Chemo-Free Regimen for Endometrial Cancer Produces Durable Responses, Favorable PFS

SAN JUAN, Puerto Rico — A chemotherapy-free regimen for advanced/recurrent endometrial cancer achieved durable disease control in a substantial portion of patients, according to a study reported here.

Almost 60% of patients met the primary endpoint of progression-free survival (PFS) at 6 months with the CDK4/6 inhibitor abemaciclib (Verzenio) and the aromatase inhibitor (AI) letrozole. Median PFS reached almost 10 months, driven primarily by patients with previously untreated disease. Median overall survival (OS) had yet to be reached.

The regimen had a manageable safety profile with no new or unexpected toxicity, and the results compared favorably with recent historical results with non-chemotherapy regimens, reported Marilyn Huang, MD, of the University of Virginia School of Medicine in Charlottesville, at the Society of Gynecologic Oncology meeting.

“The trial met the primary endpoint, with a 6-month PFS of 56.9% and more than half of patients alive after 4 years of follow-up,” said Huang. “Activity was most pronounced in the chemo-naive population… . Translational studies are planned and ongoing. These results support further development of this oral chemotherapy-sparing approach and underscores the need for a front-line, biomarker-driven trial in this population.”

The trial borrowed from experience in the field of breast cancer, where abemaciclib and letrozole are well established hormonal therapies, said invited discussant Roisin O’Cearbhaill, MD, of Memorial Sloan Kettering Cancer Center in New York City.

“This phase II, signal-seeking trial had an objective response rate of 39% and showed durable responses, in particular for those who were chemo-naive,” she said. “Moving away from the traditional chemo approach, and we have a vast landscape with many [potential options].”

“We have learned that there is a certain subset of patients who definitely still require chemotherapy, but great effort should be ongoing in terms of endocrine and targeted strategies, as these are increasingly viable options, particularly for your younger patients in the early setting,” O’Cearbhaill continued. “Non-chemotherapy approaches in breast cancer may inform mechanisms of resistance and also activity.”

Endometrial cancer has a strong biologic rationale for endocrine-based therapy, particularly in the nonspecific molecular profile subgroup, which are predominantly hormone receptor (HR)-positive endometrioid tumors, Huang noted by way of introduction to the GOG-3039 trial. However responses to hormonal therapy alone are modest and often not durable.

Estrogen signaling activates the cyclin D/CDK complex to promote cell cycle progression. CDK4/6 inhibitors target the pathway to block cell-cycle transition and induce cell-cycle arrest.

“That strategy has been highly effective in hormone receptor-positive breast cancer, providing a compelling basis for evaluation in endometrial cancer,” said Huang.

A previous study showed that a targeted agent plus endocrine therapy improved the clinical benefit rate in recurrent endometrial cancer as compared with hormonal therapy.

In HR-positive recurrent breast cancer, the combination of an AI and a CDK4/6 inhibitor has significantly improved PFS as compared with an AI alone. Combining the CDK4/6 inhibitor palbociclib (Ibrance) with letrozole significantly improved PFS in HR-positive advanced/recurrent endometrial cancer as compared with letrozole alone. Single-institution studies of abemaciclib and endocrine therapy also have shown promising activity in HR-positive endometrial cancer, leading to the multicenter, single-arm GOG-3039 trial.

Eligible patients had recurrent or FIGO stage III or IV endometrial cancer that had endometrioid histology and was not amenable to surgery or radiotherapy. Treatment consisted of abemaciclib and letrozole daily until disease progression. The primary endpoint was PFS at 6 months.

Data analysis included 51 patients who received planned treatment. A majority of the patients (n=30, 58.8%) had FIGO stage I disease, followed by FIGO stage II/III (17, 33.3%) and stage IV (four, 7.8%). In 32 cases, patients had received up to two prior lines of therapy, and the rest had no prior treatment.

The 6-month PFS of 56.9% included 46.7% in the subgroup of patients with prior chemotherapy, whereas chemotherapy-naive patients had a 6-month PFS of 71.4%. Five patients had complete responses and 15 had partial responses amounting to an overall response rate of 39.2%. An additional 16 patients had stable disease, resulting in a clinical benefit rate of 70.6%.

The patients had a median PFS of 9.5 months, diverging substantially by treatment history. Patients with no prior therapy had a median PFS of 12.7 months as compared with 6.9 months for the previously treated subgroup.

Fatigue and diarrhea were the most common all-grade adverse events (68.6% and 66.7%, respectively) followed by increased creatinine (41.2%), infection (39.2%), anemia and neutropenia (37.3% each), and anorexia (33.3%). The most common grade ≥3 AEs were neutropenia (15.7%) and fatigue and anemia (11.8% each).