Dalpiciclib-fulvestrant combination improves PFS in advanced breast cancer
The addition of dalpiciclib to fulvestrant appeared effective and safe for certain patients with advanced breast cancer, according to randomized phase 3 study results presented during the virtual ASCO Annual Meeting.
The combination significantly improved PFS among patients with hormone receptor-positive, HER2-negative advanced breast cancer that progressed or relapsed after endocrine therapy.
The regimen also exhibited a manageable safety profile.
“These findings support dalpiciclib plus fulvestrant as a new treatment option [for this patient population],” Binghe Xu, MD, director of the department of medical oncology at Cancer Hospital and Institute at Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and colleagues wrote.
Hyperactivity of the cyclin-dependent kinase (CDK) 4/6 pathway is common among patients with hormone receptor-positive breast cancer, and it is considered a key contributor to endocrine therapy resistance.
Prior studies have shown the combination of CDK 4/6 inhibitors and endocrine therapy can extend survival among pretreated patients with hormone receptor-positive, HER2-negative breast cancer whose disease progressed on endocrine therapy.
Dalpiciclib (SHR6390, Jiangsu Hengrui Medicine Co.) — a novel CDK 4/6 inhibitor — demonstrated preliminary antitumor activity and also appeared tolerable as monotherapy for pretreated hormone receptor-positive, HER2-negative advanced breast cancer.
In the double-blind DAWNA-1 study, Xu and colleagues evaluated the agent in combination with fulvestrant as treatment for hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer that progressed or relapsed on prior endocrine therapy.
The study included 361 patients with an ECOG performance status 0 or 1 who received up to one prior line of chemotherapy for recurrent or metastatic disease.
Researchers randomly assigned 241 patients to 150 mg oral dalpiciclib daily on days 1 to 21 of each 4-week cycle plus 500 mg fulvestrant administered intramuscularly on days 1 and 15 of the first 4-week cycle, followed by day 1 of each subsequent cycle. The other 120 patients received placebo plus fulvestrant.
The dalpiciclib and placebo groups appeared balanced with regard to age (median, 51 years vs. 52 years), menopausal status (postmenopausal, 56% vs. 55%), hormone receptor status (ER-positive and PR-positive, 79.7% vs. 75.8%), presence of measurable disease (82.2% vs. 83.3%), number of metastatic sites ( 4, 82.6% vs. 81.7%) and visceral metastases (yes, 58.9% vs. 62.5%).
Approximately three-quarters of patients in each group received one prior line of endocrine therapy (72.6% vs. 72.5%). A lower percentage of patients assigned the experimental regimen had received salvage chemotherapy (27% vs. 35%); however, rates of prior neoadjuvant (14.9% vs. 15.8%) and adjuvant (83% vs. 85%) chemotherapy were similar.
Investigator-assessed PFS served as the primary endpoint.
Secondary endpoints included PFS assessment by independent review committee, OS, objective response rate, clinical benefit rate, duration of response, time to first subsequent chemotherapy and safety.
Stratification factors included visceral metastases (yes or no) and menopausal status (postmenopausal vs. pre- or perimenopausal).
Xu and colleagues presented results of a preplanned interim analysis performed after 162 events (71.4% of expected), defined as death or disease progression.
Median follow-up was approximately 10.7 months. At data cutoff, 144 patients (59.7%) assigned the combination and 43 (35.8%) assigned to the control group remained on treatment.
Results showed patients assigned the dalpiciclib-fulvestrant combination achieved significantly longer median investigator-assessed PFS (15.7 months vs. 7.2 months; HR = 0.42; 95% CI, 0.31-0.58). The PFS benefit appeared consistent in an independent review committee assessment (13.6 months vs. 7.7 months; HR = 0.45; 95% CI, 0.32-0.64).
Researchers observed the PFS benefit in prespecified subgroups, such as those according to menopausal status, visceral metastases or prior lines of endocrine therapy.
Independent review committee assessment identified no complete responses in either treatment group; however, results showed a higher partial response rate (30.3% vs. 15.8%) and lower rate of progressive disease (7.5% vs. 15%) in the dalpiciclib group.
The dalpiciclib-fulvestrant combination also significantly extended median time to first subsequent chemotherapy as determined by investigator assessment (not reached vs. 14.2 months; HR = 0.47; 95% CI, 0.32-0.69).
OS data had not matured by data cutoff.
Among patients assigned the experimental combination, median duration of treatment exposure was 9.4 months (interquartile range [IQR], 4.3-11.4) for dalpiciclib and 9.9 months (IQR, 4.7-11.9) for fulvestrant. In the control group, median duration of treatment exposure was 5.8 months (95% CI, 3.1-10.4) for placebo and 6.1 months (IQR, 3.7-11) for fulvestrant.
Nearly all patients in the experimental group and control group experienced adverse events (99.6% vs. 90%), but a considerably higher percentage of patients assigned dalpiciclib experienced grade 3 or grade 4 adverse events (88.3% vs. 11.7%).
A comparable percentage of patients in the experimental group and control group experienced serious adverse events (5.8% vs. 6.7%) and discontinued treatment due to adverse events (2.5% vs. 3.3%).
Two patients (0.8%) in the dalpiciclib group and four (3.3%) in the control group experienced adverse events that led to death.
