SABCS 2021: Updates from Breast Cancer Clinical Trials

Investigators presented key findings in triple-negative breast cancer and metastatic disease

The 2021 San Antonio Breast Cancer Symposium (SABCS) heralded promising clinical trial results for breast cancer patients—particularly for those living with metastatic disease. Findings at this year’s symposium showed that we’re making progress to expand and improve treatment options and tackle some of breast cancer’s biggest challenges, including brain metastases and triple-negative disease.

Here, we report the highlights from this year’s conference presentations on triple-negative, hormone receptor (HR)–positive/HER2-negative, and HER2-positive breast cancer. Click these links to jump ahead to each section below.

Developments in Triple-Negative Breast Cancer (TNBC)

Immunotherapy benefits seen in early and advanced TNBC, and PD-L1 protein levels reported to be a key indicator of response in advanced disease

The utility of adding pembrolizumab (Keytruda®)—an immunotherapy agent that targets the PD-L1 protein—to a chemotherapy regimen for treating early-stage and high-risk TNBC or advanced TNBC was the subject of two major sessions at SABCS that detailed the results of KEYNOTE-355 (NCT02819518) and KEYNOTE 522 (NCT03036488). Pembrolizumab targets the PD-1/PD-L1 pathway, which is utilized by tumor cells to evade the immune system.

Presenting final overall survival analyses of Keynote 355, Dr. Javier Cortes of the International Breast Cancer Center in Madrid reported that a baseline level of PD-L1-positivity is a marker of response to pembrolizumab in patients with advanced TNBC tumors. KEYNOTE-355 is a phase III study of chemotherapy with and without the addition of pembrolizumab in advanced TNBC. Previous reports have confirmed that patients with newly diagnosed locally advanced or metastatic TNBC and high tumor levels of PD-L1 experienced improved progression-free and overall survival when treated with pembrolizumab plus chemotherapy compared to those receiving chemotherapy alone.

KEYNOTE-355 showed a significant (27 percent) reduction in the risk of death for patients whose tumors were highly positive for PD-L1, as measured by a Combined Positive Score (CPS) of 10 or higher. CPS measures the number of PD-L1 positive tumor and immune cells compared to all cells in a tissue sample. Overall, survival with pembrolizumab plus chemotherapy was 23 months in the group with scores over 10 versus 16.1 months in the group with scores under 10; whereas progression-free survival was 9.7 months versus 5.6 months, respectively.

“These results provide strong support for pembrolizumab plus chemotherapy as standard of care for patients with tumors strongly positive for PD-L1,” BCRF investigator Dr. Hope Rugo said in the ASCO Post.

KEYNOTE-522 is a phase III clinical study that tested the efficacy of pembrolizumab plus capecitabine (a chemotherapy agent) in people with early-stage (II or III), high-risk TNBC. Prior results revealed that this combination significantly extends treatment response duration. Study investigator Dr. Peter Schmid of Queen Mary University of London presented a subgroup analysis from this study.

At a median follow up of 39 months, results indicate that the addition of pembrolizumab to capecitabine provided a significant and clinically meaningful improvement in event-free survival (EFS) in patients with early-stage, but high-risk TNBC: 84.5 percent of patients in the pembrolizumab treatment arm were disease-free at 36 months versus 76.8 percent in the capecitabine plus placebo arm. The EFS benefit was consistent across all subgroups analyzed, including disease stage, lymph node involvement, and menopausal status.

These results provide clear support for the use of pembrolizumab in combination with chemotherapy and offer a promising treatment strategy for TNBC patients at high-risk for early-stage disease.

Genomic profiling improves treatment response in metastatic HER2-negative breast cancer

Multigene sequencing of tumors has been widely used in clinical research, but to date, it hasn’t been clear if it is useful in guiding treatment decisions. Presenting results from the SAFIR02 (NCT02299999) phase II clinical trial, BCRF investigator Dr. Fabrice André reported that multigene sequencing is able to match targeted therapies to genomic alterations in individual metastatic HER2-negative breast cancer patients in the study—thereby improving their treatment outcomes. The study further demonstrated that only genomic alterations that met a clinical threshold (tier I or II on the ESMO Scale for Clinical Actionability for molecular Targets/ESCAT) were helpful in informing targeted therapy.

