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One development in HER2-positive breast cancer stood out among the rest in 2021: A trastuzumab-based antibody drug conjugate (ADC) as second-line treatment for advanced disease. Several others suggested potential for incremental improvement in outcomes, and a surgery study continued the longstanding debate over the importance of the primary tumor in metastatic disease.

'Startling' Improvement in PFS

The ADC trastuzumab-deruxtecan (Enhertu) more than doubled 12-month progression-free survival (PFS) in a randomized comparison with trastuzumab-emtansine (Kadcyla) as second-line therapy for advanced HER2-positive breast cancer.

Initial results, reported at the 2021 European Society for Medical Oncology (ESMO) virtual congress, showed a 12-month PFS of 75.8% with trastuzumab deruxtecan (T-DXd) versus 34.1% with trastuzumab emtansine (T-DM1). The 41.7% absolute difference translated into a 71.6% reduction in the hazard for disease progression or death in favor of T-DXd. Median PFS was 6.8 months with T-DM1 versus not yet reached in the T-DXd arm by independent review. Investigator-assessed PFS yielded median values of 25.1 versus 7.2 months with T-DXd and T-DM1, respectively.

"These data support T-DXd becoming the standard of care for second line HER2-positive metastatic breast cancer," said Javier Cortés, MD, of the International Breast Cancer Center, Quiron Group, in Barcelona.

ESMO invited discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center in New York City, characterized the results as precedent setting.

"These PFS curves ... are absolutely startling, as is the hazard ratio of 0.28 and the P-value of 10^-22," she said. "I don't believe I've seen a hazard ratio like this in HER2 breast cancer before."

Cortés reported the primary analysis of the phase III trial, which involved 500 patients with unresectable/metastatic HER2-positive breast cancer who progressed after first-line treatment with trastuzumab (Herceptin) and a taxane. Before the trial, T-DM1 represented standard of care in second line on the basis of the trial.

Beyond the results for PFS, the primary outcome, a preliminary analysis of overall survival (OS) showed 12-month values of 94.1% versus 85.9% (HR 0.56, 95% CI 0.36-0.86), a difference that did not meet prespecified requirements for statistical significance. Objective response rates were 79.7% with T-DXd and 34.2% with T-DM1.

T-DXd was associated with a reassuringly low rate of lung toxicity, which reached 16% in DESTINY Breast-01 and was a concern going into DESTINY Breast-03, said Modi, who was principal investigator of the earlier trial.

Another ADC Makes Its Case in Metastatic Disease

An investigational ADC significantly improved PFS versus standard-of-care therapy for patients with previously treated metastatic HER2-positive breast cancer.

Median PFS increased from 4.9 months with investigator's choice of targeted therapy to 7.0 months with trastuzumab duocarmazine (SYD985). A preliminary OS analysis showed a trend in favor of the ADC (20.4 vs 16.3 months).

"SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic breast cancer," said Cristina Saura Manich, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, during the ESMO virtual congress.

The findings came from the phase III trial that included 437 patients who had received two prior regimens or T-DM1. Patients were randomized 2:1 to SYD985 or to one of four regimens pairing a targeted agent with chemotherapy.

ESMO invited discussant Barbara Pistilli, MD, of Gustave Roussy Cancer Center in Villejuif, France, said the two positive studies with different ADC regimens (DESTINY Breast-03 and TULIP) suggested a potential for more individualized treatment of advanced HER2-positive breast cancer, as well as the possibility of sequential treatment.

Ocular toxicity was the most common treatment-emergent adverse event with SYD985 and led to a discontinuation rate of 20.8%.

More Fuel for Debate Over Primary Surgery

An analysis of almost 13,000 patients with metastatic breast cancer and known hormone receptor status showed that surgery for the primary tumor significantly improved OS versus systemic therapy alone.

Surgery plus radiation therapy and systemic therapy (trimodal) led to a 5-year OS of 38%, 32% for surgery and systemic therapy, 21% for systemic therapy alone, and 19% for systemic therapy and radiation therapy (P<0.001). Patients with HER2-positive breast cancer had the best results with trimodal therapy (5-year OS of 48%) and with surgery and systemic therapy (41%). Systemic therapy alone led to a 5-year OS of 29% (P<0.0001).

Patients who received neoadjuvant systemic therapy, as opposed to adjuvant therapy, obtained the largest survival benefit, reported Chan Shen, PhD, of Pennsylvania State University College of Medicine in Hershey, and colleagues in the Annals of Surgical Oncology.

"In contrast to the results of other analyses, our findings were focused on a population of patients whose hormone receptor and HER2 status were known," the authors stated. "The responses of stage IV breast cancer patients with various treatment regimens stratified and analyzed by biologic subtypes has not been reported previously."

About 6% of breast cancers are metastatic at diagnosis. Although the disease remains incurable, recent treatment advances, particularly systemic therapies, have substantially improved survival. Multiple studies have examined the impact of surgery for the primary tumor and yielded conflicting results. Results of a recent randomized trial showed no OS benefit with primary surgery but could not rule out a potential benefit for selected patients with de novo metastatic breast cancer.

No Response Boost with Add-On Neoadjuvant Atezolizumab

Adding an immune checkpoint inhibitor to standard neoadjuvant systemic therapy failed to improve pathologic complete response (pCR) in early HER2-positive breast cancer, a randomized placebo-controlled trial showed.

Standard therapy, with or without atezolizumab (Tecentriq), led to a pCR rate of 62%-63%. A prespecified analysis limited to patients with PD-L1-positive tumors showed a pCR rate of 64.2% with atezolizumab and 72.5% with placebo plus standard therapy, reported Jens Huober, MD, of Cantonal Hospital in St. Gallen, Switzerland, during a ESMO virtual plenary session.

Huober said the results should be interpreted cautiously, pending analysis of longer-term outcomes, such as event-free survival (EFS). A of neoadjuvant durvalumab (Imfinzi) also showed a modest impact on pCR versus standard therapy in early triple-negative breast cancer but significant improvement in 3-year outcomes.

"So pCR may not be the appropriate endpoint to catch the long-term benefit of the response to immunotherapy," Huober said, suggesting that trials should be powered to detect the difference in survival endpoints like EFS and OS, "because this may allow a better measurement of immunotherapy's antitumor effects over time."

Investigators may have set the bar too high with statistical assumptions that the addition of atezolizumab would increase the pCR rate from 60% to 80% in the intention-to-treat population and from 70% to 90% in the PD-L1-positive subgroup.

"These are already quite high pathological complete response rates. Maybe [the researchers] were too ambitious in these endpoints," said ESMO invited discussant Evandro de Azambuja, MD, PhD, of the Jules Bordet Institute in Brussels.

The results came from the trial, which accrued 454 patients with early HER2-positive, node-positive breast cancer. They all received standard neoadjuvant chemotherapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta) and were randomized to the PD-L1 inhibitor atezolizumab or placebo. Following surgery, patients received maintenance trastuzumab and pertuzumab plus atezolizumab or placebo. The primary endpoint was pCR in the intention-to-treat and PD-L1-positive populations.

Other developments in HER2-positive breast cancer during 2021 included:

Trial Looks to Double Down on Anti-HER2 in Breast Cancer

Different Taxanes, Similar Outcomes in Advanced HER2-Positive Breast Cancer

New Chemotherapy -- Sparing Option for HER2/HR-Positive Metastatic Breast Cancer

Nancy Lin, MD, on Breast Cancer With Brain Metastasis

Clinical Challenge: HER2-Positive Breast Cancer in Older Women

Masataka Sawaki, MD, on Omitting Chemo in Older Patients With HER2+ Breast Cancer

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