Novel antibody drug conjugate TORL-1-23 shows preliminary antitumour activity in heavily-pretreated ovarian, endometrial, and testicular cancers
Prof Gottfried Konecny - University of California, Los Angeles, USA
I had the privilege to present our phase I data on a novel antibody drug conjugate targeting the protein CLDN6. It’s a novel target; it is the first in human study. We have treated 81 patients in a dose escalation and dose expansion study and this is the first presentation of this data. CLDN6 is a tight junction protein that is generally not expressed on normal tissue but expressed in some cancers. Most importantly, in ovarian cancer it’s associated with a worse outcome, shorter progression free and overall survival. We’ve become interested in this protein because it’s not expressed in normal tissue. If you look at the publicly available GTEx data that allows you to interpret the expression of receptor or surface proteins in normal tissue, you can see that CLDN6 is absent in normal tissue as opposed to other targets that we’re pursuing with ADCs such as TROP2 or HER2 or folate receptor which is expressed in normal tissue. So the hopes are that by targeting CLDN6 we will have a bigger therapeutic window to minimise toxicities and deliver chemotherapy payload with greater precision and efficacy with less toxicity.
The study has enrolled now 50 ovarian cancer patients and we’re pursuing a registration strategy in ovarian cancer with a soon to start phase II study. The overall safety data look very promising because we’ve had two main toxicities. One is neutropenia, which occurred within the dose escalation at a dose of 3.0mg/kg. We then expanded a cohort with pegfilgrastim and were able to completely ameliorate the haematologic toxicity. The other side effect has been neuropathy, which is a known potential side effect of the payload, which is MMAE which is a vedotin. The good news is that it only occurred in mild severity, grade 1, grade 2, across the now 81 patients that have been treated. There was only one patient that had grade 3 neurotoxicity which was a young male patient with a germ cell tumour that had extensive prior treatments with bone marrow transplant and platinum-based therapy. So overall very well tolerated. Particularly noteworthy is that we didn’t see ocular toxicities and we did not see pulmonary toxicity, probably attributable to the fact that CLDN6 is just not expressed in normal lung tissue.
The efficacy is promising in the sense that overall, depending on the dose cohort, we saw response rates in patients that had less dose than 2.4mg/kg of 30%. Those patients that had been treated with 2.4mg/kg or 3.0mg/kg had response rates above 40%. If we look at a subset of ovarian cancer patients, likewise those that were platinum resistant, not more than three prior lines of therapy, so the target population, the response rates were either 52% or 42%. Small numbers albeit very promising data. Also very durable responses over time as I was able to show with the spider plots. Thus a clear signal to take this forward into phase II study.
In summary, targeting CLDN6 with the ADC TORL-1-23 with a MME payload with a drug antibody ratio of 4 is a promising new approach. In a subset of patients with ovarian cancer that have high expression of CLDN6 it has shown a very favourable toxicity profile and it has shown very promising activity and we are now launching a global phase II study with 80 international sites that will test two doses moving forward, 2.4mg/kg and 3.0mg/kg, which will hopefully lead to a randomised phase III study for platinum-resistant recurrent high grade serous ovarian cancer.
What are your hopes for the clinical impact?
I think we’ve all witnessed the significance of antibody drug conjugates that allow us to deliver chemotherapy with greater precision and less toxicity. We’ve recently seen the success of mirvetuximab soravtansine as the first approved drug for platinum-resistant ovarian cancer, however, this drug is only available for about 25% of high grade serous ovarian cancer patients that express very high folate receptors. So we do need other ADCs that target other populations.
It's noteworthy that the expression of CLDN6 is inversely correlated with the folate receptor. So patients that have low folate receptor expression generally have very high levels of CLDN6 expression. So we're targeting a slightly different patient population with CLDN6 which will add to the armamentarium that we have for platinum-resistant ovarian cancer.
Also, I do think we need to focus closely on toxicities that we do see with ADCs, particularly pulmonary toxicities with pneumonitis, ocular toxicities. Therefore developing strategies that target a very clean target in the sense that’s absent in normal tissue and only expressed in malignant tissues, as CLDN6, are important strategies to really develop a new generation of ADCs with less toxicity and drugs that can be given chronically without cumulative toxicity over time.
