Matasar Looks at Various Treatment Options in the DLBCL Setting for Transplant-Ineligble Patients

Matthew Matasar, MD, MS

Chief of Blood Disorders

RWJBarnabas Health

Professor of Medicine

Robert Wood Johnson Medical School

Rutgers Cancer Institute of New Jersey

New Brunswick, NJ

Targeted Oncology^TM: What are some approved regimens for this patient with R/R DLBCL?

MATASAR: The GO29365 trial [NCT02257567] led to the approval of polatuzumab vedotin-piiq [Polivy] plus bendamustine [Bendeka] and rituximab [pola-BR].¹ This was a trial that actually had arms both for [follicular lymphoma (FL)] and for DLBCL. It had an expanded safety run-in where we gave patients BR along with obinutuzumab [Gazyva] instead of rituximab, because at that time we weren’t sure which of them was going to win in parallel studies. And then, after the safety run-in, there was a randomized trial in DLBCL and a randomized trial in FL.

The FL trial was negative, [but] the DLBCL trial was largely positive. There were 40 patients in each arm [of the DLBCL trial]; 40 patients got BR and 40 got BR plus polatuzumab. The primary end point was supposed to be complete response [CR], with overall survival [OS] as a secondary end point. The study wasn’t double blinded. Every patient got BR for 6 cycles. The bendamustine was [intended] to be given every 3 weeks, but we backed off to every 4 weeks in patients who couldn’t tolerate it. This study was for transplant-ineligible patients in the second line of therapy and beyond.²

The patients were, as you might imagine, a bit older [median age, 67 years in the experimental arm and 72 years in the control arm]. There was a relatively higher rate of high IPI score [55% and 72.5% of patients in the respective arms]. The median number of prior lines of therapy was 2, so third-line therapy was the median, although there were some patients who were getting second-line therapy and some who were getting it later line.

Most of the patients had a relatively short duration of response [DOR] for the last line of therapy. The percentage of patients who were primary refractory [was 75% and 85% for the respective arms], a small percentage of patients had received prior stem cell transplant, and there was a mixture of cells of origin.

What was the efficacy seen for patients with DLBCL receiving pola-BR?

Pola-BR clearly improved the OS rate compared with BR alone, which at the time was [not] the standard of care; gemcitabine plus oxaliplatin [GemOx] was more popular at the time. [But] we were all worried that giving polatuzumab on top of a platinum drug was going to scorch nerves. So this was seen as a safer comparator arm and a more appropriate combination.

The experimental combination dramatically improved the overall response rate [ORR; 45.0% vs 17.5% in the experimental and comparator arms, respectively] and dramatically improved the rate of CR [40.0% vs 17.5%, respectively]. We did an extension cohort with 100 more patients, and the ORR for this cohort was a little lower [41.5%] but basically confirmed the findings. The progression-free survival [PFS] was markedly improved with pola-BR vs BR alone [9.2 months (95% CI, 6.0-13.9) vs 3.7 months (95% CI, 2.1-4.5), respectively]. The median PFS in the extension cohort was a little bit shorter [6.6 months], but basically it confirmed the findings.^2,3

The OS results were a surprise to the investigators. It was a secondary end point. We didn’t think we’d see an OS benefit, but it was there. This is the first randomized trial in the rituximab era, in patients with relapsed or refractory DLBCL, to demonstrate OS improvement. The OS improved from 4.7 months [with BR alone] to 12.4 months [with pola- BR]. That 12.4-month OS was affirmed with the outcome from the 100-patient cohort [OS, 12.5 months]. These were very reasonable data.

In terms of adverse events [AEs], polatuzumab, when added to BR, does add some toxicity. Certainly, neurotoxicity is nontrivial. Thankfully, it was largely low grade and reversible in this study. We know [the regimen] was relatively well tolerated because dose reductions were uncommon. Discontinuation due to AEs did happen in approximately one-third of the patients, although most of that was due to progression as opposed to toxicity.²

Would you rebiopsy after a prior polatuzumab progression?

If somebody has clear disease and you give them polatuzumab and they are progressing, do they need a biopsy? No. We don’t have a commercial assay for CD79b, which is the target of polatuzumab.

There is no other treatment that targets CD79b, anyway. You may look for CD20 expression at that point, if you are going to consider a CD20-bispecific trial, to make sure they haven’t lost CD20. I guess it depends on your next line of therapy and whether you need tissue.

What data support the use of tafasitamab (Monjuvi) plus lenalidomide (Revlimid; tafa-len)?