In 115 patients whose tumor showed ESCAT I/II alterations, progression-free survival was 9.1 months in those receiving targeted therapy plus chemotherapy compared to 2.8 months in those receiving chemotherapy alone. Targeted therapies were not effective when matched to alterations that did not meet the ESCATI/II rating.

“These finding suggest that genomics should be part of the pathway of care, but it has no impact if the results are not interpreted using a validated framework of clinical actionability of the gene alterations identified,” Dr. André said in closing remarks.

Read more about SAFIR02 and genomic profiling in precision medicine from our coverage of Dr. André’s Outstanding Investigator Award lecture here.

Developments in Metastatic HR-Positive/HER2-Negative Breast Cancer

EMERALD trial brings hope to patients with metastatic estrogen receptor-positive/HER2-negative breast cancer that has advanced on CDK4/6 treatment

CDK4/6 inhibitors have dramatically extended the lives of many patients with metastatic estrogen receptor (ER)–positive/HER2-negative breast cancer. However, when patients experience disease progression on these agents, there are limited options available.

The EMERALD trial (NCT03778931) is an international phase III randomized trial to compare the efficacy of elacestrant—an oral selective estrogen receptor degrader (SERD)—to standard of care (fulvestrant/Faslodex® or aromatase inhibitor) in postmenopausal women and men with advanced or metastatic ER-positive/HER2-negative breast cancer. Patients enrolled on the trial had progressed on other endocrine plus CDK4/6 inhibitor therapies.

Presenting results of the primary analysis of the EMERALD study, Dr. Aditya Bardia of Massachusetts General Hospital in Boston reported that patients receiving elacestrant had a 30 percent reduction in risk of progression at 12 months compared to patients receiving standard of care. The benefit was even greater in patients with tumors that harbor mutations in ESR1, a common event in metastatic ER-positive breast cancer. In patients with ESR1 tumor mutations, the risk of progression at 12 months was reduced by 45 percent with elacestrant.

Final overall survival analysis is expected in late 2022. Read more about the study here.

MONALEESA trials confirm tumor intrinsic subtype as a prognostic marker for the CDK4/6 inhibitor ribociclib

Previous reports from the MONALEESA 2, 3, and 7 trials showed that ribociclib (Kisquali®) plus anti-estrogen hormone therapy improved progression-free survival and overall survival in patients with HR-positive/HER2-negative metastatic breast cancer. Also, as previously published by study investigator Dr. Aleix Prat of the August Pi i Sunyer Biomedical Research Institute in Barcelona, the efficacy of ribociclib as determined by progression-free survival varied by tumor subtype with luminal and HER2-enriched subtypes being responsive to the CDK4/6 inhibitor, while basal-like tumors were not.

BCRF investigator Dr. Lisa Carey presented the OS data for MONALEESA and emphasized that intrinsic subtype is important in the effectiveness of ribociclib in this patient population. The pooled analysis included 1,000 patients with HR-positive/HER2-negative metastatic breast cancer whose tumors were subtyped (luminal A, luminal B, HER2-enriched, or basal-like). As in the progression-free survival analysis, OS benefit was seen in patients with luminal and HER2-enriched tumors but not basal-like tumors. Of note, the greatest survival benefit with ribociclib was observed for patients with luminal tumors (68 months compared to 54.6 months with hormone therapy alone). Additionally, patients with HER2-enriched tumors, which are associated with worse prognosis, experienced a significant survival benefit (40.3 months with ribociclib compared to 29.4 months with hormone therapy alone).

In an interview with the ASCO Post, Dr. Carey suggested that while it is too soon to incorporate intrinsic subtyping into metastatic breast cancer decision-making, she believes it will happen in the near future.

