Sevabertinib, which is a HER2-directed TKI in HER2-mutated non-small cell lung cancer, this is a phase I study with this drug which was tested in multiple settings: first line, second line, second line post-antibody-drug conjugate, for this group of patients. Sevabertinib is associated with a high efficacy, response rate ranging between 60%-70% in those patients. We also saw the results in the CNS lesions with this drug during this meeting. But one issue is the adverse event profile with frequent diarrhoea.
Diarrhoea was observed in about 80% of the patients; in the late-line setting 23% grade 3 in this trial where prophylactic management of diarrhoea had not been implemented. So in those patients we see that diarrhoea is occurring very quickly, from the second day of administration of sevabertinib. We see that diarrhoea is more frequent also after prior exposure to immune checkpoint inhibitors. So there is a need to manage diarrhoea, mostly with loperamide which is the key treatment for those patients. At the end, diarrhoea is controlled over time and we have a minimal number of patients showing discontinuation related to diarrhoea. You may reduce the dose, you may adapt, you may do some kind of dose interruptions but at the end it is clearly manageable.
In the first-line setting grade 3 diarrhoea is less frequent, less than 5% of the patients, so it shows that with wellness of the physicians the management is actually better with more proactive management of diarrhoea which facilitates, again, the administration of the drug. What we show also in the poster is that diarrhoea is related to the actual exposure to the drug so this is where dose reduction probably has to be done in patients with severe diarrhoea.
Did the change in dose affect the efficacy? What are the clinical implications of the findings?
When we do a dose reduction with sevabertinib it doesn’t impact the outcome, it was well demonstrated across this cohort. What we also see is that the global frequency is the same in the first-line setting, second-line setting. So the key message is that we need to have a prophylactic management of these patients. My practice is to prescribe loperamide to all the patients at a small dose when starting this drug and then proactive monitoring of the patient. It’s something that you have to discuss also with the patients at baseline to avoid the grade 3 events.
Sevabertinib is now being tested in the first-line setting in the SOHO-2 trial. It’s a situation where we have multiple options coming – zongertinib has just been approved by the FDA, it’s another oral TKI with a similar profile in terms of efficacy and also safety. So this prophylaxis of diarrhoea is something that we need to integrate into the clinical practice for these patients.
