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An antibody-drug conjugate (ADC) targeting HER2 significantly slowed progression of previously treated metastatic breast cancer versus chemotherapy, a multinational randomized trial showed.

Median progression-free survival (PFS) improved from 4.9 months with investigator's choice of chemotherapy to 7.0 months with trastuzumab duocarmazine (SYD985). A subgroup analysis showed a consistent benefit across prespecified subgroups. A preliminary analysis of overall survival (OS) showed a trend in favor of the ADC (20.4 vs 16.3 months).

Ocular toxicity was the most common treatment-emergent adverse event (TEAE) with SYD985 and was associated with a discontinuation rate of 20.8%, reported Cristina Saura Manich, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, during the virtual European Society for Medical Oncology (ESMO) meeting.

"Treatment with SYD985 significantly improved progression-free survival in comparison with standard physician's choice treatment in patients with HER2-positive metastatic breast cancer with two prior regimens or T-DM1 (trastuzumab emtansine, Kadcyla) in the metastatic setting," she said in conclusion. "Ocular toxicity is the most prevalent safety event, and ILD [interstitial lung disease]/pneumonitis was reported, including grade 3 or worse, in 2.4% of patients. These toxicities have to be carefully monitored and treated appropriately."

"SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic breast cancer," she added.

The results, combined with those of the precedent-setting DESTINY trial of trastuzumab deruxtecan (T-DXd), suggest that optimal sequencing of treatment for metastatic HER2-positive breast cancer will change in the near future, said ESMO invited discussant Barbara Pistilli, MD, of Gustave Roussy Cancer Center in Villejuif, France. SYD985 demonstrated efficacy in the post-T-DM1 setting, and T-DXd demonstrated superiority to T-DM1 in a head-to-head comparison.

The obvious question is how to integrate results of the SYD985 trial into the changing clinical framework, Pistilli continued. That question leads to another: Is it possible that SYD985 has activity in the post-T-DXd setting? The likely answer is that one ADC does not fit the needs of all patients with metastatic HER2-positive breast cancer. Future studies should focus on identifying biomarkers that will guide treatment selection.

"The number of ADCs approved by the FDA has doubled in 1 year, with an impressive improvement in the therapeutic index," said Pistilli. "I think over the next 10 years we will be able to define the best combination strategies of the ADCs that can lead to improvement in the delivery to the tumor tissue and improve immune response to the ADC to improve target expression and internalization of the payload activity."

"I think we can move in the direction of more personalized ADCs that can be created on the basis of specific tumor characteristics in terms of biopsies for multiple receptor targets, endosomal proteins, and biomarkers of warhead sensitivity," she added.

Saura Manich reported findings from the phase III comparing SYD985 and investigator's choice of standard therapy for previously treated metastatic HER2-positive breast cancer. SYD985 consists of trastuzumab linked to the alkylating agent duocarmazine.

Eligible patients had received at least two prior therapies or T-DM1 for metastatic disease. They were randomized 2:1 to SYD985 or investigator's choice of four standard second-line HER2-targeted therapies: lapatinib (Tykerb) plus capecitabine or trastuzumab plus capecitabine, vinorelbine, or eribulin.

The study included 437 patients enrolled at 83 sites in North America, Europe, and Singapore. The trial had a primary endpoint of centrally reviewed PFS and assumed a median PFS of 4.1 months for the standard-care arm. Statistical assumptions included a 20% dropout rate in the control arm and a 30% rate in the SYD985 arm, subsequently increased to 30% and 40%, respectively.

The study population had a median age of about 57, a median duration of metastatic disease of 3 to 3.5 years, and a median of four to five prior metastatic regimens. Almost 90% of the patients had received both trastuzumab and T-DM1, and about 60% had received pertuzumab (Perjeta).

The primary analysis showed that SYD985 reduced the PFS hazard by 36% versus standard care (95% CI 0.49-0.84, P=0.002). Among patients with measurable disease at baseline (about 85% of the population), the overall response rate was 28-29% in each group, but the average reduction in the target lesion was 70.2% with SYD985 versus 58.2% with standard therapy.

The most common TEAEs with SYD985 were conjunctivitis (38.2%), keratitis (38.2%), fatigue (33.3%), dry eye (30.2%), nausea (25.3%), decreased appetite (21.5%), diarrhea (20.8%), and asthenia (20.8%). The most common grade ≥3 TEAEs were keratitis (12.2%), conjunctivitis (5.6%), neutropenia (4.9%), and dry eye (4.2%). Six fatal TEAEs occurred in the SYD985 arm; four were considered related to treatment (respiratory failure, pneumonia, and two cases of pneumonitis), and two were considered unrelated (acute respiratory failure and COVID-19 pneumonia).

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