We did a study of sacituzumab govitecan, also known as IMMU-132. It is an antibody drug conjugate so the antibody recognises an antigen called Trop-2; Trop-2 is expressed on epithelial cells and is overexpressed in a number of different tumour types including urothelial carcinoma. The antibody is linked to SN-38 which is the most active metabolite of the chemotherapy irinotecan and with that antibody drug conjugate it’s given systemically and is preferentially taken to areas of excess Trop-2 expression. So the mechanism of action is a cytotoxic that is preferentially delivered near tumours.
What was the methodology used in this study?
Overall the study was what many people call a basket study initially. So there was an initial phase I dose escalation component where a dose of 10mg/kg day 1 and day 8 of a 21 day cycle was determined and then there were a number of different tumour types that looked interesting. So we saw six patients in the initial dose escalation phase of the study that, interestingly, did much better than we expected. This is in the setting of not having a lot of options for advanced urothelial carcinoma and that led to an expansion cohort, or a phase II cohort, of this drug. So we’re presenting essentially a phase II study of 45 patients with refractory advanced urothelial carcinoma who received IMMU-132 at the recommended phase II dose.
What were the main findings from this study?
What we found is a number of things so I’ll separate efficacy and toxicity. Efficacy I’ll start with which looked impressive. This is a non-randomised study but based on what we expect for patients that have received the standard therapies before, so this was started in an era where there was really just chemotherapy and then later immune checkpoint inhibitors came into the market, so in the tail end of the study there were patients that also had received those. A median of two lines of prior therapy but up to six prior lines of therapy, there was no limit provided the inclusion criteria were met in terms of performance status and organ function and we saw an impressive response rate. Historically speaking we’d expect that if I were to give someone an available chemotherapy agent, doing a study we’d expect approximately a 10% response rate. What we saw overall in these 45 patients was an approximate 30% response rate in this heavily pre-treated patient population. We looked at the subsets, these are not big subsets but the vast majority, about three-fourths, had visceral metastases including a third with liver metastases; those that had or hadn’t received prior immunotherapy. The response rates were similar in all of the different subgroups so it looks like it works despite sites of disease as well as prior therapy.
Were there any adverse effects?
Adverse effects, if we concentrate first on the more serious, or grade 3 and 4, adverse events there were no non-laboratory adverse events that were in the double digits, meaning above 10%. Diarrhoea was about 9% but lower than we’d expect with the free drug irinotecan that likely has to do with the drug delivery mechanism, that it’s not going through the liver, so that’s likely. But we didn’t see as much diarrhoea as we might with the free drug irinotecan. We saw essentially no significant neuropathy or anything else. The dose-limiting toxicity of the drug that was discovered in phase I and also confirmed in phase II is myelosuppression. So there is a reasonable amount of grade 3 and grade 4 myelosuppression; it did not result in a lot of neutropenic fevers, fortunately. But myelosuppression is the dose-limiting toxicity of the drug, reasonably easily managed with either dose reduction or the addition of growth factors.
What are the next steps for this study?
You can call this a proof of concept study; only 45 patients, maybe it was patient selection why it looked so good. So what has been launched now is called the TROPHY U-01 study which is a more definitive phase II study with a primary cohort that is going to enrol a hundred evaluable patients. There is a poster also on this today looking at specifically patients that have received both platinum chemotherapy as well as a PD-1 or a PD-L1 antibody. There is no limit to additional therapies but at least having those two types of drugs, separately or together, and we’re looking to really confirm the response rate as well as tolerability of the drug. There’s a separate cohort of non-cisplatin eligible patients that’s more exploratory that is just after immunotherapy. But really what we’re considering as the potentially pivotal cohort is this cohort of approximately a hundred patients that could, at least in theory, lead to registration.
Are there any other studies that have looked at the therapeutic effects of sacituzumab govitecan in other cancers?
The initial basket study looked at a number of different cancers and many of them looked interesting, so in a refractory patient population there were responses across the board. The single biggest data set was in triple negative breast cancer where there are now hundreds of patients that have been treated and that has been submitted to the FDA. We think that there’s a reasonable chance that that may lead to approval. Urothelial we’re hoping, as a GU oncologist I’m hoping, that will be the second label. It’s also being explored in other cancers. So, like I said, a number of different solid tumours did respond to the drug. There is a new study that’s being launched that is selecting for Trop-2 expression and enrolling those studies that will include lung, GI cancers and various other cancers.