Tafasitamab, formerly known as MOR208, is a naked anti- CD19 antibody. It was tested as a monotherapy and led to stable disease in DLBCL and got a lot of responses. So it was [then] tested in combination with lenalidomide to produce a mechanistic synergy. You have high rates of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis with this antibody, and [it achieves] T-cell and natural killer–cell activation, [so] it makes a good combination.^4,5

The combination of tafa-len was tested in patients with relapsed DLBCL in the trial known as L-MIND [NCT02399085]. This was a single-arm, phase 2 study. The patients had no more than 3 prior lines of therapy.^4,6 Patients had to be transplant ineligible, and primary refractory patients were excluded.

The definition of primary refractory changed during the study…[so a subgroup of patients who relapsed] between 3 and 6 months were included. The lenalidomide starting dose was 25 mg. The primary end point was ORR, and there were several secondary end points.

How did patients do in terms of efficacy and safety in the L-MIND trial?

Patients did very well. There was a 40.0% CR rate and an ORR of [57.5%]. Probably the most interesting data from the L-MIND results were how durable the responses could be. The median DOR was [43.9 months].^6,7

If a patient achieved a CR, those patients had extremely durable disease control with this treatment. And the OS for those CR patients is extraordinary [median OS for all patients was 33.5 months; for patients with CR, median OS was not reached].⁷ We’ve never seen [Kaplan-Meier] curves like this with routine therapies in patients with DLBCL. How much of this was due to patient selection and how much was due to treatment? We are still trying to figure that out. But, if a patient fits this profile, these are very attractive curves.

Regarding toxicity, [this study combination] was well tolerated. Certainly, the data supported that. There was some myelosuppression, [but] nothing exciting.⁶ It doesn’t seem that the CD19 antibody added a lot of toxicity. It does have scheduled toxicity because of the way the trial was written; patients received the tafa-len combination and then, if they achieved stable disease or better, they went on to tafasitamab maintenance every 2 weeks until progression or intolerance. So those patients who are in CR for many years [would be] coming into your office and getting a lot of infusions. It’s a nice problem to have. Some would say that [these] patients would have a median survival of less than year, but still, it’s a challenge.

Patients in this study had a very low rate of treatment discontinuation [12%]. Among the treatment-emergent AEs leading to death [affecting 13% of patients], none were attributed to the therapy; those were all due to progression. The tafa-len combination had lots of cytopenias. The tafasitamab monotherapy didn’t have a lot [of associated toxicity]. There was mild myelosuppression from the naked antibody, but not a lot of toxicity. That’s probably largely placebo-type things that you would see in this patient population.⁴

I usually start patients at 20 mg of lenalidomide [as opposed to 25 mg]. When I use tafa-len, I typically start at 20 mg or lower, sometimes 10 mg, sometimes 5 mg, depending on the patient.

What data support the use of loncastuximab tesirine-lpyl (Zynlonta)?

Loncastuximab is an antibody-drug conjugate, as is polatuzumab vedotin, but loncastuximab is very different, with a different target. It targets CD19 and carries a different payload. The payload here is pyrrolobenzodiazepine [PBD], which is an intercalator, so there is no neurotoxicity. It doesn’t have the MMAE payload of polatuzumab. PBD has its own toxicity profile, but it is important to remember that it has a different target, so you can use [these drugs] sequentially without thoughts about cross-resistance.⁸

The approval of this drug was based on the LOTIS-2 trial [NCT03589469].⁹ This was another single-arm, phase 2 study looking at loncastuximab monotherapy in patients with relapsed or refractory DLBCL in the third line of therapy and beyond. The patients received treatment for up to 1 year, and they were monitored subsequently, with no treatment until progression or loncastuximab intolerance. Patients started with a loading dose [0.15 mg/kg] for the first 2 cycles and then the dose was backed down to 0.075 mg/kg, and from then it continued every 3 weeks for the year. The primary end point was ORR.¹⁰

The patient population here was more [like the] real world than the patient population from L-MIND. It did allow refractory patients. There were patients with high-grade lymphoma [8%], some with double-hit lymphoma. The median number of prior systemic therapies was 3, and some more [patients] had been pretreated.

There were some patients with prior CAR [chimeric antigen receptor] T-cell therapy [9%] and some with prior stem cell transplant [allogeneic, 1%; autologous, 14%; both allogeneic and autologous, 1%]. So this was a more real-world, sicker patient population than in the L-MIND study.¹⁰

What was learned from the LOTIS-2 trial?

