Eli Lilly and Co. said that a phase III study combining its cyclin-dependent kinase (CDK) inhibitor abemaciclib with the chemotherapy fulvestrant to treat metastatic breast cancer will continue without modification despite failing to meet "stringent" interim efficacy criteria.

Though declining to define what criteria were considered when an independent data monitoring committee (DMC) advised Lilly to continue the trial, Richard Gaynor, senior vice president of product development and medical affairs for Lilly Oncology told BioWorld Today that "to declare early efficacy, we set a really high bar for the DMC."

The double-blind trial will carry on into 2017 when a final analysis of the progression-free survival (PFS), overall survival and safety will be conducted.

The development convinced the Indianapolis-based company to relax plans it had made to file an FDA new drug application for single-agent abemaciclib as soon as later this quarter while it awaits further data and dialog with the FDA. Lilly isn't specifying what data it's looking for at this point, though full results of the phase III study, called Monarch 2, or other ongoing combination trials seem like safe bets.

"At this point, we believe it is unlikely that it will be able to file for monotherapy in 3Q," wrote Leerink analyst Seamus Fernandez. The trial's interim readout was also out of step with consensus expectations, Fernandez said, given that trials of other CDK inhibitors — namely Pfizer Inc.'s FDA-approved Ibrance (palbociclib) and Novartis AG's ribociclib — had both been stopped early for efficacy. "The expectation was that Monarch 2 had a decent chance to do the same. Now the market opportunity for abemaciclib becomes even narrower," he said.

Pfizer's Ibrance was approved to treat metastatic breast cancer in February 2015. It's intended for postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who have not yet received an endocrine-based therapy. In 2015, it generated $723 million in sales for Pfizer, a figure that analysts expect to more than double this year, with a projected $2.13 billion in sales.

Novartis' ribociclib, which received an FDA breakthrough designation on Aug. 3, also is being tested in combination with fulvestrant vs. fulvestrant alone, but in men and post-menopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.

Abemaciclib, which was discovered and developed at Lilly, predominantly inhibits CDK-4, but also CDK-6. The candidate gained FDA breakthrough status for metastatic breast cancer in October 2015. It can be dosed continuously and can cross the blood-brain barrier — theoretically enabling it to treat brain metastases. Monarch 2 was designed to evaluate the safety and efficacy of the candidate in combination with fulvestrant in 669 patients randomized to receive either abemaciclib or placebo orally every 12 hours on a continuous dosing schedule in combination with fulvestrant until disease progression.

Patients enrolled in the study had experienced disease progression on or within a year of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for metastatic disease. Patients who had received chemotherapy in the metastatic setting were not eligible for the study. The primary endpoint is progression-free survival.

In Monarch 1, the single-arm abemaciclib monotherapy study, Lilly enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, with either progressive disease on or after prior endocrine therapy, and prior chemotherapy with one or two chemotherapy regimens for metastatic disease. The primary objective of the trial was investigator-assessed objective response rate (ORR).

At the final analysis of Monarch 1, the response, patients treated with abemaciclib achieved an ORR of 19.7 percent (95 percent confidence interval: 13.3 - 27.5 percent), with a median time to response of 3.7 months and a median durability of response of 8.6 months. The median PFS was six months.

In addition to Monarch 1 and 2, Lilly currently has three other Monarch trials evaluating abemaciclib in breast cancer underway. Monarch 3 is a phase III trial of abemaciclib in combination with a nonsteroidal aromatase inhibitor in patients with HR+, HER2- loco-regionally recurrent or metastatic breast cancer. There are also two phase II Monarch trials: NeoMonarch, which is evaluating abemaciclib in combination with a nonsteroidal aromatase inhibitor in the neoadjuvant setting, and MonarcHER, which is evaluating abemaciclib plus trastuzumab (with or without fulvestrant) in women with HR+, HER2+ locally advanced or metastatic breast cancer.

Breast cancer is the second most common type of cancer in the U.S. and the most common cancer in women worldwide with about 1.67 million new cases diagnosed in 2012. Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body.