By Christina Bennett, MS
At ESMO Virtual Congress 2020, the results from two randomized phase 3 trials monarchE and ASCENT showed that success is possible for breast cancer subtypes that have long eluded treatment. However, the results of IMpassion131, IMpassion130, and IMpassion031 for atezolizumab were a mixed bag.
The addition of the CDK4/6 inhibitor, abemaciclib, to endocrine therapy reduced the risk of recurrence among early breast cancer patients with hormone receptor (HR)-positive, HER2-negative disease who had a high risk for relapse, according to a prespecified interim analysis of the open-label, randomized phase 3 monarchE trial.
“This is the first study to show that adding a CDK4/6 inhibitor to endocrine therapy significantly improves invasive disease free survival in the adjuvant setting,” said Giuseppe Curigliano, Associate Professor of Medical Oncology at the University of Milan, Italy, and Chair of the ESMO Guidelines Committee in a press release statement. Dr. Curigliano was not involved in the trial.
The trial included 5,637 patients and met its primary endpoint, showing a significantly prolonged invasive disease-free survival for patients who received endocrine therapy plus two years of abemaciclib compared with patients who received endocrine therapy alone. This benefit translated to a 25.3% reduced risk of recurrence (HR=0.747; 95% CI, 0.598 – 0.932; P=0.0096).
The absolute difference for disease relapse between treatment arms was 3.5% at two years, with 11.3% of patients on the standard of care arm having relapse compared with 7.8% on the abemaciclib arm.
The distant relapse-free survival was also prolonged for the abemaciclib arm compared with the standard of care arm (HR=0.717, 95% CI, 0.559 – 0.920).
The most common adverse events in the abemaciclib arm were diarrhea, neutropenia, and fatigue. Adverse events led to 16.6% of patients discontinuing abemaciclib, with diarrhea being the most common reason for discontinuation.
Dr. Curigliano asserted that these results will change practice and that once approved the new standard of care for patients with high-risk HR-positive, HER2-negative early breast cancer will be to add two years of abemaciclib to endocrine therapy.
Currently, abemaciclib is approved only as a monotherapy or in combination with fulvestrant for previously treated patients with HR-positive, HER2-negative advanced or metastatic breast cancer.
Sacituzumab govitecan led to an improved progression-free survival (PFS) and overall survival (OS) compared with standard of care chemotherapy for patients with metastatic triple-negative breast cancer (TNBC) without brain metastases, according to data from the randomized phase 3 ASCENT trial.
“Metastatic triple-negative breast cancer is associated with poor prognosis, and there’s a need for better therapies,” said study presenter Aditya Bardia, MBBS, MPH, Massachusetts General Hospital.
An antibody–drug conjugate, sacituzumab govitecan contains an antibody for Trop-2, which is expressed in breast cancer and associated with poor outcomes, and the drug SN-38, which is the active metabolite of irinotecan.
The FDA granted sacituzumab govitecan accelerated approval in April 2020 for patients with metastatic TNBC who received two prior lines of therapy for metastatic disease. This decision was based on the 33% overall response rate and 5.4 median PFS seen with the agent in the single-arm phase 1/2 IMMU-132-01 trial.
In the ASCENT trial, 529 patients were randomized to receive sacituzumab govitecan or treatment of physician’s choice, which included capecitabine, eribulin, vinorelbine, or gemcitabine. All patients had relapsed or refractory disease and received at least two prior lines of chemotherapy for advanced or metastatic disease, one of which had to be a taxane.
Most patients (468 of 529) had no brain metastases and the data presented at ESMO were only for these patients.
The trial met its primary endpoint, showing a median PFS gain of nearly 4 months among patients who received sacituzumab govitecan compared with standard of care (5.6 vs 1.7 months; HR=0.41; P<0.0001). Patients who received sacituzumab govitecan also lived a median of more than 5 months longer compared with standard of care (12.1 vs 6.7 months; HR=0.48; P<0.0001).
A significantly higher portion of patients who received sacituzumab govitecan achieved a response compared with standard of care (35% vs 5%; P<0.0001). Most of the responses were partial responses (72 of 82), but 10 patients (4%) did achieve a complete response. By comparison, 1% of patients on the standard of care arm achieved a complete response and 4% a partial response.
Neutropenia was common for sacituzumab govitecan, with 46% of patients having grade 3 treatment-related adverse events and 17% grade 4. Also, 8% of patients who received sacituzumab govitecan had grade 3 anemia and 10% had grade 3 diarrhea.
Dr. Bardia described the treatment discontinuation rate because of adverse events as “very low.”
He concluded, “This study confirms that sacituzumab govitecan should be considered as a new standard of care for patients with pretreated metastatic triple-negative breast cancer.”
ESMO featured widely anticipated results of three randomized phase 3 studies evaluating the PD-L1 inhibitor, atezolizumab, in TNBC: IMpassion131, IMpassion130, and IMpassion031. The trial results, however, were mixed.
IMpassion131 and IMpassion130 evaluated atezolizumab under similar conditions — with the key difference being the choice of chemotherapy backbone — but demonstrated disappointing results.
The IMpassion131 trial, which enrolled 651 patients, evaluated whether adding atezolizumab to paclitaxel benefited patients with previously untreated, inoperable locally advanced or metastatic TNBC. The IMpassion130 trial, which enrolled 902 patients, evaluated whether adding atezolizumab to nab-paclitaxel benefited patients with previously untreated locally advanced or metastatic TNBC.
However, the addition of atezolizumab to paclitaxel in IMpassion131 showed neither a significant PFS nor OS benefit in the intention-to-treat (ITT) population (PFS HR=0.86; 95% CI, 0.70 – 1.05; OS HR=1.11; 95% CI, 0.87 – 1.42). A lack of significant PFS and OS benefit was also seen in the PD-L1 positive subpopulation (PFS HR=0.82; 95% CI, 0.60 – 1.12; OS HR=1.12; 95% CI, 0.76 – 1.65).
Because the addition of atezolizumab to nab-paclitaxel in IMpassion130 failed to show a significant OS benefit in the ITT population (HR=0.87; 95% CI, 0.75 – 1.02; P=0.0770), further evaluation of the PD-L1 positive population could not be formally done. (Prespecified hierarchical testing required an OS benefit in the ITT population before the PD-L1 population could be evaluated.)
As for the IMpassion031 trial, success was finally met: The addition of atezolizumab to neoadjuvant chemotherapy led to a higher pathologic complete response (pCR) rate among treatment-naïve patients with early stage TNBC.
The trial enrolled 333 patients who were randomized to receive atezolizumab and nab-paclitaxel followed by atezolizumab, doxorubicin, and cyclophosphamide (n=165) or placebo and nab-paclitaxel followed by placebo, doxorubicin, and cyclophosphamide (n=168).
Overall, 57.6% of patients who received atezolizumab and chemotherapy achieved a pCR, while only 41.1% of patients who received placebo and chemotherapy achieved a pCR, a difference that was statistically significant (P=0.0044).
However, among patients with PD-L1 positive disease, a statistically significant improvement in pCR was not seen for atezolizumab and chemotherapy compared with placebo and chemotherapy (68.8% vs 49.3%; P=0.021).
“We conclude that the PD-L1 status is not predictive for response like we see in the metastatic setting,” said study presenter Nadia Harbeck, MD, PhD, University of Munich, Germany. “I expect this therapy to become a new standard in early triple-negative breast cancer in patients who are fit for immunotherapy.”