Loncastuximab [proved to be] a very active regimen, with a 48% ORR [95% CI, 39.9%-56.7%] and a 24.0% rate of CR. It worked quickly; the median time to response was [41.0] days.10 And there was some durability of CR [57% maintained at data cut-off].¹¹ We are still following these patients. The median DOR [was 13.4 months for all patients and not reached for patients with CR]. Patients with a partial response, with loncastuximab, did not do so great.10 So in some ways, these results were not different [from] what we’ve seen with other treatments. But there was a reasonable DOR, particularly given the patient population treated in this study.

Based on the results of the subgroup analysis, there was no obvious group of patients that didn’t benefit from loncastuximab. One group that I want to note is the patients with high-grade lymphoma….There are not a ton of data for what to do with patients with relapsed high-grade lymphoma, frankly. There weren’t a lot of high-grade patients treated in the GO29365 study.² There were no high-grade data for [the study of] tafa-len.4 But in the results of the LOTIS-2 trial, the small number of patients with high-grade lymphoma and beyond achieved a [45.5%] ORR [95% CI, 16.7%- 76.6%].¹⁰ That’s a differentiating factor for loncastuximab in my practice.

Did this regimen show efficacy in patients who had received prior CAR T-cell therapy?

Loncastuximab did have activity post CAR T-cell therapy. It was an inclusion criterion in LOTIS-2 that if a patient had prior CAR T-cell therapy, the physician had to rebiopsy and confirm ongoing expression of CD19.10

I would say that the experience with most CAR T-cell therapies is that you lose [CD19 expression] 20% to 30% of the time following CAR T-cell therapy for progressors. There are not as [many] data out there for the loss of CD19 after tafa-len or loncastuximab, and none dealing with double-digit anecdotal series…in terms of CD19 expression on biopsies after progression. [Advocates of] tafa-len and loncastuximab are trying to put together a more robust experience around this, because the question of how to sequence CD19-targeted treatments is a real challenge for us. But, yes, if a patient got prior CAR T-cell therapy and still has CD19 [expression, this regimen is] appropriate and active.

Right now, for monitoring post CAR T-cell therapy, the best way we have to do it is scans, and then biopsy it if it shows. But we always rebiopsy after [progression following] CAR T-cell therapy, both to look for CD19 for consideration of sequencing therapies, as well as to see what’s going on.

[Another question is,] can you do CAR T-cell therapy after loncastuximab? And there were some patients that progressed after loncastuximab on the LOTIS-2 trial and still had CD19 expression at that point and went on to get CAR T.¹² It seems like both of those sequences are appropriate in select patients.

Patients who relapse after CAR T-cell therapy and those with high-grade BCL are 2 challenging patient populations. Post–CAR T-cell relapse is an emerging area of data. Loncastuximab now has data here.¹² There are some data for polatuzumab, not a lot, but [that regimen is also] clearly active in that situation. Bispecifics are collecting these data. There are a lot of trials that are now being written and run to look specifically at patients who failed CAR T-cell therapy, which is an unmet need.

Are there toxicity concerns when using a PBD payload?

PBD does have some toxicity. There was some degree of myelosuppression and a little gastrointestinal toxicity with it. Elevation of γ-glutamyltransferase [GGT] was a problem for patients in this study. It wasn’t clinical hepatitis; mostly it was a lab abnormality. When I [use] loncastuximab, I don’t check GGT elevation. I will call your attention to the edema [observed in the LOTIS-2 trial], which is real [and which affected 20.0% of the patients].¹⁰ For whatever reason, fluid accumulation with PBD treatment [occurred]. There are other PBD delivery antibody-drug conjugates….Pleural effusions are not a big problem in my experience with loncastuximab, although it is a risk. But [the concern is] more with peripheral edema, weight gain, and fluid accumulation. This is manageable. It is better with corticosteroid premedication, and if your patients are getting soggy, early intervention with diuretics— spironolactone [Aldactone] being the diuretic of choice for these patients—keeps them out of trouble.

_REFERENCES

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_{4. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single-arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Hematol Oncol. 2019;37(suppl 2):173-174. doi:10.1002/hon.130_2629}

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_{7. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958}

_{8. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493}

_{9. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. FDA. April 23, 2021. Accessed November 10, 2022. https://bit. ly/3UNKdEQ}

_{10. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/ S1470-2045(21)00139-X}

_{11. Caimi P, Ai WZ, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2. J Clin Oncol. 2021;39(suppl 15):7546. doi:10.1200/JCO.2021.39.15_suppl.7546}

_{12. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T cell therapy. Clin Lymphoma Myeloma Leuk. 2022;22(5):e335-e339. doi:10.1016/j. clml.2021.11.005}