Earlier-Line CAR T–Cell Therapy Integration: Predictable Delivery Through Clinical and Operational Alignment: Chapter 2

Watch Chapter 3 here.

Sarah Nikiforow: Hi to everyone joining. My name is Sarah Nikiforow. I'm a physician at Dana-Farber Cancer Institute in Boston, and I have roles as a clinician in allogeneic stem cell therapy, a technical director in our immune effector cell program, which delivers CAR T–cells to patients, and the medical director of our cell processing lab. My colleague, Kelly Tomlinson, and I will be speaking to you today about some tips we've learned at our treatment centers for operational alignment and system readiness in delivering CAR T–cells, especially as this moves into earlier lines of therapy, making more patients eligible for this potentially lifesaving therapy. Kelly?

Kelly Tomlinson: Hi, I'm Kelly Tomlinson, and I'm the executive director of the Immune Effector Cell Therapy Program at City of Hope.

Sarah Nikiforow: Excellent. We're going to move on to the transition to earlier lines of therapy and focus on some of the challenges that that has raised.

Kelly Tomlinson: Dr Nikiforow, the evidence of earlier use for CAR-T therapy has been moving quickly. Can you walk us through the key data and explain what they mean for when and how to refer patients?

Sarah Nikiforow: Sure. As everyone knows, relapsed/refractory multiply treated patients were those on multiple lines of therapy, while treated patients were those on the first-line therapy. Over the last two years, several trials have been conducted, and I'll mention a few key ones. In lymphoma, there were the ZUMA-7 trial, which involved axi-cel, and the TRANSFORM trial, which involved liso-cel using CD19 CARs. And both of those showed statistically significant benefits in progression-free survival for those two products, with hazard ratios of 0.98 and 0.34, so impressive, moving progression-free survival from 2.3 months with standard of care out to 8 or 10 months.

And then in the myeloma setting, what we saw for both ide-cel and for cilta-cel were impressive differences between the first to third and second to fourth lines of therapy patients, when you compare to standard of care and improvement in progression-free survival, which, for ide-cel, was an improvement at 18 months from 19% with standard of care to 41%. And then with cilta-cel, it went from 22% with standard of care to about 73% having a complete response. You have response rates and progression-free survival. And overall survival, these trials weren't necessarily powered for, but that is looking positive, too. We are really moving into earlier lines of therapy with those products, which now have FDA labels that encompass that. And I had mentioned at the beginning that, especially for ... I'm familiar with the axi-cel study that we have at our center, which I think is ZUMA-23, where patients in their initial R-CHOP therapy, if they're not responding well after a few cycles, will be randomized to continuing standard of care or CAR. It really is moving up.

Taken together, we are seeing not just the data but practice patterns that physicians are treating earlier, but we also think not just can we get the patients in sooner, and they have less complications waiting for therapy or through later lines of therapy, but we also are intrigued to ask, if a patient hasn't had their bone marrow and their T cells beaten with all sorts of other therapies, will these T–cells be more active when we collect them in apheresis, when we manufacture them into CAR? Will we see, as we get earlier in the lines of therapy, even better response rates, more durable duration of therapy, and a longer duration of response? Right now, with cilta-cel, it looks like the overall survival is plateauing out at 40% and progression-free survival at 50%. Maybe we can do better with earlier lines of therapy for patients and more robust T cells.

What does this mean for a treatment center beyond just seeing more patients who are at that line of therapy? One is that community referral patterns may need to change. We are used to seeing patients who, for allo and auto, are at certain lines of therapy, and the CARs have been coming in really late. A lot of education in the community to alert community physicians to the types of patients we may want to see and who may benefit.

I think it is also educational for clinicians to see how much we take on as a central treatment center and when we would hand patients back. This has implications for both providers and patients regarding how close they can be to home. And if they don't live next to a major metropolitan center, how disruptive will this be to their lives? That's important to emphasize, regardless of the patient's treatment line.

And then, what can be shared locally as we have more patients? One, because there are limited resources internally at any one center, but two, because patients are more likely to participate if there's some shared care. We're thinking about apheresis at local sites, communication there, and maybe even bridging therapy, which could be chemo or another type. It may be just steroids, but other therapies are used to keep the patient's disease under control, maintain their performance status, and enable them to tolerate subsequent lymphodepleting chemo and CAR T–cells during that period.

Kelly, that's what I think about from the MD point of view, and the medications and the referral pattern. What do you see on the treatment center’s operational and nursing side?

Kelly Tomlinson: The operational implications are so important to make sure that there's a developed formalized referral pathway between the community hematologists and oncologists and the treatment center, one that's established before a patient is identified, rather than after. A standardized referral packet with all the required documents reduces back-and-forth communication and can accelerate eligibility confirmation. I do think that your point of education in the community is very important. These lines of therapy have been advancing rapidly. I believe that sometimes community oncologists are not always knowledgeable that some are actually in the second-line therapy space. Really letting them know that they don't need to keep giving more and more chemo; if they can get them to a center, they have other options that, as you mentioned, may really improve their overall outcomes in the end. Coordination is absolutely essential.

The bridging plan must be clearly communicated to both the referring physician and the treatment center, and the timing of the bridging completion has to align precisely with the confirmed manufacturing completion and the scheduled infusion date. As you mentioned, there are also the washout periods after there's bridging therapy. Each site's designated communication contact must be verified and validated, and a structure check-in schedule must be established. That can help prevent gaps and misalignments that could jeopardize the patient's eligibility. It's very important to have a clear communication path because you are working between two centers overseen by two physicians. It can be a spot where gaps in care can form. This is, once again, a place where the one who's coordinating this care, usually a nurse coordinator, can make sure that they're really communicating well with the physician.

And because this is newer, it really does require a standardized process. We have created an actual referral program that we are getting ready to implement. We haven't yet because we have seen this as a huge need, helping referring physicians hand off patients and say, "Hey, is this someone that you are able to help?" And they can do it earlier on without having to know all of the ins and outs. And then through that process, we have time points that we have set standardized communication that we reach back out and constantly let the physician know where that patient is at in the process, where we need their help in still overseeing the patient, especially if they were to get bridging therapy back at their site depending on how far away they have come, and then also all the other steps in the process of apheresis being infused. And then also, before we're getting ready to discharge. And then after discharge, we also have standardized communication practices.

I think having very clear communication is what's going to help bridge those gaps and ensure the patient moves through the process smoothly.

Sarah Nikiforow: And I'll close this particular topic by saying this is a moving target. And specifically as I think about standardized checklists to say patient meets criteria for apheresis to start lymphodepleting chemotherapy and to receive cells, our institution had started off with taking those criteria pretty directly from the registrational studies of the original ZUMA-1 and all these other relapsed refractory trials, but we have realized in the real world that people who don't meet the initial trial eligibility criteria may do as well.

The axi-cel label has been expanded to no longer exclude patients with CNS lymphoma. We feel more comfortable with patients who have slightly impaired renal function or even less-than-ideal cardiopulmonary status. We are now able to get on these therapies. Having standardized checklists to say who's ready to proceed, but recognizing that you always have to build in the flexibility to your program that, as you learn and as not just from trial data but your own personal experience, some of these standardized metrics may change and may be different when we go to different diseases.

I'll wrap up this section with that thought, and then we'll move on to scaling the programs and what treatment centers might need to invest in infrastructure. Both Kelly and I would like to thank you, the audience, for listening, and encourage you to explore more resources on the Oncology Learning Network about CAR–T cells or anything else that tickles your fancy. Thank you.

Kelly Tomlinson: Thank you.