by Chase Doyle
Cyclin-dependent kinase (CDK) inhibitors have improved survival of patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, but which subsets of patients benefit most from these agents, and when to administer them, remain unanswered questions.
Day 2 of the 2020 San Antonio Breast Cancer Symposium (SABCS) virtual meeting featured important updates to the landmark CDK inhibitor trials in both the early-stage and metastatic settings of HR-positive (HR+) breast cancer as well as follow-up analysis of the antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), which continues to demonstrate unprecedented durations of response against HER2-positive disease.
Abemaciclib Could Change Practice in Early Breast Cancer
Updated results of the monarchE study provided encouraging results to oncologists who have already begun to prescribe adjuvant abemaciclib for patients with very high-risk early breast cancer (EBC).
MonarchE is a global, randomized, Phase 3 trial that is evaluating the combination of the CDK4/6 inhibitor abemaciclib and standard endocrine therapy (ET) among 5,637 randomly assigned patients with HR+, HER2−, node-positive EBC at high risk of early recurrence.
Priya Rastogi, MD, associate professor at the University of Pittsburgh School of Medicine and medical director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, presented extended follow-up data, which continued to show a reduction in the risk of developing invasive disease-free survival (iDFS) and distant relapse-free survival (DRFS) in combination with standard endocrine therapy (Abstract GS1-01). Abemaciclib in combination with endocrine therapy is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+, HER2-negative, node-positive, high-risk early breast cancer.
With 395 events and an additional 3.6 months of median follow-up (now at approximately 19 months), the combination of abemaciclib and endocrine therapy also resulted in statistically significant improvement in iDFS in patients whose tumors are a high Ki-67 level, an indicator of cell proliferation.
Safety was consistent with the second interim analysis and the known safety profile of abemaciclib, said Dr. Rastogi, who noted that most discontinuations due to adverse events occurred within the first five months of study treatment and that patients who required a dose hold or discontinuation were able to remain on study treatment.
During Tuesday’s press conference, C. Kent Osborne, MD, of Baylor College of Medicine, in Houston, called the results “very encouraging,” especially in the subgroup of tumors with high proliferation.
Nevertheless, Dr. Osborne urged caution in the interpretation, given the relatively short follow-up and the fact that ER-positive disease often recurs years later. Dr. Osborne also noted that this class of inhibitors is largely cytostatic rather than cytocidal, and “it remains to be seen whether the iDFS curves will come together when the drug is stopped,” he said.
“With these caveats in mind, this is still an extremely important trial that could be practice-changing in this very high-risk patient population if the results continue to be positive and show improved overall survival with longer follow-up,” Dr. Osborne concluded.
The study is ongoing until the final assessment of overall survival.
Ribocliclib: Biomarker Analysis Shows Benefit Across Main Intrinsic Subtypes of Metastatic Breast Cancer
Findings presented at the SABCS could also lead to better understanding of which patients benefit from CDK4/6 inhibition. Biomarker analysis of the Phase 3 MONALEESA trials has confirmed the independent prognostic value of intrinsic subtypes in patients with HR+, HER2-negative metastatic breast cancer treated with endocrine therapy and CDK4/6 inhibitor (abstract GS1-04).
“This study clearly shows that HER2-enriched, luminal A, and luminal B subtypes exhibited a consistent PFS benefit with ribociclib treatment, while patients with the basal-like subtype did not,” said lead study author, Aleix Prat, MD, PhD, Associate Professor at the University of Barcelona, in Spain.
Importantly, said Dr. Prat, the HER2-enriched subtype, which represents 13% of all breast cancer patients and had a very poor prognosis in the placebo arm, exhibited the greatest relative reduction in risk of progression or death with ribociclin plus endocrine therapy.
Although this is an exploratory and retrospective analysis, further validation studies will be required to firmly establish the clinical utility of intrinsic subtyping in this particular context, according to Dr. Prat.
Trilaciclib Plus Gemcitabine/Carboplatin Improves Overall Survival in Metastatic Triple-Negative Breast Cancer
Another CDK inhibitor associated with improved survival, trilaciclib is a first-in-class myelosuppression agent.
A previously reported primary analysis of a Phase 2 study of patients with metastatic triple-negative breast cancer showed, somewhat surprisingly, that administering trilaciclib prior to gemcitabine plus carboplatin significantly increased overall survival compared with gemcitabine plus carboplatin alone.
During the SABCS virtual symposium, Joyce A. O’Shaughnessy, MD, chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, reported final anti-tumor efficacy results for the whole study population (n=102) as well as for subgroups, according to CDK4/6 dependence and immune subtyping (Abstract PD1-06).
“Patients receiving trilaciclib prior to gemcitabine and carboplatin had higher response rates, longer PFS, and significantly improved overall survival, compared with those receiving gemcitabine and carboplatin alone,” said Dr. O’Shaughnessy, “The addition of trilaciclib significantly increased overall survival from 12.6 months to 19.8 months, with a hazard ratio of 0.37.”
Subgroup analyses also showed that anti-tumor efficacy outcomes were similar in patients with tumors categorized as CDK4/6-dependent, confirming that trilaciclib did not antagonize the anti-tumor effects of gemcitabine and carboplatin in the CDK4/6-dependent population. Furthermore, adding trilaciclib prior to gemcitabine and carboplatin appears to preserve and enhance immune system function, said Dr. O’Shaughnessy.
“These data support further investigation of the association between enhanced anti-tumor immunity and improved survival in patients with triple-negative breast cancer receiving trilaciclib prior to chemotherapy,” she concluded.
Trastuzumab Deruxtecan: Unprecedented Duration of Response in HER2-Positive Metastatic Breast Cancer
Updated results from DESTINY-Breast01, a Phase 2 study of trastuzumab deruxtecan (T-DXd) in 184 patients with HER2-positive metastatic breast cancer who had received at least two lines of anti-HER2 based therapies, continues to demonstrate clinically meaningful and durable efficacy (Abstract PD3-06).
Lead study author, Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, called the updated median duration of response of 20.8 months “striking and unprecedented.”
With 20.5 months median duration of follow-up, the median PFS has also increased to 19.4 months, and the estimated percent of patients alive at 12 and 18 months is 85% and 74%, respectively. The preliminary median overall survival of 24.6 months is estimated at 35% maturity, so additional follow-up is required, said Dr. Modi.
Although the overall safety profile of T-DXd continues to demonstrate general tolerability with few treatment discontinuations, the antibody-drug conjugate is associated with the risk of lung toxicity called interstitial lung disease (ILD). Three new cases of T-DXd-related ILD were reported, including one death.
Most of the ILD events occurred during the first 12 months of treatment, suggesting that the risk is not related to a cumulative dose of T-DXd, said Dr. Modi. Continued attention to pulmonary symptoms and monitoring is warranted.
“The consistent benefit/risk profile provides confidence in treatment efficacy, which will be further evaluated in the ongoing, randomized controlled Phase 3 DESTINY-Breast02 trial of T-DXd versus investigators choice of treatment,” concluded Dr. Modi.
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