The most common grade 3 or grade 4 adverse events reported more frequently in the dalpiciclib-fulvestrant group included neutropenia (84.2% vs. 0%), leukopenia (62.1% vs. 0%), thrombocytopenia (5.8% vs. 0.8%) and lymphopenia (5% vs. 0%).
In the experimental group, median time to first onset of neutropenia was 15 days (range, 14-15) and median duration of grade 3 or higher events was 3 days (range, 2-4). No neutropenia cases led to treatment discontinuation, and researchers reported no cases of febrile neutropenia.
When we look at the baseline characteristics of patients in this study, those assigned dalpiciclib-fulvestrant had a bit less exposure to chemotherapy; otherwise, the groups were well-balanced, as expected in a randomized study.
We see a dramatic improvement in PFS — the primary endpoint — in favor of dalpiciclib added to fulvestrant, showing this is an active agent. The toxicity profile seems to be consistent with the CDK 4/6 inhibitor class effect, with neutropenia being the most common adverse event and no major signals of adverse events.
So what are the take-home messages [of this study and others of CDK 4/6 inhibitors presented at ASCO]?
Fulvestrant plus a CDK 4/6 inhibitor remains the treatment of choice for patients who experience disease progression on front-line systemic therapy. There is no role for biomarkers beyond the classic hormone receptor and defining HER2 positivity or negativity. The benefit is maintained across subgroups, such as disease-free interval, prior chemotherapy and visceral disease. There also is confirmed activity with this new agent, dalpiciclib.
Sequencing remains a very interesting open question. One could imagine there could be differences if we tried to give endocrine therapy with CDK 4/6 inhibitors in the first-line setting ... and would the results be different based on specific subtype?
There are novel endocrine therapy backbones — novel selective estrogen receptor degraders with the ability to target ESR1 mutations with more efficacy. Those studies are ongoing, and it will be very interesting to see how the data play out. It also will be particularly interesting to see the benefit of CDK 4/6 inhibitors for patients who have HER2-positive, ER-positive disease.
I really believe we are just touching the tip of the iceberg when comes to thinking about underlying mechanisms of resistance. We need to be clear about trying to evaluate endocrine sensitivity at the tissue level and not just focus on the classic mutations as we have been doing in more recent studies. There also are novel CDK inhibitors being developed, so we’ll continue to learn a lot from these agents.
Perspective
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The results of the DAWNA-1 study add to the existing body of evidence that supports significant activity of CDK 4/6 inhibitors in combination with endocrine therapy for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.
This presentation was important to see alongside the follow-up presentations for the PALOMA-3 and MONALEESA 3 studies, as all three reinforce the importance of utilizing the combination of a CDK 4/6 inhibitor with fulvestrant for patients who have not previously received a CDK4/6 inhibitor. The study also reinforces the safety profile of the CDK 4/6 inhibitors with no new toxicity signals being observed.
It is key to note that this study was started when no CDK 4/6 inhibitors were approved in China and, thus, provided an important therapeutic option for patients.
Although the results of DAWNA-1 likely are compelling enough to bring dalpiciclib to clinical practice, this makes the CDK 4/6 inhibitor space even more crowded while leaving clinicians without biomarkers that aid in patient and/or specific agent selection. Many questions remain regarding sequencing therapies in this disease space and determining therapeutic differences between agents in the class of CDK 4/6 inhibitors. Studies that address these questions are the necessary next steps forward in improving our ability to best utilize these drugs.
In the immediate future, I see dalpiciclib being added to our treatment arsenal for patients but do not envision that the results of this study will significantly influence current practice patterns with respect to individual provider preference for a particular CDK 4/6 inhibitor.
Perspective
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When we look at the baseline characteristics of patients in this study, those assigned dalpiciclib-fulvestrant had a bit less exposure to chemotherapy; otherwise, the groups were well-balanced, as expected in a randomized study.
We see a dramatic improvement in PFS — the primary endpoint — in favor of dalpiciclib added to fulvestrant, showing this is an active agent. The toxicity profile seems to be consistent with the CDK 4/6 inhibitor class effect, with neutropenia being the most common adverse event and no major signals of adverse events.
So what are the take-home messages [of this study and others of CDK 4/6 inhibitors presented at ASCO]?
Fulvestrant plus a CDK 4/6 inhibitor remains the treatment of choice for patients who experience disease progression on front-line systemic therapy. There is no role for biomarkers beyond the classic hormone receptor and defining HER2 positivity or negativity. The benefit is maintained across subgroups, such as disease-free interval, prior chemotherapy and visceral disease. There also is confirmed activity with this new agent, dalpiciclib.
Sequencing remains a very interesting open question. One could imagine there could be differences if we tried to give endocrine therapy with CDK 4/6 inhibitors in the first-line setting ... and would the results be different based on specific subtype?
There are novel endocrine therapy backbones — novel selective estrogen receptor degraders with the ability to target ESR1 mutations with more efficacy. Those studies are ongoing, and it will be very interesting to see how the data play out. It also will be particularly interesting to see the benefit of CDK 4/6 inhibitors for patients who have HER2-positive, ER-positive disease.
I really believe we are just touching the tip of the iceberg when comes to thinking about underlying mechanisms of resistance. We need to be clear about trying to evaluate endocrine sensitivity at the tissue level and not just focus on the classic mutations as we have been doing in more recent studies. There also are novel CDK inhibitors being developed, so we’ll continue to learn a lot from these agents.
Harvard Medical School
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Xu B, et al. Abstract 1002. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.