Could trastuzumab deruxtecan become the new standard of care for pre-treated HER2-positive breast cancer patients?
Dr Ian Krop - Dana Farber Cancer Institute, Boston, USA
Right now for patients with HER2 positive advanced breast cancer there really is no standard of care once patients’ cancers have progressed on drugs like trastuzumab, pertuzumab and TDM1. So trastuzumab deruxtecan, which is a new HER2 directed antibody-drug conjugate, was designed basically to try to improve upon the current standard of care for these patients who progressed on the previous agents. Trastuzumab deruxtecan is an antibody-drug conjugate, it differs, though, in some ways from the current generation of ADCs. One thing that is different is that the payload of trastuzumab deruxtecan is a type of chemotherapy called a topoisomerase-1 inhibitor. This is a type of chemotherapy that is not typically used in HER2 positive breast cancer so it’s less likely the cancers are going to be resistant to this because they haven’t seen this type of chemotherapy before. Also the payload, there’s about eight of them on each antibody, so this drug to antibody ratio of about eight is substantially higher than what is currently being used in antibody-drug conjugates. Lastly, the payload is membrane permeable which means in pre-clinical studies it is able to defuse out of the targeted cell and hopefully kill neighbouring cancer cells, regardless of their HER2 expression.
In a previous phase I study of trastuzumab deruxtecan in patients who had HER2 positive advanced breast cancer, that study demonstrated a response rate of about 59%. So this phase II study was designed not only to try to confirm the outcomes of patients treated with trastuzumab deruxtecan but also just make sure we’re using the right dose. So in this new study patients with HER2 positive advanced breast cancer, all of whom had had TDM1, which was one of the standard of care treatments, were initially randomised to one of several doses of trastuzumab deruxtecan to try to figure out what is the recommended phase II dose. Based on the efficacy and safety data from that early part of the trial 5.4mg/kg was established as the recommended phase II dose. At that point in the trial an additional 130 patients were then all treated at that dose of 5.4mg/kg. There was an additional small cohort of four patients who were intolerant of TDM1.
So overall the primary objective of the study was to analyse all 184 patients treated at this dose of 5.4mg/kg and the endpoint was confirmed objective response by an independent radiology review committee.
In terms of efficacy we found that in terms of this primary endpoint of objective response by independent review the response rate was 60.9%. 6% of those were complete responses, 54.9% were partial responses. The clinical benefit rate at six months was about 76% and the median duration of response was over 14 months. What’s called the disease control rate was 97% so less than 2% of patients actually had progressive disease at the time of first restaging. So there was pretty much uniformity of at least some type of sensitivity to this agent across this population of 184 patients.
In terms of safety the most common side effects seen were fatigue, nausea and vomiting but these were almost all low grade and that’s very similar to what we’re seeing in the phase I study of this agent. But there’s one important toxicity that was seen not only in the phase I trial but in this phase II trial as well and that’s something called interstitial lung disease, also commonly known as pneumonitis. Because we knew that this was seen in the prior study, in this phase II trial all patients who had had evidence of pulmonary toxicity were adjudicated by an independent expert panel of pulmonary specialists and they found 25 patients, or 13.6%, who had what they felt was drug-related interstitial lung disease. 20 of those 25 cases were mild and manageable but four cases, 2.2% of patients actually died of drug-related interstitial lung disease. So going forwards, based on recommendations from this panel of experts, it’s recommended that for patients who are being treated with trastuzumab deruxtecan that they be monitored closely for symptoms of ILD which include dyspnea, cough and fever and if ILD is suspected that the drug be held and that we have a low threshold for starting corticosteroids and also that the patients be evaluated closely with a high resolution CT scan and a pulmonology consult.
We don’t know exactly why ILD occurs with this drug. We do know that ILD can be seen with most HER2 directed therapies and we also know that ILD can be seen with this type of chemotherapy that’s included as part of the molecule, this topoisomerase-1 inhibitor. So it may be a combination of those things; again, pneumonitis is a side effect that’s seen in many HER2 directed therapies but it seems to be more common with this drug. But exactly why that is in this particular drug we’re not sure.
In putting the data together we see this very high rate of objective response and a very durable amount of disease control with a median progression free survival of over 16 months. That’s really substantially higher than what we would see historically in other trials of patients who have this very heavily pre-treated population. So in this trial the median number of prior therapies in the metastatic setting was six so this is a very pre-treated population and the fact that we see this high level of activity is very compelling. So based on these data we do think that trastuzumab deruxtecan could become a new standard of care for patients who have pre-treated advanced HER2 positive breast cancer.
Already there are several randomised phase III trials of trastuzumab deruxtecan, two trials in patients who have HER2 amplified or HER2 positive metastatic breast cancer, one in a similar population to this study in patients who have already had TDM1 and then another trial in patients who haven’t had TDM1 in which trastuzumab deruxtecan is going to be compared to TDM1. There’s a third trial in patients who have what we call HER2 low cancer, so those are patients whose HER2 expression by immunohistochemistry is either 1 or 2 but they’re not amplified by FISH. This is a patient population right now that’s considered HER2 negative because the current generation of HER2 directed therapies don’t have any efficacy in that population. So I think it would be very interesting and very good for patients if this trial shows that trastuzumab deruxtecan actually is effective in this HER2 low population because it would basically open up a whole new subtype of breast cancer with an availability of a targeted therapy.