Munoz Discusses Promises and Challenges With Emerging Treatments in DLBCL

Javier L. Munoz, MD, MBA

Director, Lymphoma Program

Mayo Clinic

Phoenix, AZ

Targeted Oncology^TM: What data support the use of polatuzumab vedotin in transplant-ineligible patients with relapsed or refractory DLBCL in the second-line setting?

MUNOZ: We have established that patients with transplant-ineligible relapsed or refractory DLBCL fare poorly with standard chemotherapy, as they usually have an ominous prognosis. The antibody-drug conjugate [ADC], polatuzumab vedotin [Polivy], is a novel agent that targets CD79b, a B-cell receptor component. The phase 2 study of POLA-BR [polatuzumab plus bendamustine (Treanda) and rituximab (Rituxan)] included transplant-ineligible patients or those with treatment failure with prior ASCT [autologous stem cell transplant] who were [randomly assigned] to get either POLA-BR or BR.

It is a 21-day cycle treatment for 6 cycles, and the dose doesn’t go up or down unless there’s toxicity. If there is neuropathy, then one can tweak the dose. But if the patient does well, it is a flat dose of 1.8 mg/kg of polatuzumab [intravenously], 90 mg/m² of bendamustine, [and 375 mg/m² of rituximab], as many of us prescribe.¹

This POLA-BR study [NCT02257567] led to an accelerated approval of POLA-BR in 2019.² More than 80% of patients had advanced-stage DLBCL. The median prior lines of therapy were 2, but some patients had received up to 7 prior therapies. Seventy-five percent to 85% of patients were refractory to the last prior therapy.² Anyone who has treated someone with an aggressive lymphoma refractory to the last therapy knows one is in a hurry because of being a little bit against the ropes. For the POLA-BR, the overall response rate [ORR] was approximately 45%, primarily driven by complete responses [CRs],² which was attractive.

With so many bad actors for a treatment that you give every 3 weeks, it is reasonable to have an ORR of more than 40% that is mainly driven by CRs. One can have high response, but if it’s only going to put you in remission for 1 month, then it’s just not worth your effort.

You need to get some months, so maybe you could pivot on this treatment and do something else, whether it is CAR [chimeric antigen receptor] T-cell therapy or transplant, if the patient is a candidate for that. With that, I was thinking allogeneic SCT, because by now you are thinking of third-line therapy. The duration of response [DOR] is not a panacea [or] a home run, but it does help a lot of patients, particularly with the over 40% ORR [Figure³]. And there is 9 to 10 months DOR in these patients.³

Could this treatment be a bridge to transplant or CAR T-cell therapy?

Perhaps. I must admit I do use it pre-CAR T-cell therapy, but I deviate from the label, so I navigate with caution when it comes to my comments. Obviously, follow the FDA label and the National Comprehensive Cancer Network guidelines.

I must also admit I prescribe it without bendamustine because I’m afraid of the effects of chemotherapy on T cells. Bendamustine is lymphotoxic. In the ZUMA-2 study [NCT02601313] that used CAR T-cell therapy in mantle cell lymphoma, patients who got bendamustine before CAR T-cell therapy did a little worse than those who did not. I think that is interesting and because of that, I have a bias extrapolating. Of course, take this with a grain of salt. I’ve been doing some POLA-R instead of POLA-BR, but POLA-BR [is approved].

The overall survival [OS] was better for [patients on] POLA-BR compared with BR, at approximately 12 months vs 5 months, which is a big difference.³ Now, would you go just with BR in a patient with relapsed or refractory DLBCL? You can, but the responses are not going to be as good, and they’re not going to last like that of POLA-BR.

Remember that ADCs have a small amount of chemotherapy. In this case, vedotin monomethyl auristatin E [MMAE]. It is internalized once the linker with the antibody is cleaved, so the payload is delivered in a smart fashion. Vedotin [MMAE] is a tubulin antimitotic agent reminiscent of vincristine [Oncovin], which can cause neuropathy. Not surprisingly, POLA-BR has more peripheral neuropathy than BR. Of note, grade 3 or 4 toxicity is 0% in both arms, which is reassuring. That means the disabling neuropathy is not there, but the garden-variety neuropathy does appear with POLA-BR. One [must] keep an eye on it and [ensure] it is not getting worse.

What treatments do you consider for patients with newly diagnosed DLBCL compared with further lines of treatment?

We have plenty of newly diagnosed patients with DLBCL to go around. It’s the most common aggressive lymphoma. But as we go along in the journey—second line, third line, fourth line, fifth line, and so on—patients get fewer, which means our chances of trying all the drugs in multiple patients is going to get smaller. So it makes sense that in some of these agents, we may have less personal experience than in others.

Tafasitamab [Monjuvi] is a naked antibody against CD19. It is not an ADC, so it is different from polatuzumab. Lenalidomide [Revlimid] is an immunomodulator. We honestly do not understand it well. I’ve seen slides trying to explain how lenalidomide works, and they tell you 10 different mechanisms of action. To me, that just means we don’t understand why or how lenalidomide works.

