Dr. Maura N. Dickler
Dr. Nicholas C. Turner
Researchers provided updates on two drugs in development for therapy against ER–positive breast cancer during the June 3 Clinical Science Symposium, “Future Directions in Breast Cancer Treatment: New Drugs, New Markers.”
Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, provided an update on MONARCH 1, a phase II study of abemaciclib used as monotherapy in patients with HR-positive/HER2-negative breast cancer whose disease progressed on or after endocrine therapy and chemotherapy.
Nicholas C. Turner, MD, of the Royal Marsden Hospital and Institute of Cancer Research, presented an analysis of the PALOMA3 study on the efficacy of palbociclib plus fulvestrant in patients with metastatic breast cancer and ESR1 mutations in circulating tumor DNA.
MONARCH 1 Study Results
According to Dr. Dickler, previous research has shown the CDK4/6 pathway to be relevant in the progression of breast cancer tumors, whereby its activation leads to phosphorylation of the Rb gene and subsequent G1 to S cell progression. Furthermore, estrogen stimulates cyclin D1, which in turn initiates activation of CDK4/6, in ER-positive breast cancer, “making the cyclin D1 and CDK4/6 axis a rational target in this subset of breast cancer,” she said.
Studies have shown that short-term inhibition of CDK4/6 arrests G1 cell cycle progression, with rebound upon withdrawal of the agent. This, in turn, led to a hypothesis that continuous inhibition may be an effective strategy in ER-positive subtypes, Dr. Dickler said.
The single-arm phase II MONARCH 1 study evaluated abemaciclib, a highly potent inhibitor of cyclin D1 and CDK4 activity, with respect to confirmed objective response rate based on investigator assessment, which was measured using the RECIST guideline, version 1.1. Secondary objectives included duration of response, progression-free survival (PFS), overall survival (OS), clinical benefit rate, and safety.
A total of 132 patients with a median age of 58 were enrolled to the trial. Visceral metastatic disease was identified in 90.2% of patients (liver 70.5%; lung 23.5%). Bone metastatic disease was noted in 62.1% of patients. Involvement of more than one metastatic site was common, with 34.8% having two sites and 50.8% having three or more active sites of metastatic disease.
The study included a heavily pretreated patient population with patients receiving a median of three lines of prior therapy for advanced disease, including a median of two lines of chemotherapy for advanced disease. The investigator-assessed confirmed objective response rate to single agent abemaciclib was 19.7%.
Overall, 22.7% of patients had stable disease lasting for 6 months or more, translating into a clinical benefit rate of 42.4%. Among patients who responded to treatment, the median time to response was 3.7 months and the median duration of response was 8.6 months; median duration of response was at least 6 months in 70.4% of patients and 12 months in 28.2%. Median PFS was 6.0 months (95% CI [4.2, 7.5]) and median OS was 17.7 months (95% CI [16.0, not reached]).
Abemaciclib was well tolerated, as only 7.6% of patients discontinued therapy because of adverse events. Serious adverse events were reported in 32 patients (24.2%), and three patients died within 30 days of initiating study treatment.
High-grade neutropenia was an uncommon event in the safety analysis, with grade 3 neutropenia in 22.3% of patients and grade 4 in 4.6%. Creatinine elevation was observed in almost all patients but was not considered to be a clinically significant elevation as it resulted from a competitive inhibition of creatinine secretion, Dr. Dickler said.
The most commonly reported adverse events were diarrhea, fatigue, nausea, and loss of appetite. Grade 3 diarrhea was reported in 19.7% of patients; grade 3 fatigue was reported in 12.9%. Most cases of diarrhea occurred within the first cycle of treatment and resolved quickly after temporary suspension of the study drug, anti-diarrheal medications, and dose reductions for grade 3 events.
“MONARCH 1 confirmed single-agent activity of abemaciclib, a CDK4/ 6 inhibitor, in a heavily pretreated population with HR-positive, HER2-negative metastatic breast cancer,” Dr. Dickler said.
