Modest PFS Win With Fatal Lung Signal Cannot Displace Enhertu Standard

BioNTech & DualityBio's ADC Shows Modest Benefit in Breast Cancer Study

BioNTech and DualityBio announced that their antibody-drug conjugate (ADC), trastuzumab pamirtecan, met its primary endpoint in a Phase 3 study for HER2-low metastatic breast cancer by delaying tumor progression. However, the companies noted the benefit was “modest” and observed higher rates of interstitial lung disease, including severe and fatal events, compared to earlier testing. Given the competitive landscape, particularly with AstraZeneca and Daiichi Sankyo’s Enhertu, the partners suggest the treatment's potential benefit may be limited and will discuss next steps.

• Trastuzumab pamirtecan successfully achieved its main goal in the Phase 3 trial, demonstrating a delay in tumor progression for patients with HER2-low metastatic breast cancer. Despite meeting this primary endpoint, the overall improvement was characterized as “modest” by the companies.
• Safety concerns emerged from the trial, with trastuzumab pamirtecan associated with increased rates of interstitial lung disease (ILD), a potentially deadly lung inflammation. Additionally, the study reported “severe and fatal events” in a small proportion of patients, which were higher than observed in previous testing.
• The companies acknowledged that the potential benefit of trastuzumab pamirtecan to patients would be “limited” given the current treatment landscape, which includes established therapies like Enhertu. They also noted the trial had not run long enough to detect a clear survival benefit and plan to discuss the data to determine future steps.
• Trastuzumab pamirtecan was acquired by BioNTech through a 2023 licensing deal with DualityBio, valued at over $1.6 billion. This acquisition marked BioNTech's initial entry into antibody-drug conjugates as part of its broader strategy to expand oncology research beyond its core messenger RNA technology.

Trastuzumab Pamirtecan's Phase 3 Efficacy and Safety

Recent studies evaluated trastuzumab deruxtecan (T-DXd) in HER2-low metastatic breast cancer in meta-analytic and real-world settings, including patients with brain metastases. T-DXd prolonged median progression-free survival and median overall survival and increased objective response rate compared with control, with activity also observed in HER2-low/zero cohorts.

Addressing Unmet Needs in HER2-low Metastatic Breast Cancer

Accurate identification of HER2-low metastatic breast cancer remains difficult, and current treatment approaches are constrained by diagnostic uncertainty and toxicity. HER2-low does not represent a distinct or specific subtype of cancer, and encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations.

• Poor reproducibility of HER2 testing at the low expression range. HER2 IHC testing is affected by pre-analytic, analytic and post-analytic challenges, interobserver variability among pathologists and inter-assay variabilities. Inter-laboratory concordance was moderate (68.89%), being poorest for HER2 1+ (57.58%; Kappa = 0.566), with significant staining variability observed between antibodies: the 4B5 clone was associated with more HER2 0 and 1+ scores, while MXR001 yielded higher rates of HER2-low results. Differentiating between a HER2 IHC score 0 and score 1+ has not been clinically significant until now.

• Intratumoral heterogeneity and dynamic shifts in HER2 expression over time. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%, and 32% of metastases currently classified as HER2-zero were HER2-ultralow. A total of 370 patients (28.5%) experienced primary-to-metastatic HER2 conversion, with intrapatient intermetastasis spatial heterogeneity and temporal heterogeneity detected. Extrapolating HER2-low status from the original diagnosis may lead to misleading results.

• Discordance between specimen types and reliance on a single assay. Kappa statistics were 0.78 and 0.85 for inter-pathologist agreement of core biopsy and surgical resections, and 0.13 for agreement in HER2 consensus scores between outside core and surgical resection and 0.49 for inside core and surgical resection. Low HER2 expression was found in 28 of 57 (49%) core biopsy and in 25 of 57 (44%) surgical excisions. Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy.

• Toxicity and tolerability burden of trastuzumab deruxtecan (T-DXd). Treatment discontinuation due to adverse events occurs in ∼20% of patients. T-DXd also increased the incidence of adverse events such as anemia, nausea, vomiting, constipation and interstitial lung disease. In real-world patients, common AEs included fatigue (95.3%), alopecia (14.1%), and peripheral neuropathy (14.1%), with permanent discontinuation due to AEs in 10.6% and 40% requiring further dose reductions.

