Teclistamab is a BCMA and CD3 directed bispecific antibody. How this works is BCMA is a non-
unique target for multiple myeloma. When you’re looking at any bispecific antibodies in this space
targeting BCMA the T-cells redirect them to cause the myeloma cell lysis and helps with the myeloma
cell kill. The space it has been evaluated in is a pretty crowded space – patients who have previously
been exposed to the immunomodulatory agents, patients who have been previously exposed to the
proteasome inhibitors, the CD38 antibodies. There is an unmet need for these patients to have new
therapeutic strategies. So the prognosis probably is not as good as we want so we definitely want to
improve on what we have at this point in time and bispecifics make a nice place in there with a good
safety profile. That’s what has been evaluated in this setting.
What was the methodology?
It’s a phase I/II study. The phase I portion had 40 patients or so and the phase II portion has three
cohorts. Cohort A is the patients who were initially thought to be in the earlier lines of therapy; Phase
B are the ones who are penta-refractory patients and Cohort C are the ones who are the prior
exposed BCMA patient population. Cohort B was quickly discontinued because Cohort A is accruing
all these penta-refractory patients. So now we only have two cohorts that are existing out there –
Cohort B got dropped out; Cohort C was presented as a poster discussion; Cohort A is the one that
was combined with part 1 and that contributed to a total of 165 patients, that’s what we have
presented the data on.
So the primary endpoint for this specific data was overall response rate; there are several secondary
endpoints including the duration of response, the progression free survival, overall survival, several
other PK parameters as well as quality of life issues as well.
What did you find?
The patient cohort is 165 patients; their median age is 64 years old. You see a heavily pre-treated
patient population so the median prior lines of therapy in this patient population is five. These patients,
as I alluded before, 30% of these patients are penta-refractory; almost 75% of these patients are triple
refractory; 100% of them are exposed to any of these three drugs, all of these three drugs. So in this
patient population it is hard to see a good response. Teclistamab at a dosing of 1.5mg/kg given
weekly, this is, of course, after receiving the step-up dosing, patients were given until you get a
response. So we were able to see those responses happening very quickly, at 1.2 months as a
median, and the best time to response is less than 4 months. You are able to see an overall response
rate of close to 63%.
When you have a response these responses are deep, the VGPR rates are 58%; the complete
responses are close to 40%. So you see those deep responses, quick responses and those are
durable over time which leads us to believe that this is a good agent in this space.
What we also presented was the median progression free survival which is 11.4 months. Putting it
into context, this is equal to what was approved, what was seen, in the approved ide-cel in the cohort
that received 450 million CAR T-cells. So that approved ide-cel had a PFS of 8.5 months in a similar
patient population; this has a median PFS of 11.5 months, rivalling what I alluded to earlier about the
450 million CAR T-cell cohort. So a very effective strategy, able to deliver the benefits like what you
get from a CAR T yet not being subjected to all the process issues and the logistical issues of the
CAR T which is a win-win situation.
What is next for the study?
We do have… this is the median duration of response, median PFS, these are all well maintained.
There are some safety issues that really we need to work on to make these agents much, much
better; these can be improved. So, number one, there is an infection signal that was seen – there are
a higher number of COVID patients and there were 12 COVID deaths through the study. One can
only assume this is happening in the midst of a pandemic, thanks to the patients that participated in
this, but it’s a huge number of COVID deaths that happened. So we cannot say that these are related
to the drug, this is happening, again, in the midst of a pandemic, but we need to figure out strategies
that would minimise the infection potential, provide good prophylaxis yet be able to deliver the drug.
There are several strategies that could be worked out and currently some of these trials are working
on those, like spacing the interval between the dosing. Trying to look for alternative dosing schedules
is absolutely essential so that we can deliver the drug at much farther intervals.
None of the side effects have led to the discontinuation of the drug except in two patients. So this is a
very safe drug, the drug intensity that was intended to be delivered is almost beyond the 94% or so
which always tells you that this is one of the drugs that you want to deliver, you’re able to deliver
without any dose reductions or dose interruptions.
Anything else to add?
The CRS rates and the neurotoxicity rates, these are not quite different than what you see in the other
bispecific antibodies. If there are higher grade CRS rates then it would make me worry but that’s not
the signal that we are seeing here. The CRS grade 1 is in the range of around 70% or so, grade 2 in
the range of around 30%; grade 1 and 2 together is 70%, grade 2 30%. The number of people that
received teclistamab is in the range of around 30% as well. So these all happened during the priming
dose or the first dose which makes it very comfortable when you have a predictive toxicity profile. You
can plan for the next cycles to be delivered in the community so that’s probably what’s going to
happen ultimately for this class of drugs where the drugs can be given to the patients in the
community through the community doctors.
