First in-human trials of rovalpituzumab for SCLC
Dr Charles Rudin - Memorial Sloan Kettering Cancer Center, New York, USA
I’ll be presenting on a new therapeutic that we’re testing in the context of small cell lung cancer. It’s a particularly aggressive type of cancer with a very short median survival, highly responsive to initial chemotherapy but it recurs very quickly and when it recurs it’s extremely lethal. So the majority of patients with this disease present with metastatic disease, that is disease that has spread outside the chest, and for those patients the average duration of survival is only about 9-10 months. There’s really only one drug that has been approved for use in the context of recurrent disease, at least in the United States, and that drug is not particularly effective. So we think this is a space where there’s really an urgent need for drug development and for better therapeutics.
The strategy that I’ll be presenting on is an antibody drug conjugate, so there’s an antibody which binds to the cell surface of cancer cells, it binds to a particular protein called DLL3 that’s highly upregulated in small cell and essentially absent from normal cells. The antibody is linked to a warhead, a toxin, that the antibody essentially brings to the cancer cell that is internalised and the warhead is released and kills cancer cells. It’s been shown to be very effective in preclinical models and this is the first test of this particular antibody drug conjugate in people.
Could you tell us more about the clinical results that you’re seeing now?
Yes, we were encouraged to see evidence of response in these patients so a fair fraction of the patients had what we consider to be objective partial responses. This is when the tumour shrinks by at least 30% in maximal diameters. That occurred in about 18% of patients overall but importantly in the subgroup that had high level expression of the target for this antibody, high level expression of DLL3, the response rate seemed to be substantially greater at about 39%. So we think this may be the first demonstration of a predictive biomarker for small cell lung cancer that is an assay that we could use to selectively identify those patients who are more likely to benefit from this therapy and to exclude patients who are not likely to benefit from the same drug.
With this biomarker in mind, have there been any efforts towards drug escalation, finding the right kind of dose limits.
Yes, so part of the designof this trial was to identify the correct dose. We started at a very low dose and, as is typical for first in human clinical trials, we gradually escalated doses in subsequent cohorts to define a dose range at which we were seeing efficacy and also tolerability. So we defined what we would consider to be a maximally tolerated dose and backed off from there and then expanded at what we would consider to be the recommended doses in a larger cohort of patients to look at the efficacy within that patient population.
Is there anything that you think clinicians should be watching out for? Are there any next steps?
The next steps are really confirmatory trials to see whether the preliminary data from this first in human study really holds up in defined cohorts, larger cohorts of patients. So there’s a trial that has been launched called TRINITY which is in patients with at least two prior therapies for small cell lung cancer to evaluate the efficacy of this drug within that context. That trial will focus on the patients who have expression of the target, DLL3, on the surface of their tumours and that trial will allow patients with any level of expression of that target. Our hypothesis is that it’s really the patients who have high level expression of the target that may selectively benefit from the drug but we will see what the results of that will be.
That’s all I can think to ask, is there anything that you would like to add?
We’re very encouraged by the initial signals with this drug but clearly larger, confirmatory trials are needed.