Two phase III studies are currently ongoing with abemaciclib in combination with endocrine therapies: MONARCH 2 is studying abemaciclib plus fulvestrant in endocrine pretreated metastatic breast cancer, and MONARCH 3 is studying abemaciclib plus a nonsteroidal aromatase inhibitor (AI) as initial treatment for metastatic breast cancer.
Although AI therapy may be successful in the early treatment of metastatic breast cancer, progression to advanced disease is common in less than 1 year, Florian Clatot, MD, PhD, of Centre Henri Becquerel, University of Normandy, France, said. One potential mechanism that has gained a lot of attention in recent years, he said, is mutations of the estrogen receptor 1 gene (ESR1), which may confer resistance to AI therapy.
Dr. Clatot presented results of a retrospective analysis conducted in 144 patients with HR-positive metastatic breast cancer who progressed after first-line AI therapy. The study’s aim was to understand the prognostic and predictive value of detecting ESR1 mutations with digital droplet polymerase chain reaction (PCR).
The analysis showed that 30.6% of samples presented at least one ESR1 circulating mutation; of those samples with an ESR1 mutation, 75% were detectable with digital PCR 3 to 6 months before clinical progression. Further, presence of ESR1 mutations was strongly associated with poor prognosis: median OS after progression was 15 months (range, 2-44) for patients with an ESR1 mutation and 24 months (range, 2-70) for patients without an ESR1 mutation. Presence of ESR1 was also independently prognostic of worse PFS.
However, patients with ESR1 mutations “had the worst outcomes regardless of treatment. Thus no predictive value of ESR1 mutation was observed in this study,” Dr. Clatot said.
According to Dr. Turner, an analysis of prospectively collected plasma samples of pre- and postmenopausal women with HR-positive/HER2-negative metastatic breast cancer enrolled in PALOMA 3 suggests that palbociclib may have a beneficial effect for those with ESR1 mutations.
Mutations were analyzed in 265 samples from patients randomly assigned to palbociclib and fulvestrant and in 130 patients randomly assigned to fulvestrant plus placebo. ESR1 mutations were present in 27% of the study population.
“Because of the frequency of estrogen receptor mutations in this population, the combination of palbociclib and fulvestrant presents an attractive treatment option for ESR1 mutant cancer,” Dr. Turner said.
Sarat Chandarlapaty, MD, PhD, of Memorial Sloan Kettering Cancer Center, discussed testing for ESR1 mutations. Digital PCR provides a viable means for detecting ESR1 mutations, as liquid biopsies are a potentially more sensitive detection method, he said. He added that two recent studies clearly show that ESR1 mutations are highly prevalent in patients with metastatic breast cancer who have received prior AI therapy.
Although ESR1 mutations portend an undeniably poor prognosis, Dr. Chandarlapaty said, “the weight of evidence, from biologic to clinical, implies that patients with ESR1 mutations are unlikely to benefit from second-line AI monotherapy.”
The question of whether testing should be made available when deciding on a second course of AI therapy, however, is more complicated, he said, adding that AI monotherapy as second-line therapy may no longer be a viable approach and the adoption of palbociclib as primary therapy may alter resistance patterns.
Removing Regulatory Hurdles
The “breakthrough therapy designation” was created by the FDA Safety and Innovation Act with the intent of improving collaboration between the regulatory body and industry developing drugs intended to treat serious conditions.
To be granted breakthrough designation, a drug must be intended to treat a serious or life-threatening disease or condition and must demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints in preliminary clinical testing. If those conditions are met, the FDA will expedite the development and review of the qualifying drug’s application.
In the therapeutic area of metastatic breast cancer, the new designation has already been granted to four drugs (Fig. 2), which has significantly accelerated the development process, Dr. Prowell said.
“[Breakthrough designation] provides for an ‘all hands on deck’ approach to craft an efficient development program and allows for early input from subject matter experts from all disciplines in review divisions and real-time response to development challenges while providing a proactive approach to the challenge of manufacturing readiness,” said Dr. Prowell.