Abemaciclib/Pembrolizumab Combo Shows Early Promise for HR+/HER2- Breast Cancer

The combination of abemaciclib and pembrolizumab showed preliminary signs of activity without additive toxicity for patients with pretreated HR-positive, HER2-negative metastatic breast cancer.

Hope S. Rugo, MD

The combination of abemaciclib (Verzenio) and pembrolizumab (Keytruda) showed preliminary signs of activity without additive toxicity for patients with pretreated HR-positive, HER2-negative metastatic breast cancer, according to early results from a pilot trial presented in a poster at the 2017 San Antonio Breast Cancer Symposium (SABCS).1

At a 16-week analysis, the objective response rate (ORR) with the combination was 14.3%, which was less than the response rate seen with single-agent abemaciclib in the MONARCH-1 trial (19.7%).2 However, the trial investigators noted that the median time to response for abemaciclib has historically been 3.7 months, suggesting the efficacy is likely to improve with longer follow-up. At 16 weeks, the ORR in the MONARCH-1 trial was 6.8%.

"These patients were similar to the single-agent abemaciclib MONARCH-1 data that we previously published. What's interesting about that data is that we saw that response rate only after we evaluated patients 12 months after the last patient was enrolled," lead investigator Hope S. Rugo, MD, from the University of California, San Francisco, told OncLive.

"What we saw [in the pilot study] was a response rate just over 14%, and for some patients that response appeared to be quite durable. This is very encouraging," she said. "These are patients who are not receiving any hormone therapy but are really receiving a MONARCH-1 type treatment with abemaciclib alone and then we're adding pembrolizumab on this. And, encouragingly, we really did not see any increase in toxicity."

The rationale for the trial came from preclinical data showing that abemaciclib may induce intratumor immune inflammation with synergy and enhanced efficacy seen when combined with PD-L1 blockade in the setting of anti—PD-L1 refractory disease. "The trial was based on real elegant preclinical data that showed that abemaciclib can increase the T cell infiltration of tumors and may enhance the efficacy of subsequent combined pembrolizumab," said Rugo.

In the study, which was known as JPCE, 28 patients with HR+, HER2- metastatic breast cancer were treated with abemaciclib at 150 mg every 12 hours and pembrolizumab at 200 mg on day 1 of each 21-day cycle. The study also contained two cohorts of patients with stage IV non—small cell lung cancer, one with KRAS mutations and the other with squamous histology. Findings from these cohorts were not presented at SABCS.

The median age of patients in the study was 55 years (range, 31-76), and 25% were 65 or older. Patients had an ECOG performance status of 0 (57.1%) and 1 (35.7%) and the majority had visceral metastases (78.6%). Most patients had ≥3 sites of metastatic disease (64.3%) and had received a median of 3 prior therapies for metastatic disease, which included a taxane for 82% of patients. In the MONARCH-1 study, patients received abemaciclib at 200 mg every 12 hours. The trial enrolled 132 patients following a median of 3 prior therapies.

The combination of pembrolizumab and abemaciclib did not demonstrate any unexpected adverse events (AEs), with the most common treatment-emergent AE being diarrhea (78.6%), which is a known toxicity associated with abemaciclib. Most of these events were grade 1 or 2 in severity and 7.1% of patients had grade 3 diarrhea. Serious AEs were experienced by 21.4% of patients and AEs led to discontinuation for 14.3% of those treated with the combination. There were no grade 4 or 5 AEs.

Outside of diarrhea, the most common treatment-emergent AEs of clinical interest were pruritus (25%), rash (10.7%), renal failure (7.1%), dermatitis acneiform (7.1%), and colitis, hypothyroidism, hyperthyroidism, pneumonitis (3.6% each). Grade 3 neutropenia occurred in 28.6% of patients treated with the combination.

"We're continuing our follow-up, with our real hallmark follow-up being at 24 weeks. Obviously, we need to follow these patients out until they are also a year after the last patient was enrolled, in order to really make a post-hoc comparison with the MONARCH-1 data," she said. "We're also evaluating PD-L1 status, which I think is going to be really important, as well as tumor infiltrating lymphocytes and tumor samples, which we required for all patients."

The data cutoff for the SABCS presentation was June 2017, and examined data after a minimum of 16 weeks of follow-up. With this timeframe, 12 months of follow-up for the trial should be available for analysis in the first quarter of 2018.


  1. Rugo HS, Kabos P, Dickler MN, et al. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Presented at: 2017 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 5-9, 2017. Presentation P1-09-01.
  2. Dickler MN, Tolaney S, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218-5224.

In the JPCE trial, the partial response (PR) rate at 16 weeks was 14.3% and it was 6.8% in the MONARCH-1 trial. There were no complete responses in either trial. The rate of stable disease was similar between both trials at 60.7% in JPCE and 60.6% in MONARCH-1. Fewer patients had developed progressive disease in the JPCE trial (17.9% and 25.0%). In JPCE, the disease control rate (DCR) was 75% and in MONARCH-1 it was 67.4% at the early assessment.