Transcript
My name is Martin Hutchings. I'm a senior consultant at the Department of Hematology in the phase I unit at Rigshospitalet in Copenhagen, Denmark.
I'm talking to you today because of your interest in a recent publication in the "Journal of Clinical Oncology," which has me as the first author and which is a presentation of the primary results of the dose-escalation part of the NP30179 study of glofitamab in R/R B-cell NHLs.
NP30179 is an ongoing phase I study of glofitamab in R/R B-cell NHLs. Glofitamab is a bispecific antibody targeting CD3 surface tumor antigen on the effected T cells and CD20, which is a well-known B-cell target present on the majority of malignant cells in the B-cell lymphomas.
The idea behind the bispecific antibody is to bind simultaneously to the effected T cells into the malignant B-cells, thereby engaging T-cells in anti-tumor activity, and also, in turn, apart from releasing cytokines and chemokines that attack the tumor cells, also recruiting other cytotoxic T-cells, the size of the tumor.
All the patients that were enrolled in this study from the beginning were patients with either refractory or relapsed B-cell NHL of various histologies, and the vast majority of these patients have been quite heavily pretreated, all failing prior chemotherapy lines and prior anti-CD20 monoclonal antibody-containing lines.
The vast majority of patients are refractory to the immediate prior lines of therapy given. These are patients going into the study with quite aggressive and developing disease. The majority of patients with diffuse large B-cell lymphoma (DLBCL) or other subtypes of aggressive B-cell non-Hodgkin lymphoma, and a smaller minority with indolent histologies and most prominently follicular lymphoma (FL).
As in any dose-escalation study, this study started at very low doses because the primary objectives of a dose-escalation phase I, first-in-human study is to assess toxicity, safety, and to determine the optimal dose. This is the maximum tolerated dose or the optimal biological dose. Both can be referred to as the recommended phase 2 dose.
Now, we didn't in the course of this study meet a real dose-limiting toxicity, but the recommended phase 2 dose or the optimal biological dose in the end was determined at 30 milligrams. First patient received just 5 micrograms. That difference of effect is 6,000 between the smallest dose in the first patient and the dose at which we ended in the last cohort.
This is really quite important: On the way up to 30 milligrams, patients were treated with flat doses. That means the only pretreatment before the first bispecific treatment was a pretreatment with obinutuzumab, the anti-CD20 antibody that was given 7 days prior to the bispecific in all patients in this study.
In the beginning, we thought this was enough to mitigate cytokine release syndrome, which is the most serious and most prominent side effect of this class of drugs. Reaching biologically meaningful doses, it became clear to us that too many of our patients experienced cytokine release syndrome. Too many patients had cytokine release syndrome of relatively severe grade, grade 2 and above.
When we reached 25 milligrams, all patients experienced cytokine release syndrome. We've stepped back and introduced step-up dosing. Patients, instead of getting the full dose from day 1, would start at a relatively low dose. Then a week later, an intermediate dose. From the third week and onward, the full dose given every 3 weeks. The last 47-ish patients had step-up dosing.
We can see that these patients have just as high anti-tumor activity as the patients who were treated in the highest doses of the flat dosing cohorts.
But they had less severe grades of cytokine release syndrome, so more manageable, more safe but just as effective and possibly a little bit more effective even because we could continue dosing on patients and not taking them out because of cytokine release syndrome.
What about the tumor activity?
We see responses in roughly two-thirds of the patients. In more than 50 percent of patients regardless of whether you're looking at indolent histologies or whether you're looking at aggressive non-Hodgkin lymphoma including diffuse large B-cell lymphoma, the complete response rates are higher than 50 percent.
This is extremely high in this disease setting.
We're used to looking at new knowledge in these very difficult to treat patients where we happy to see response rates of 30-35 percent with maybe half of those being complete. Here, we're looking at least two-thirds of patients responding and more than half of the patients going into complete response.
That has been presented before, I think, a recent update at the ASH meeting in 2020, in December of last year where we did present these response rates and looked at responses in different disease categories. What's in the recent paper is also the durability of the responses.
Of course for the individual patient, depth of response is not in itself a clinically so meaningful endpoint. It's about not only controlling disease at one point, but keeping that controlled. What we demonstrate is that among the patients who entered complete responses in this study—like I said, that's over 50 percent so far—the vast majority of these responses seem to be very durable.
In approximately 80 percent of patients at the most recent follow up who had gone into complete response had kept that response. This is a follow-up, which is ranging between just a few months but all the way up to 27-28 months. So, more than 2 years of follow-up in the longest-responding patients. Of course, we will keep following these patients for as long as we can, and they allowed us to.
Now, many novel agents in these diseases are given until progression. Glofitamab, on the other hand, we only give for up to 12 cycles. That's every 3 weeks. It's approximately 8 months. All patients stay on study, we follow them and then with the option to retreat responding patients if and when the disease comes back.
When you look at the durability of the responses, you must keep in mind that no patient has been treated for more than 12 cycles. These are responses that are durable even after completion of treatment even more than a year, year and a half, after the completion of treatment.
Also, we've presented along with the data showing durability of the responses. We've also presented data demonstrating progression-free survival, which is a very preliminary analysis. It's a secondary endpoint. It's not normally an endpoint that you look at in phase I studies that is left to phase 2 and 3 studies, but the results are really so good and the progression-free survival, so relatively promising that it's worthwhile looking at even at this very early point in time in the development of this drug in these diseases.
