Meet the Trialist: Prof. Giuseppe Curigliano on DESTINY-Breast06

Thank you so much for your time, Professor Curigliano. Congratulations on your nomination as president of ESMO. That’s a big deal and it’s going to shape your next years, no doubt. I wanted to start by talking about the DESTINY-Breast06 trial  (NCT04494425) that you presented at ASCO 2024.¹ What were the main findings? How are we supposed to interpret them?

‘DESTINY-Breast06 was a prospective randomised trial including patients with HR-positive and HER2-low or HER2-ultra-low metastatic breast cancer who previously received endocrine therapy plus CDK4/6 inhibitors in the first line, and eventually a second line of endocrine therapy,’ described prof. Curigliano. ‘Participants were randomised to receive trastuzumab deruxtecan versus chemotherapy of physician’s choice. The chemotherapy options in the standard arm included capecitabine, paclitaxel, or non-paclitaxel.’

‘A total of 866 participants were randomised, and trastuzumab deruxtecan improved the median PFS from 8,1 months to 13,2 months, with a hazard ratio of 0,63. Similar results were observed for the HER2-low and HER2-ultra-low populations,’ prof. Curigliano continued. ‘We define HER2-ultra-low as anywhere between 0-1% positivity on immunohistochemistry. In this subgroup, which included 153 participants, the median PFS also improved from 8,1 months to 13,2 months. The response rate was 57%, including complete and partial responses, in the intent-to-treat population, and 61% in the HER2-ultra-low population.’

Prof. Curigliano summarised: ‘We anticipated the use of trastuzumab deruxtecan in earlier lines of therapy compared with DESTINY-Breast04, as the DESTINY-Breast06 included patients who had never received chemotherapy. We also expanded the use of trastuzumab deruxtecan to a patient population defined as HER2-ultra-low, with HER2 expression between 0-1%.’

What about safety? I know that interstitial lung disease (ILD) is always a concern. Was there anything here that we need to be aware of? And I also noticed that nausea and vomiting were quite prevalent. How does this compare to other DESTINY trials?

‘No, the rate of ILD observed in DESTINY-Breast06 was very similar to that in DESTINY-Breast04, DESTINY-Breast03, and other DESTINY trials,’ assured prof. Curigliano. ‘Overall, the incidence of ILD was 11%, making it the most common cause for discontinuation. Three patients died due to ILD in the DESTINY-Breast06 trial.’

‘Regarding dose reduction, the most common cause was treatment-emergent adverse events, particularly nausea. This was also very common in the DESTINY-Breast06 trial, similar to other trials. However,’ said prof. Curigliano, ‘this is not a major concern because using a triplet combination anti-emetic therapy can completely prevent nausea and vomiting related to trastuzumab deruxtecan. For ILD, it is crucial to increase patient awareness and conduct screening, as early identification and treatment with steroids can manage ILD effectively.’

What do the results mean about the importance of improving the sensitivity of HER2 testing? It seems that with HER2-ultra-low, the current immunohistochemistry approach might be limiting our ability to identify certain patients?

‘This is an excellent question. In the DESTINY-Breast06, we used immunohistochemistry. The majority of screening failures were due to discordance between local and central assessments. It is indeed challenging for pathologists to detect HER2 expression levels between 0-1%,’ prof. Curigliano stated.
‘I am not sure if we will use proteomic analysis in the future for this purpose, but I am confident that digital pathology and AI will be instrumental in better detecting patients with HER2 expression between 0-1%. We are planning digital pathology studies in this regard.’

Thank you. So, I’d like to move on to some questions about the ESMO presidency. Can you share your vision for the leadership role you’re taking on and how you anticipate new developments in the coming years to impact the oncology field?

‘You know, ESMO is a great society with now 34.000 members. My vision is to integrate the multiple disciplines involved in cancer care,’ said prof. Curigliano. ‘I believe it is time to transform ESMO into a multidisciplinary society beyond just medical oncologists. This includes incorporating surgeons, radiation oncologists, basic scientists, nurse practitioners, and nurses to work together and offer the best treatment and prevention strategies to patients worldwide, beyond geographical boundaries.’

What are some of the challenges you anticipate in the field this year?

‘Complexity is the major challenge. Cancer is a complex disease biologically and in terms of therapeutic algorithms. Additionally, the approach to cancer care varies significantly depending on whether you are in Europe, the United States, Asia, or Africa. Addressing these complexities is essential to provide the best care to every patient, regardless of where they live,’ prof. Curigliano concluded.