Study Overview: COLUMBA and PLEIADES

Transcript:

Ajai Chari, MD:I think this is a great segue into a very new way of giving DARA [daratumumab]. We talked about the infusion-related reactions, the time of infusion, the volume, the management of all of these things, the concentration. So a lot of factors to consider but a good segue into giving daratumumab subcutaneously [subQ]. We know that, for example, rituximab was recently approved to be given subcutaneously; IVIg [intravenous immunoglobulin], which is commonly used, to be given subcutaneously. And of course, the question is what about daratumumab? So daratumumab can be given subcutaneously, but one of the limitations of giving antibodies is the volume of the antibody would not necessarily diffuse through the subcutaneous compartment.

In order to give daratumumab subcutaneously, it’s mixed with hyaluronidase, and what this does is it allows the drug to be given subcutaneously in a relatively small volume of 15 mL, and it can be given in the abdominal site. The important study that led to this, the phase III study that compared subcutaneous IV daratumumab, it’s called the COLUMBA study, and that was recently published in The Lancet Haematology by Maria-Victoria Mateos, MD. The eligibility criteria were patients with at least 3 lines of prior therapy, including a PI [proteasome inhibitor] and an IMiD [immunomodulatory drug], or they had to be refractory to PI and an IMiD. Patients were stratified by 3 different criteria, body weight being less than or greater than 85 kg, less than or greater than 4 lines of therapy, and IgG [immunoglobulin G] versus non-IgG subtype.

The randomization was 1:1, and about 260 patients got daratumumab subcutaneously. Importantly, this is a flat dose, 1800 mg, and it was given subcutaneously, as I mentioned, in 15 mL, and it was given at the same schedule that Danny just outlined for IV. And the comparator group was standard daratumumab IV at the standard dose and schedule, 16 mg/kg.

There were 2 co-primary end points. One was the response rate, and the second is the maximum C trough. C trough is basically the dose concentration of daratumumab after you finish those 8 weekly doses. That’s cycle 3, day 1, if you will, because that C trough level has been correlated to efficacy in other studies. In this study, obviously one of the most important and interesting findings is that the median duration of infusion in the first administration was 421 minutes for the IV versus 5 minutes for the subQ. And that goes to 255 minutes and 5 minutes for the second dose; and 205 minutes and remains of course 5 minutes. So we’re looking at 7, 4, and a little over 3 hours for the IV, whereas the subQ remains flat at 5 minutes.

That primary end point was response rate with a median follow-up of 7.46 months, response rate of subQ 41% versus 37%; VGPR [very good partial response] and better, 19% versus 17%, so looking comparable or noninferior. The co-primary end point of C trough was also very comparable. The 107.93%, so C trough, if anything, was slightly higher with daratumumab subQ than IV. But really, again, this was noninferior and that criteria were met.

When we looked at the patient, their cancer treatment satisfaction, it continually improved with daratumumab subQ. Who wants to spend more time in the infusion center? And importantly, I think one of the things that we’ve been talking about with the IV[daratumumab is the infusion-related reactions [IRRs]. When we look at the so-called IRRs, subQ daratumumab, the rate was only 13% compared to 34% for IV. And most of these infusions occurred during that first dose, as we would expect, even with IV. Grade 3 was very uncommon, 2% versus 5%. There were no grade 4 or 5 [IRRs]. And the infusion-related reactions are what you would expect in IV as well—chills 5% versus 12%, pyrexia 5% and 3%, dyspnea 1% versus 7%.

One difference is the median time to infusion-related reactions. With daratumumab, the subQ was 3.4 hours. Again, the drug is being diffused slowly, versus intravenous, which was 1.5 hours. I think that was an important study to show the benefits of intravenous versus subcutaneous daratumumab. The primary end point of response rate was comparable—C trough comparable. So we have basically comparable efficacy with what appears to be an improved safety profile, with lower rates of infusion-related reaction, obviously way more convenient, and then finally the rates of infusion-related reactions were lower.

Moving to the other study, which is important because this was a single-agent noninferiority study, this was a phase III. There’s also the PLEIADES study, which I’ve updated at ASH [the American Society of Hematology 2019 annual meeting]. Basically, this was a slightly different study because it’s daratumumab in combination with some of our standard backbones that we covered. So daratumumab in combination with VRd [bortezomib, lenalidomide, dexamethasone], as was done in the GRIFFIN study, so it’s subcutaneous daratumumab. Daratumumab in combination with VMP [bortezomib, melphalan, prednisone] as was done in ALCYONE with subQ. And finally in DRd [daratumumab, lenalidomide, dexamethasone] as per MAIA, but again the subQ daratumumab. So subQ daratumumab given with the backbones.

The primary end points were different for these 3 arms. The primary end point for the D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone] was VGPR and better because this was only 4 cycles of administration. Whereas the D/VMP [daratumumab with bortezomib, melphalan, prednisone] and DRd [daratumumab, lenalidomide, dexamethasone] were overall response rate. There were some key secondary end points. But each group had about 67 patients in each arm, what you would expect for the patient populations. The response rate for D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone] was 97%; 89.6% for D/VMP [daratumumab with bortezomib, melphalan, prednisone]; and finally 94% for DRd [daratumumab, lenalidomide, dexamethasone]. So kind of comparable to what you would expect for the intravenous regimens.

Importantly, the rates of infusion-related reactions were very low, 9% for D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone]and D/VMP [daratumumab with bortezomib, melphalan, prednisone], and only 4.6% for DRd [daratumumab, lenalidomide, dexamethasone]. So really very low rates, very easy to administer. And again, most of these occurred in that first dose, very little in subsequent doses.

Transcript Edited for Clarity