Liquid biopsy is a potential tool to inform treatment decisions before detectable tumor progression in metastatic breast cancer

PADA-1 (NCT03079011) is a randomized phase III trial in patients with newly diagnosed ER-positive/HER2-negative metastatic breast cancer receiving an aromatase inhibitor (AI) plus Palbociclib (Ibrance®). Using liquid biopsy, patients were screened for circulating blood ESR1 mutations at the start of the trial and at regular intervals throughout treatment. Patients with detectable increases in ESR1 were randomized to either receive fulvestrant instead of the AI or continue with the AI. All patients continued to receive palbociclib.

Presenting results following a median of 26 months after randomization, Dr. François-Clément Bidard of Institut Curie in Paris reported that patients randomized to fulvestrant were 37 percent less likely to have experienced disease progression compared to patients who continued standard care with the aromatase inhibitor. The study highlights the potential utility of liquid biopsy in identifying patients at risk of progression before they have detectable new metastasis.

Developments in HER2-Positive Breast Cancer with Brain Mets

HER2CLIMB confirms tucatinib benefit

HER2CLIMB (NCT02614794) is a randomized phase II clinical trial testing the HER2-targeting agent, tucatinib (Tukysa®) in combination with standard of care treatment with Herceptin® and capecitabine in people with advanced HER2-positive breast cancer, including those with brain metastases. Patients had received prior lines of treatment such as Herceptin®, Perjeta®, and chemotherapy, but unfortunately experienced a worsening of their disease on these drugs. The results of this trial led to the FDA approval of tucatinib, the first ever drug with notable activity in brain metastases.

At SABCS, BCRF investigator Dr. Nancy Lin presented updated results on overall survival. She reported that after a total of 29.6 months (median 15.6 months) tucatinib in combination with trastuzumab and capecitabine provided an improved overall survival benefit of 9.1 months above that seen with trastuzumab and capecitabine alone. Moreover, this represented an increase of three months in overall survival compared to what was reported in previous analysis. Read more about trial here.

Fam trastuzumab deruxtecan outperforms ado trastuzumab emtansine

DESTINY-Breast03 (NCT03529110), an international randomized phase III trial, compared the efficacy of two HER2-targeted antibody drug conjugates (anti-cancer drugs that attach a drug to an antibody that targets the HER2 protein on tumor cells) called fam trastuzumab deruxtecan (T-DXd/Enhertu®) and ado trastuzumab emtansine (T-DM1/Kadcyla®).

This study was conducted in patients with metastatic HER2-positive breast cancer whose cancer was inoperable and had progressed on trastuzumab and taxane chemotherapy. Results from DESTINY-Breast01 led to FDA approval of T-DXd in 2019. In previous results presented at the 2021 ESMO Breast meeting, Breast03 trial investigators reported that T-DXd showed significant improvement over T-DM1 in progression-free survival with a 72 percent reduction in risk of progression compared to T-DM1.

Presenting at SABCS, Dr. Sara Hurvitz of the University of California, Los Angeles reported on the outcomes in patients with brain metastases. Results showed a median progression-free survival of 15 months with T-DXd versus three months with T-DM1, including a 27.8 percent complete response in intracranial disease (no evidence of disease in the brain) with T-DXd versus 2.8 percent with T-DM1. Thirty-two percent of patients progressed on T-DXd compared to 60 percent receiving T-DM1. Dr. Hurvitz cautioned that while the response rate seen in intracranial disease is intriguing and exciting, it will be important to see the results of large, randomized trials to understand the activity of T-DXd in untreated or progressing brain metastases.

More from BCRF’s coverage of SABCS 2021:

• Three BCRF Investigators Honored at 2021 San Antonio Breast Cancer Symposium
• Behind the Breakthroughs: The Future of Personalized Medicine with Fabrice André
• SABCS 2021: Highlights and Takeaways from The Conference