Third-Line DLBCL Therapy Choice Depends on Access to Bispecifics

Krish Patel, MD

Director of Lymphoma Research

Executive Chair Lymphoma Research Executive Committee

Sarah Cannon Research Institute

Nashville, TN

CASE SUMMARY

• A patient with diffuse large B-cell lymphoma (DLBCL) relapsed after first-line therapy and received chimeric antigen receptor (CAR) T-cell therapy as a second line. ​​
• They achieved complete response, then had disease progression 14 months later. ​
• Biopsy confirmed CD19 positivity.
• The patient is unable to travel to the academic center. She is the primary caretaker for her mother who has dementia.​

Krish Patel, MD: The most common answer choice here was loncastuximab followed by bispecific T-cell engager. Is this colored by what's available to you in your clinic? Is this something that you're thinking about as you choose a therapy? What can we give here? I ask that, recognizing that bispecific antibodies are perhaps making their way into more community settings, but are not there yet in all.

Govinda Brahmanday, MD: We don't do bispecifics yet, but I think there's some discussion at the pharmacy and therapeutics committees of trying to bring in the bispecifics, not for the induction, but for the subsequent [doses] after they received it at a [tertiary care] center. But if this patient's logistical issues prohibit her [from getting a] bispecific, I think loncastuximab would be a good option.

Patel: I'm assuming that's the challenge of managing cytokine release syndrome [CRS] during the step-up dosing. That can be the barrier to being able to do the initial dosing. Is that right?

Brahmanday: That's right, yes.

Peter Jiang, MD: We have started using bispecifics for different malignancies like small cell lung cancer. We plan to start for DLBCL.

Patel: It's always going to depend on your exact setting. I recently moved to the Southeast, but where I came from in the Pacific Northwest, we treated all our patients out of the hospital. Part of that is we also did outpatient CAR T-cell therapy, but we had the infrastructure to do that. So, I think it certainly can be done, but it depends on the exact approach and resource setting. To hear from some of you who are using bispecifics in your practice, are you using these [in the setting of] inpatient or outpatient? Are you hospitalizing patients? If so, for how long and when?

Andrew Weil, MD: We had a clinical trial for follicular lymphoma and DLBCL using epcoritamab [Epkinly], and the clinical trial was solely outpatient. It's closed to referral now, because it was a great trial, but we didn't have to admit patients and none of my patients [required hospital admission], so we were able to give this drug in the outpatient setting and not have any issues, which taught us we can do it.

Patel: [What is important is] your comfort level with managing grade 1 CRS [and] grade 2 CRS. We were able to manage grade 1 and some grade 2 CRS in the outpatient setting, but that's also because we had the resources, the infrastructure, and the experience to do it. That may not be what you want to do the first time you treat a patient in your institution with a bispecific. There are lots of different models of care that you can approach, but a lot of this is going to be that balance between patient factors and your health system factors. For this patient, we picked this answer.

DISCUSSION QUESTIONS

For patients with a suboptimal second-line response:​

• How do you determine the timing and selection of subsequent therapy?​
• What criteria guide your preferred sequencing strategies.

Krish Patel, MD: For patients who have a suboptimal second line response—in a setting where we're still trying to cure the patient, any recurrence is a suboptimal response. How do you determine the timing and selection of subsequent therapy? Most of these patients, I expect, are going to need therapy right away. Do you feel like you have time in this setting to either phone a friend and seek some input on what treatment to get, or, if not, how do you go through the sequence of therapies in the third-line setting and beyond?

Venu Madhav Konala, MD: If the patient is able to tolerate bispecifics, particularly where I practice, I have to send them to a hospital to a colleague who can do the step-up dosing and send them back to me to do that. If they're not able to do that, then you go with what is readily available, like loncastuximab or other regimens.

Krish Patel, MD: Thinking about preferred sequencing, it sounds like one preferred sequence could be a bispecific and then maybe loncastuximab. The most common answer choice from the poll was loncastuximab. For patients who might be going from CD19-directed CAR T-cell therapy to loncastuximab, we shared in the case vignette that the patient still expresses CD19. Is that something that you would want to know? Is that information that would influence your choice of third-line therapy?

Peter Jiang, MD: When you use loncastuximab, do you have to confirm CD19 positivity?

Krish Patel, MD: It's a good question. In the clinical trial that enrolled patients [LOTIS-2; NCT03589469], if they'd had a prior CD19-directed therapy, then they were required to confirm CD19 expression. I think we do a poor job of being able to define CD19 expression. When you look at patients who have very low or even absent CD19, there can still be some responders there. That's probably more of a limitation of immunohistochemistry and the fact that there aren't necessarily standardized ways to define CD19 expression.

In my own experience, I used to look for it more than I do now. I used to look for it in almost all patients. I don't know that it ever made a difference. That’s also borne out by some of the data we have. Antibody-drug conjugates may be very different than monoclonal antibodies or other immunotherapies. The level of antigen expression may need to be low because of the so-called bystander effect. This is something that [non-specialist oncologists] deal with a lot more than me, because you treat other cancers where low expression still leads to treatment, for example breast cancer and HER2 expression. At least from the data that we have, I don't think it's an absolute that people need to look for CD19, albeit it may make us feel a bit better about the therapy choices we pick.

Brahmanday: I recently had a patient who had relapse almost out of 3 years after CAR T-cell therapy. I referred the patient back to the to the center where he had a CAR T-cell therapy, and they gave him 3 options. One was a clinical trial where CAR T-cell therapy could be used again. The second thing was the bispecific, and then third option was loncastuximab. Luckily for the patient, he is eligible for the clinical trial and right now [is receiving] bridging therapy with polatuzumab vedotin [Polivy] plus rituximab [Rituxan] right now, and then the plan is to go for CAR T-cell therapy as a clinical trial.

Patel: Most of these trials are looking at different antigen targets for other CAR T-cell therapy. I think usually we would not treat with the same CAR T cell again. That is a good point, which is to say, I think this is also an area where we often want to think about clinical trials. We have a number of these clinical trials now with all kinds of different wrinkles on the next generation of CAR T cells, whether that be alternative immune effector cells, differences in engineering, or a different antigen. That's always a good callout to think about clinical trials as a potential for these patients.

DISCLOSURES: Patel previously reported consulting fees from AstraZeneca, AbbVie, ADC therapeutics, BeiGene, Bristol Myers Squibb, Caribou, Fate Therapeutics, Genentech, Janssen, Kite, Lilly, Merck, Nurix, Pfizer, Pharmacyclics, Sana, and Xencor; received research funding from AstraZeneca; received travel expenses from Lilly; and received payment for lectures from AstraZeneca and Kite.