conference, where Regeneron vice president of investor relations Justin Holko acknowledged “other anti-PD-1 competition out there, but this is the first study to show overall survival in a randomized study.”

Libtayo was first approved in September 2018 for metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. It was the first FDA approval of a drug specifically for advanced CSCC. Advanced basal cell carcinoma was added to the label in February 2021, followed the same month by first-line advanced non-small-cell lung cancer in patients whose tumors have high PD-L1 expression (tumor proportion score ≥50%) as determined by an FDA-approved test.

Baird analyst Brian Skorney’s reaction to the cervical cancer findings was circumspect. “While we do believe this is an incremental positive, we think the prevailing theme of competition amongst the checkpoint inhibitors will dampen excitement about this opportunity, particularly given cervical cancer is less [prevalent] than other cancers in the checkpoint universe,” he wrote in a March 15 report. Kenilworth, N.J.-based Merck & Co. Inc.’s Keytruda (pembrolizumab) is approved for use in cervical cancer based on results of the 77-patient, phase II Keynote-158 trial, which showed a 14.3% response rate in patients with PD-L1-positive disease. The company is testing Keytruda as a first-line pharmacological therapy in the ongoing, phase III Keynote-826 experiment, weighing the drug plus chemo in women with recurrent or metastatic cervical cancer who are refractory to surgery/radiation but haven't started chemo. Keytruda was first approved in September 2014; the go-head in cervical cancer was granted in June 2018. “It is worth noting there are also phase III studies of Tecentriq [atezolizumab, Roche Holding AG] and Imfinzi [durvalumab, Astrazeneca plc] being conducted in cervical cancer,” Skorney wrote, adding that “given the general similarity of these assets, we expect this space will evolve to be highly competitive,” he said.

$1B market by 2026

Others busy in cervical cancer include Lexington, Mass.-based Agenus Inc. with PD-1 inhibitor balstilimab, for which a rolling BLA began last September. Late in 2020, the company disclosed a delay of the balstilimab BLA filing to satisfy the FDA, which has called for investigators to follow all patients in its trial for a median of 12 months and to keep track of responders for a minimum of six months. Due to two newly-identified late responses in the study, completion is planned for the first half of this year. Agenus also is working with regulators to clarify diagnostic requirements for PD-L1 testing. Balstilimab has gained response rates of 19% in PD-L1-positive tumors, with 14% in all tumors (PD-L1 positive and negative) and a median duration of response (DOR) of 15.4 months in a phase II trial. Data were presented at the European Society for Medical Oncology Virtual Congress 2020 and in an Oncogene editorial. Agenus is testing the prospect alone and with its CTLA4 therapy zalifrelimab. The duo in second-line cervical cancer has achieved response rates of 27% in PD-L1 positive tumors with 22% in all tumors, with a median DOR. Responses continue to improve as the data mature, the company said this month.

Tumor-infiltrating lymphocyte specialist Iovance Biotherapeutics Inc., of San Carlos, Calif., intends the phase II C-145-04 study of lifileucel, formerly LN-145, to support a BLA submission. Including of pivotal cohort 1 (post-chemo) and cohort 2 (post-anti-PD-1/PDL-1) in the package may strengthen the label, the company said. Enrollment in both cohorts has been completed. The compound has won breakthrough designation.

Bothell, Wash.-based Seagen Inc. and partner Genmab A/S, of Copenhagen, Denmark, submitted a BLA in February seeking accelerated approval for tisotumab vedotin for patients with recurrent or metastatic cervical cancer with disease progression on or after chemo. The submission is based on the Innovatv 204 pivotal phase II single-arm study testing tisotumab, an antibody-drug conjugate, as monotherapy.

Accelerated approvals for oncology drugs are coming under scrutiny. Compounds gained add-on indications through the pathway are losing some of them as the result of an FDA evaluation of confirmatory trials. The agency plans to convene its Oncologic Drugs Advisory Committee April 27-29 to discuss six indications for three cancer drugs – Tecentriq, Keytruda, and New York-based Bristol Myers Squibb Co.’s Opdivo (nivolumab) – all granted accelerated approval.

SVB Leerink analyst Geoffrey Porges, who covers Regeneron, pegged the 2020 cervical cancer market at about $60 million, with Keytruda taking about $17 million of that, but said it could reach $1 billion by 2026. “We believe Libtayo could be competitive in this emerging indication, if the approved label forgoes PD-L1 testing,” he wrote in a March 15 report. Meanwhile, artificial intelligence (AI) methodology’s far-reaching tentacles have touched cervical cancer screening. Scientists at the Karolinska Institute in Sweden discovered that point-of-care AI cytology exams of pap smears, carried out with portable scanners, were at least as accurate as those done by human pathologists. The discovery could be valuable in a resource-limited setting, noted the authors of a paper published in JAMA Network Open.