“Dang, that gave me goosebumps”

Oncologists are not famed for outbursts of emotion. I assume other specialties, perhaps cardiologists or transplant surgeons, become accustomed to big victories, curing patients through skill and brilliance. Oncologists are no less skilful or brilliant, but they work with incremental progress and small gains, where the possibility of cure often exists in the future. They rely on data to support difficult decisions. So, it is heart-warming to hear the claps and cheers accompanying the release of trial data that will bring a tangible improvement to their day-to-day work, allowing them to have more positive conversations with their patients.?

The Sunday Plenary session raised the loudest and longest applause of ASCO 2022 so far*. The response from the audience clearly moved Dr Vokes, ASCO President, who emotionally remarked “Welcome back to the live conference!”. The abstract under discussion reported results from DESTINYBreast-04, a phase 3 study of trastuzumab deruxtecan (T-DXd) in HER2-low advanced breast cancer (mBC), presented by Shanu Modi of Memorial Hospital in New York.

Oncology is intrinsically complex. For the last 20+ years, oncologists have become used to a very clear classification in breast cancer; segmenting patients into HER2+ve or HER2-ve subtypes. After all this time, re-definition of HER2 classification has potential to raise a degree of anxiety (it certainly does for me), but it also is likely to be game-changing. It takes the current HER2-ve population (widely reported as ~80% of mBC patients), and segments them further into HER2-ve and HER2-low. The HER2-low bucket is large; quoted by Dr Modi as up to 50% of all mBC patients

The trial compared T-DXd with single-agent chemotherapy (of physician’s choice) in HER2-low patients who had 1-2 prior lines of chemotherapy in the metastatic setting. Hormone receptor positive (HR+) patients were refractory to endocrine therapy, and 70% had cycled through a CDK4/6 inhibitor (standard of care for this population). The trial results from DESTINYBreast-04 are remarkable and drew audible excitement from the audience when the first outcomes slide was revealed. The degree (and speed) of separation of the progression-free survival (PFS) curves is impressive; being both statistically significant and – importantly – appearing to be clinically meaningful for the oncologists in the room. The median PFS within the HR+ cohort increased from 5.4 months in the control arm to 10.1 months in the T-DXd arm. Overall survival (OS) data for this cohort showed an improvement of over 6 months with T-DXd. Exploratory endpoints in the TNBC cohort (HER2-low/HR-) show a median PFS with T-DXd of 8.5 months, compared to 2.9 months on chemotherapy. Progressive TNBC is a hard-to-treat disease, often resistant to chemotherapy, making the data even more impactful.

Almost all efficacy data shown during the presentation were positive. Almost all. One data point stood out in the HR+ PFS subgroup analysis. The only data point not showing clear benefit of T-DXd was the ‘Other' (defined as non-White, non-Asian) Race sub-group. This is not to say that T-DXd does not work in this subgroup, but the scarcity of patients within the trial makes it difficult to determine. The importance of ASCO’s 2022 tagline ‘Advancing equitable cancer care’ came into clear focus.

?Dr Modi’s presentation was followed by inspiring commentary from Dr Patricia LoRusso of Yale Medical School. Dr LoRusso’s summary left no question in the audience as to the practice-changing impact of this data, which could offer positive outcomes for a large proportion of patients suffering from the most common solid tumour amongst women.

However, LoRusso did not finish the presentation on this note. Her final remarks discussed ‘What Next?’. What impact does this data have on the development of the next generation of antibody-drug conjugates (ADCs)? What can we learn about T-DXd drug resistance in order to build a longer duration of response? How can this drug be used in other tumours? As ever in Oncology, researchers are not satisfied with the progress made. The self-congratulation lasts for just minutes. And then they move on to try to understand how to do better.

*This was the loudest applause of the day, but not my favourite, which is reserved for Sebawe Syaj of Jordan, a young oncologist who (uniquely) thanked his mother in his Stage III NSCLC abstract acknowledgements, raising smiles and cheers from an otherwise hushed audience. I highly approve.

Note: All opinion within this article is that of the author