Abemaciclib Fails to Improve OS in KRAS+ NSCLC

Abemaciclib (Verzenio) failed to meet its primary endpoint of improving overall survival versus erlotinib (Tarceva) in patients with&nbsp;<em>KRAS</em>-mutated, advanced non&ndash;small cell lung cancer who progressed after platinum-based chemotherapy, according to topline results from the phase III JUNIPER trial.

Levi Garraway, MD, PhD

Abemaciclib (Verzenio) failed to meet its primary endpoint of improving overall survival (OS) versus erlotinib (Tarceva) in patients withKRAS-mutated, advanced non—small cell lung cancer (NSCLC) who progressed after platinum-based chemotherapy, according to topline results from the phase III JUNIPER trial.

However, the drug showed activity in an analysis of the secondary endpoints of progression-free survival (PFS) and overall response rate (ORR), according Lilly Oncology, the manufacturer of the CDK4/6 inhibitor.

“While the outcome is unfortunate for patients withKRAS-mutated, advanced lung cancer, we remain encouraged by the antitumor activity observed with abemaciclib in this form of lung cancer where few clinical advances have been achieved,” Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology, said in a press release.

“As we analyze secondary endpoints and explore specific patient subgroups in order to better evaluate the prospects for abemaciclib in NSCLC, we will continue to work with the oncology community to inform potential future treatment avenues for patients with KRAS-mutated advanced lung cancer. Moreover, we have several studies ongoing of rational combinations that include abemaciclib in non—small cell lung cancer and other malignancies. We look forward to seeing the results of these studies.”

JUNIPER is a global phase III, interventional, open-label study that was designed to evaluate the efficacy and safety of abemaciclib versus erlotinib in patients with stage IV NSCLC with a detectableKRASmutation who progressed after platinum-based chemotherapy and who may have received 1 additional systemic therapy.

A total of 453 patients were randomly assigned to receive 200 mg of abemaciclib orally twice daily or 150 mg of erlotinib at its approved dose and schedule until disease progression, unacceptable toxicity, or death. The primary endpoint of the study was OS, with key secondary endpoints of safety, ORR, and PFS.

Lilly reported that it plans to submit full findings from JUNIPER for presentation at a medical meeting in 2018.

In September 2017, the FDA approved abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer with disease progression following endocrine therapy, and as a monotherapy for patients with HR+/HER2- breast cancer with metastatic disease who have previously received endocrine therapy and chemotherapy.

The combination approval was based on data from the phase III MONARCH 2 trial, which showed that abemaciclib plus fulvestrant reduced the risk of disease progression or death by 45% versus fulvestrant alone.1The single-agent approval was based on the single-arm phase II MONARCH 1 trial, in which the median PFS in this patient population was 6 months (95% CI 4.2-7.5) and the median OS was 17.7 months (95% CI, 16 to not reached).2

In the international, double-blind phase III MONARCH 2 trial, patients were randomly assigned to abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease. Individuals were excluded from enrollment if they were administered chemotherapy or more than 1 endocrine therapy in the metastatic setting.

Following 379 PFS events in the intent-to-treat population, the median PFS was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group (HR, 0.553; 95% CI, 0.449-0.681;P<.0000001). The overall response rates (ORRs) among patients with measurable disease favored the abemaciclib group, were 48.1% versus 21.3%.

In MONARCH 1, 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. The median age was 58 years (range, 36-89), 44.7% of patients had an ECOG performance status of 1, 90.2% had visceral disease, and 85.6% had at least 2 metastatic sites. Patients with CNS metastases were excluded from enrollment.

The investigator-assessed, confirmed ORR was 19.7% (n = 26; 95% CI, 13.3-27.5), which included all partial responses (PR), and the clinical benefit rate was 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months. Thirty-four patients had progressive disease.

In MONARCH 2, the most frequently reported grade 3 AEs in the abemaciclib versus fulvestrant-alone arms were neutropenia (23.6% vs 1.3%) and diarrhea (13.4% vs 0.4%). Grade 4 neutropenia occurred in 2.9% versus 0.4% of the abemaciclib and fulvestrant-alone groups, respectively. There were 3 deaths in the abemaciclib arm linked to treatment-related AEs, compared with none in the control arm.

Leukopenia (27.4%) and neutropenia (22.3%) were the most common laboratory AEs in MONARCH 1. The only grade 4 AE of any kind in the trial was neutropenia, which occurred in 4.6% of patients.

Serious AEs occurred in 24.2% (n = 32) of patients, with AEs leading to treatment discontinuation in 7.6% (n = 10) of patients. Dose reductions were required for 49.2% of patients (n = 65). The most common reason for dose reductions were diarrhea (20.5%) and neutropenia (10.6%). There were 2 patient deaths during treatment and 1 patient death within 30 days after study discontinuation.


  1. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy.J Clin Oncol35, 2017 (suppl; abstr 1000).
  2. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease.J Clin Oncol34, 2016 (suppl; abstr 510).