ASCO 2024: Personal Insights and a Look into the Future from an International Expert Group

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Tarantino: The presentation of the results of the DESTINY-Breast06 (DB06) phase 3 trial certainly was a highlight of ASCO 2024, leading to an immediate change in practice for the treatment of metastatic breast cancer (MBC).Ditsch: In my opinion, the Destiny Breast 06 study – presented by Prof. Guiseppe Curigliano – was the most important one at ASCO 2024 that will have an impact on the everyday treatment of our patients with breast cancer. Following the outstanding data from DB 04 (ASCO 2022), which showed a significant improvement in PFS and OS with T-Dxd in HR-positive Her2-low MBC from line 2 onward, data on Her2-low expression using TDxd in the chemo-naive setting were now shown, which were also associated with a significant benefit over the therapy chosen by the physician. The study thus shows for the first time an excellent efficacy of TDxd, which also persisted when the group of Her2-ultralow tumors (≤10% membrane staining) was added. In special cases and in consideration of the side effects, this has great significance for future use in everyday clinical practice.Wolfrum: There is no doubt that DB-06 is the most impactful study for HR+ Her2-negative patients in the metastatic setting. The good news is that 85% of patients in this subgroup express Her2 and could benefit from TDxd. So we can treat a broader spectrum of patients with an anti-Her 2-directed therapy in the future. But there are still questions about testing methods and Her2 thresholds. So for me and my patients, the most interesting abstract in terms of what would I apply tomorrow is abstract 513: the impact of adjuvant endocrine omission in ER-low (1–10%) early-stage breast cancer presented by Grace M. Choong from Mayo clinic.A national cancer database analysis between 2018 and 2020 was performed and identified 10,396 patients as ER-low. A median 3-year follow-up showed a 25% higher risk of death for those patients who omitted adjuvant endocrine therapy compared to those who received endocrine therapy. Clear data to encourage patients in ER-low early-stage breast cancer to stick to endocrine therapy in the adjuvant setting.Marmé: To pick one single study, DESTINY-Breast06 will impact our clinical practice most in the near future. This study will ultimately extend the population of patients with HR+ MBC that will be able to benefit from trastuzumab deruxtecan and include more 1st-line patients as well as patients with HER2-ultralow status (IHC0 with faint and incomplete membrane staining in ≤10% of cells). While we await the formal extension of the label, these data will help to apply for reimbursement for individual patients at least in some countries.Tarantino: The importance of DB-6 is twofold: on one side, the demonstration of the relevant activity of T-DXd in patients with HER2-ultralow (i.e., IHC 0 with up to 10% of cells having weak staining) MBC will significantly expand the use of this drug in clinical practice. Approximately 20–25% of patients with HR+ MBC have HER2-ultralow disease, and DB06 found an ORR >60% and an mPFS of 13 months with T-DXd in this population, which was impressive. Based on this finding, T-DXd will now become a treatment option for 90% of patients with HR+ MBC. Of note, HER2 IHC seemed to matter in DB06: the largest PFS benefit (HR: 0.43) was seen in IHC 2+, followed by IHC 1+ (HR: 0.74) and IHC 0 ultralow (HR: 0.78). Given this observation, I think it remains relevant to test for HER2 within the HER2-negative space, although I hope we will have available fit-for-purpose quantitative assays soon.On the other side, the major aim of the trial was to evaluate the role of T-DXd in chemo-naive patients. In this population, T-DXd significantly improved PFS (13.2 vs. 8.1 months, HR: 0.62, p < 0.0001) compared with chemotherapy, becoming the preferred ADC for chemo-naive patients and a new first-line chemotherapy option. Given that the trial mostly included patients with visceral metastases, this represents the population where I would consider an early use of T-DXd (i.e., before chemotherapy), whereas for patients with non-visceral and/or indolent disease, I will still consider capecitabine a valid alternative, given the oral route of administration, lack of alopecia, and low cost.Ditsch: For me, the most important aspect is the significant effect on PFS of TDxd has now been shown for the earlier use in chemo-naive (after endocrine therapy) situation (HR+ and Her2-low) as well as in an extended patient group (Her2-ultralow). This also results in a temporal sequence in favor of TDxd when using ADCs. Whether Her2 still needs to be tested cannot currently be conclusively assessed with this study. However, as Prof. Curigliano mentioned in his presentation, there is already an effect from a single positive cell. For me, this is at least an indication of a possible positive effect for Her2-negative tumors as well.Wolfrum: The most impressive aspect of DB06 is the comparatively long mPFS of around 13 months in the Her2-low and -ultralow situation. Therefore, according to the results of DB-04 and now new from ASCO 2024 of DB-06, the preferred ADC to start with would be TDxd in the endocrine-resistant setting while we are waiting on more robust phase III data from Dato-DXd. In the triple-negative metastatic setting, sacituzumab deruxtecan would be the preferred initial ADC since DB-04 included only a small number of triple-negative patients.It is obvious that IHC is not the best methodology to test Her2 and that we need new quantitative Her2 testing assays or alternative biomarker scoring strategies. Several assays are in development and are actually incorporated into trials. For some ADCs, levels of biomarkers do not matter, e.g., Nectin-4 and Trop-1. But for trastuzumab deruxtecan, preclinical data suggest that there is a lower limit of Her2 expression below which TDxd shows no efficacy. So we need those assays. Until then, we have to talk to our pathologists and tell them that any staining matters. DESTINY-Breast15, an ongoing phase 3 study, will answer the question if patients with IHC 0 will profit from TDxd as well.Marmé: DB-06 has clearly demonstrated compelling activity in terms of ORR and PFS in patients HR+ HER2-low and -ultralow MBC. A response rate approaching 60% is unprecedented in this patient population; thus, this is a very effective treatment option.One of the most important questions to me is, if every eligible patient should receive T-DXd in the first-line setting. In other words, what is the ideal treatment sequence in individual patients? For some patients, the tolerability of alterative mono-chemotherapies might be preferable, so different options could be discussed in the first-line setting. It is also important to note that patients included in DB-06 have been selected based on endocrine resistance (either ≥2 lines of ET ± targeted therapy for MBC or 1 prior line for MBC and either progression within 6 months of first-line CDK4/6i or within the first 2 years of adjuvant endocrine). We are now able to base our treatment decisions on 2 large randomized trials, DB-04 and DB-06. DB-04 was largely run in the second-line setting with few first-line patients with rapid progression after chemotherapy. DB-04 demonstrated significant and clinically meaningful improvements in ORR, PFS, and also OS. The absolute difference in median PFS was very similar in DB-04 and DB-06 (4.7 and 5.1 months) with a slightly better HR in DB-04 (0.51 vs. 0.62). The first OS interim analysis did not yield significant results yet. In DB-04, OS was significantly improved at the first analysis with a very similar maturity. This might be partly due to 20% of patients receiving post-study T-DXd in DB-06, which was not possible in DB-04, but also due to a worse performance of the control arm in second-line, while T-DXd retained most of its activity. This can be demonstrated by looking at the ORR in the control arm and the delta between arms in both trials. The ORR in the con

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