The first report of a significant and clinically meaningful overall survival benefit for postmenopausal women with HR-positive, HER2 negative advanced breast cancer has been achieved by adding a CDK 4/6 inhibitor to first-line hormonal treatment, according to findings presented at ESMO 2021.
The addition of ribociclib plus the aromatase inhibitor letrozole prolonged survival by one year, results from the MONALEESA-2 trial showed.
After a median follow-up of more than 6.5 years, the median OS improvement was more than 12 months for ribociclib plus letrozole compared to letrozole plus placebo, the study involving 668 patients found.
Study investigator Professor Gabriel Hortobagyi of the University of Texas MD Anderson Cancer Center, Houston, said previous studies had shown improvements progression-free survival (PFS) of about one year when CDK 4/6 inhibitors were used in combination with standard hormonal treatment. The median PFS was 25.3 months for ribociclib plus letrozole and 16.0 months for placebo plus letrozole
“These drugs were subsequently approved by the regulatory agencies and have been available for patients with HR positive, HER2 negative advanced breast cancer. Today’s results add to this by showing that the CDK 4/6 inhibitor ribociclib extends survival by one year,” he said.
In the trial, patients were excluded if they had previously received a CDK 4/6 inhibitor, chemotherapy or endocrine therapy in the advanced setting.
The results released at ESMO related to overall survival evaluated after 400 deaths and showed a median duration of 63.9 months for ribociclib plus letrozole compared with 51.4 months for placebo plus letrozole (HR, 0.76; 95% CI, 0.63-0.93; P=.004) .
Estimated 6-year OS rate was 44.2% for ribociclib vs 32.0% for placebo. Time to first chemotherapy (median, 50.6 vs 38.9 mo; HR, 0.74; 95% CI, 0.61-0.91) and chemotherapy-free survival (median, 39.9 vs 30.1 mo; HR, 0.74; 95% CI, 0.62-0.89) showed a consistent benefit for ribociclib vs placebo.
Among patients who discontinued study treatment, 87.8% vs 90.2% received a subsequent antineoplastic therapy for ribociclib vs placebo, respectively, and 21.7% and 34.4% received a subsequent CDK4/6i. No new safety signals were observed.
“To put these results into perspective, in my 45 years as an oncologist there have been tens of thousands of clinical trials for breast cancer and while a PFS benefit has been shown many, many times, we have rarely observed an improvement in overall survival,” he said.
“It is difficult to show a statistically significant extension in survival for first-line therapy in this type of breast cancer because due to the development of resistance, patients receive four to 15 different types of treatment over the course of their disease and these dilute the effect of the first therapy.”
However it is important to note that these data are related to endocrine-sensitive patients who had not previously received endocrine therapy for metastatic disease, commented Professor Giuseppe Curigliano, Clinical Director, Division of Early Drug Development for Innovative Therapy, European Institute of Oncology, Milan.
“My advice would be to compare the exceptional responders and long-term survivors with the exceptional progressors and short-term survivors,” he told the conference.
“This could identify biological features that may predict which patients benefit the most from this therapy. If a mechanism of resistance is found, then research could be conducted to develop new therapies for the non-responders.”
Professor Hortobagyi said research is ongoing to examine whether there are any subgroups in the study that benefitted more or less from treatment. “We are also looking for biomarkers, meaning proteins or other substances that could be tested to tell the physician which patients are likely to respond to therapy and which patients are unlikely to respond,” he said. “Those are very important decisions because these drugs are enormously expensive and while they are well tolerated, they do produce some side-effects and toxicities.”
He added that while this is the only CDK 4/6 inhibitor to demonstrate an overall survival benefit in this patient population so far, “we are still waiting for results of the palbociclib and abemaciclib trials. And of course there are other emerging treatments such as other kinase inhibitors so there is more research to come in this field.”