At the BGICC I talked about antibody-drug conjugates as a new therapy for HER2 negative metastatic breast cancer. This whole development of antibody-drug conjugates has revolutionised our treatment for patients with metastatic disease across the spectrum, actually, now including HER2 positive, hormone receptor positive and triple negative disease. I talked some about the constructs of the new generation of antibody drug conjugates with a plasma stable linker that’s not digested until the antibody-drug conjugate itself is incorporated into the cell. The identification, of course, of receptors where we can target antibodies and the receptors themselves that internalise the antibody-drug construct. We already knew this was successful for HER2 targeting but we’ve gone a long way from there, of course.
The other aspect of these new ADCs that’s very important is the payload itself, the toxin. The important part of successful ADCs has been that the payload itself doesn’t result in cumulative toxicity that’s unrecoverable to a large extent. One example of that would be neuropathy which is really hard and limits the exposure to treatment and also quality of life and can be long lasting. So, these newer antibody-drug conjugates don’t have payloads that cause neuropathy, which is really important.
Then, lastly and potentially one of the most important aspects of these ADCs is that the payload itself is membrane permeable so it actually is hydrophilic, it can leak out of the cancer cell so that once it’s released from its antibody by digestion of the linker, the antibody itself can be available to kill neighbouring tumour cells. The importance of that is thought to be really that you can kill tumour cells that don’t express the target at high levels. What level is actually required of expression of the target or the receptor in order to see efficacy is not well understood. Of course, it’s difficult with heterogeneity and both expression levels, the lack of testing measures that have been developed to actually determine very low levels of expression of any one of these receptors, and then the variability within the tumour itself. So we see a lot of heterogeneity from organ to organ. In one study that was done and presented at San Antonio where they looked at patients who had multiple biopsies, and in one study patients who died of breast cancer, they found differing levels of expression of HER2 across different tumour sites. We have seen that HER2 low status, for example, low expression of HER2, varies considerably from a biopsy to a tumour sample removed after neoadjuvant therapy from early to late stage and throughout the spectrum of late-stage disease.
So there is a lot that we still need to learn but, regardless of that, we have some very efficacious antibody-drug conjugates – trastuzumab deruxtecan for HER2 low, hormone receptor positive disease demonstrated remarkable improvements in progression free and overall survival that in subset analyses presented at San Antonio this last year, in 2022, demonstrated no difference based on a number of different factors, including prior treatment. Also, there was no variation in safety based on extent of prior treatment. Use of CDK4/6 inhibitors was the marker of extent of treatment, and burden of disease also didn’t seem to make a difference as it had been postulated that if you had a high burden of disease you’d deliver more of the payload and therefore it could potentially have more toxicity but that wasn’t seen in this subset analysis. A subset analysis of 58 patients in this trial who had triple negative, centrally defined HER2 low disease, 1+ or 2+ without gene amplification, we also saw a remarkable improvement in progression free and overall survival. But this is a tiny number of patients, it was a 2:1 randomisation of 58 patients. So we really do need to understand better the potential efficacy of trastuzumab deruxtecan in HER2 low triple negative breast cancer and understand the correlations of HER2 low status with biologic subtypes in triple negative disease.
We also talked about other important antibody-drug conjugates. The other approved new antibody-drug conjugate is sacituzumab govitecan. This is a TROP2 directed ADC with a topoisomerase payload, different from deruxtecan, the payload for trastuzumab deruxtecan. This drug showed in a phase III trial improvements in progression free and overall survival in patients with triple negative breast cancer. In the DESTINY-Breast04 trial where trastuzumab deruxtecan showed this remarkable benefit in HR positive HER2 low disease, patients had received a median of one line of prior chemotherapy. In the ASCENT trial patients had received a median of three lines of prior chemotherapy and could receive any number of lines of treatment yet we still saw this remarkable improvement in PFS and OS in the hardest to treat subset of breast cancer.
The most common toxicities for T-DXd are nausea and we don’t see a lot of cytopenias. The most treatment-limiting toxicity is interstitial lung disease, occurring in somewhere between 12-15% of patients and can result in grade 5, or mortal, toxicity in a small percentage of patients, less than 1% in the most recent trials in HER2 low and HER2 positive disease. But there are strict criteria for monitoring for ILD with CT scans and if you see asymptomatic ground-glass opacities you hold the drug, you use steroids and then repeat your CT scan. We usually repeat at three weeks, give 0.5mg/kg of steroid and then when we see clearance of the ground-glass opacities we restart drug and slowly taper off the steroid. That has been a very effective approach, although we need to look at this in the context of clinical trials to better understand how it is being used.
For grade 2 or symptomatic interstitial lung disease the current recommendation is to stop the drug permanently to try and avoid progression to grade 3 and higher ILD. What’s remarkable is we never saw grade 4 ILD, so once you progress past grade 3 where you need additional support and generally hospitalisation, the next step is dying of interstitial lung disease. So we definitely see more grade 1 and then less grade 2 and 3 and it’s a tiny percentage, relatively, for a huge benefit. But understanding the toxicity, identifying it earlier, is the way to try and avoid mortality from this drug which I think we can avoid in all patients. In one study in HER2 positive disease there were zero deaths so it’s clearly achievable in the right setting.
For sacituzumab govitecan, the most common toxicity is neutropenia, although febrile neutropenia has not been increased. We also see diarrhoea as a toxicity and the combination of neutropenia and diarrhoea is also very risky because you can have infiltration of the bowel wall when a patient is neutropenic and having diarrhoea with bacteria that can have serious consequences. So we really have recommended that neutropenia be very carefully monitored and treated. One way that we have been treating it more recently has been using long-acting growth factor pegfilgrastim after day 8 sacituzumab govetecan. Then we don’t use other growth factor and that has been very successful overall in the majority of patients in avoiding neutropenia.
I’ve actually recommended that patients also who have had prior neutropenia to chemotherapy, that they receive prophylactic growth factors up front and then you taper off if they don’t need them. We’ve also found in clinical practice that sacituzumab govitecan is approved for patients who have received at least one line of chemotherapy in the metastatic setting and as we’ve moved the treatment earlier in the course of the number of treatment lines we’ve seen less early neutropenia and less toxicity so that’s really encouraging.
Overall, the toxicities for both agents are fairly well managed, we just need to understand them and make sure that you monitor for them and not treat without thinking about these in advance. In fact, for sacituzumab and T-DXd, as we refer to trastuzumab deruxtecan, we tend to start low in patients who are very high risk. So frail older patients, patients with organ dysfunction, I usually start at a lower dose and increase as tolerated to try and avoid that immediate toxicity, although most patients can tolerate starting at full dose.
Lastly, there’s one additional antibody-drug conjugate worth mentioning - patritumab deruxtecan, a HER3 directed ADC. Again, the same toxin, you need new payloads maybe, hard to know, with deruxtecan but this agent actually showed efficacy in hormone receptor positive disease in the metastatic setting regardless of HER3 expression and then in a small number of patients who had HER3 high expressing triple negative and HER2 positive disease. I believe that the next step in the development of patritumab deruxtecan will be a neoadjuvant trial in hormone receptor positive disease regardless of HER3 expression.
So we have a lot of ADCs out on the horizon, it’s a very exciting time. We’re looking at how we’re defining HER2 low and I think we’ll have a lot of discussions about this going forward to try and better manage effective treatment for our patients with metastatic disease. Of course, the next step is to move to the early stage setting where there are already trials ongoing and already early evidence of efficacy.