Trastuzumab Pamirtecan's Position in a Crowded Landscape

Trastuzumab deruxtecan (T-DXd) improved survival versus standard chemotherapy in previously treated HER2-low metastatic breast cancer. In DESTINY-Breast04 in patients with HER2-low metastatic breast cancer treated with one prior line of chemotherapy, T-DXd demonstrated significantly longer progression-free survival and overall survival than physician's choice chemotherapy (10.1 v 5.4 months; hazard ratio, 0.51; P < .001, and 23.4 v 16.8 months; hazard ratio, 0.64; P < .001, respectively). In DESTINY-Breast06 in hormone receptor-positive, HER2-low/-ultralow metastatic breast cancer, T-DXd (5.4 mg/kg) once every 3 weeks improved progression-free survival versus physician's choice of chemotherapy (TPC) regardless of time to progression on prior first-line endocrine therapy + CDK4/6 inhibitor: <6 months: 14.0 (11.2-15.9) versus 6.5 (4.2-8.4) months for T-DXd versus TPC; 6-12 months: 13.2 (8.6-16.4) versus 6.9 (4.3-10.4) months; >12 months: 12.9 (9.8-17.1) versus 8.2 (6.9-10.9) months. In all subgroups, confirmed objective response rate favored T-DXd (36.7%-67.7%) versus TPC (16.7%-37.5%), and median duration of response (confirmed response) was longer with T-DXd, with T-DXd also prolonging time from randomization until second progression or death versus TPC across subgroups.

Real-world cohorts confirm robust activity of T-DXd in both HER2-positive and HER2-low disease but show shorter outcomes for HER2-low relative to HER2-positive disease. In a retrospective cohort of 98 patients at Fudan University Shanghai Cancer Center, median progression-free survival was 15.0 months, with objective response rate, disease control rate, and clinical benefit rate of 48.0%, 69.4%, and 41.8%, respectively, and HER2-positive patients experienced longer progression-free survival compared to HER2-low patients (not reached vs 9.0 months). In a Singapore registry of 87 metastatic breast cancer patients treated with T-DXd, overall median real-world progression-free survival was 8.1 months, with human epidermal growth factor receptor 2-positive patients showing significantly better real-world progression-free survival outcomes compared to HER2-low patients (8.8 versus 2.5 months, P<0.001). In 111 patients with breast cancer brain metastases treated with T-DXd across seven U.S. health systems, median overall survival was longer in HER2-positive than HER2-low disease (35.2 vs. 12.8 months, respectively).

Sequencing data highlight cross-resistance considerations after T-DXd and alternative antibody-drug conjugate options in HER2-negative disease that includes HER2-low populations. In 793 patients receiving post-T-DXd treatment, median real-world progression-free survival was 4.6 months for HER2-positive, 3.4 months for hormone receptor-positive/HER2-negative and 2.8 months for triple-negative metastatic breast cancer (p < .001), with the use of sacituzumab govitecan immediately after T-DXd associated with relatively short real-world progression-free survival across subtypes. In the randomised, open-label, multicentre, phase 3 TROPiCS-02 trial in pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14.4 months [95% CI 13.0-15.7] vs 11.2 months [10.1-12.7]; hazard ratio 0.79, 95% CI 0.65-0.96; p=0.020).

Beyond HER2-low Breast Cancer: Trastuzumab Pamirtecan's Future

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ADC Challenger Stumbles in HER2-Low Breast Cancer

The landscape of HER2-low metastatic breast cancer has seen transformative advancements with the advent of antibody-drug conjugates (ADCs). These targeted therapies offer a new paradigm for patients whose tumors express low levels of HER2, a population previously underserved by HER2-directed treatments. Trastuzumab deruxtecan (T-DXd), marketed as Enhertu, has set a formidable benchmark in this space, demonstrating statistically significant and clinically meaningful improvements in progression-free survival and overall survival across various HER2-positive and HER2-low settings. Its efficacy, including high objective response rates, has solidified its position as a standard of care.

Against this backdrop, the recent announcement regarding trastuzumab pamirtecan's Phase 3 results is particularly telling. While the drug met its primary endpoint by delaying tumor progression, the characterization of this benefit as 'modest' immediately raises concerns. More critically, the observation of higher rates of interstitial lung disease (ILD), including severe and fatal events, presents a significant safety challenge. While ILD is a known adverse event associated with T-DXd (with all-grade rates typically ranging from 10-16% and grade 5 events around 1.7-2.7% in clinical trials), its management protocols are well-established. A 'higher' incidence of severe and fatal ILD for a new entrant suggests a less favorable safety profile, which could severely limit its clinical utility and market acceptance.

This outcome underscores the intricate balance between efficacy and safety in ADC development. The specific design elements of an ADC—its payload, linker, and drug-to-antibody ratio—profoundly influence its therapeutic index. For BioNTech and DualityBio, these results necessitate a critical re-evaluation of trastuzumab pamirtecan's future. Given the high bar set by T-DXd, any new ADC must offer a compelling advantage in either efficacy or safety to carve out a meaningful market share. This event further solidifies T-DXd's dominance in HER2-low metastatic breast cancer, highlighting the ongoing challenge for competitors to deliver truly differentiated and superior therapeutic options.