It is approved for the treatment of [patients with] mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma. Polatuzumab was approved in 2019, and tafasitamab and lenalidomide got accelerated FDA approval 1 year later. The approval included DLBCL arising from low-grade lymphoma and patients who were not eligible for ASCT.⁴

What data support the use of tafasitamab plus lenalidomide in transplant-ineligible patients with relapsed or refractory DLBCL in the second-line setting?

The phase 2 trial for tafasitamab plus lenalidomide had the catchy name, L-MIND [NCT02399085], and the primary end point was ORR. Patients included were those with relapsed or refractory DLBCL who had 1 to 3 prior therapies and were transplant ineligible. Primary refractory patients were excluded.

The induction from cycle 1 to 3 is more intense. It gets better from cycle 4 to 12—we’re still prescribing the doublet but not as often for tafasitamab. Finally, you have maintenance tafasitamab after cycle 12, without lenalidomide until progression of disease.⁵ POLA-BR is just a little easier, [as] it is given every 3 weeks. If you are having no severe adverse effects [AEs], it’s just a flat dose, but it doesn’t mean this is a bad combination by any means. It’s just a little different than how we dose POLA-BR.

The median line of previous therapy was 2 but up to 4. It was mainly 1 or 2 prior therapies, which were 50% and 43% of patients, respectively. There were also 44% of patients who were refractory to prior therapy and 11% of patients with prior ASCT,^5,6 so some bad actors there for sure. The primary end point, which was ORR, was 57.5%, [which] is encouraging. And from that, 40% were CRs, like with POLA-BR, and the median DOR was 43.9 months, which is quite impressive.^5,6

The median progression-free survival [PFS] was 11.6 months, so almost 1 year. The median OS was 33.5 months, so almost 3 years.⁶ Again, I understand why several of our colleagues chose tafasitamab plus lenalidomide. It has a good ORR, PFS, and OS. It is a treatment you can prescribe, and it is not available only in boutique centers.

Now, trying to be the devil’s advocate, I always have some pause outside of a randomized trial to compare a trial that has a finite duration of therapy. POLA-BR— 6 cycles and you’re done—compared with a regimen that has some sort of maintenance plugged into it, particularly with drugs that have activity like tafasitamab, which you keep pushing for weeks, months, and so on.

Some of these trials are designed until progression of disease, and if the drug you continue to prescribe is active, you will assume that duration could be a little more handsome than the ones that have a finite duration of therapy. That is something to consider. The trial designs were different, so it’s not necessarily apples to apples.

What AEs should be highlighted with this treatment?

For polatuzumab, it was neuropathy. For tafasitamab plus lenalidomide, the toxicity is mainly hematologic. Regarding grade 3 or 4 toxicity, the No. 1 toxicity was neutrophilia, No. 2 was thrombocytopenia, [and] No. 3 was anemia and leukopenia. There were no grade 5 events. Grade 4 toxicities are single digits, except neutropenia, which is something expected in the relapsed or refractory setting.

To me, beyond the neutropenia, what matters the most is febrile neutropenia. [Although] 21% of patients had grade 4 neutropenia, only 2% of patients had grade 4 febrile neutropenia.^5,7 So between those 2, I would go by the febrile neutropenia as a more actionable and more relevant variable. Regarding nonhematologic toxicities, there were no grade 5 events. Grade 3 to 4 toxicities were single digits. Numerically, the highest grade 3 toxicity was rash,^5,7 [which is] somewhat expected in a regimen that uses lenalidomide [and] something I have seen, even in single-agent lenalidomide.

If toxicity is low, then discontinuation should be low, too. Only 12% of patients discontinued [because of] toxicity. Of course, you have some other variables there, [such as] serious AEs, AEs of special interest, or treatment-emergent AEs [that] lead to death, which was up to 13%.^5,7 Remember some of these patients are preordained to have an outcome, and death is going to happen with or without these agents. Not surprisingly, lenalidomide has a large contribution regarding toxicity.

What data support the use of loncastuximab tesirine in transplant-ineligible patients with relapsed or refractory DLBCL in the third-line setting?

The debate was between POLA-BR and TAFA-LEN [tafasitamab plus lenalidomide]. They are available as second-line therapy. Loncastuximab [tesirine; Zynlonta] is available as third-line therapy. Maybe that is why as we go along, we start seeing less and less patients through this journey. It makes sense that the numbers are lower when it comes to our own experience with loncastuximab [tesirine].

The catchy name for the loncastuximab tesirine [LONCA-T] trial is LOTIS-2 [NCT03589469]. If you notice the accelerated approvals, POLA-BR received it in 2019, TAFA-LEN in 2020, and LONCA-T in 2021.⁸

So there was that beautiful crescendo 1 year after another as these 3 agents got their accelerated approvals. LONCA-T is another ADC; [however], the payload is not MMAE but an agent called pyrrolobenzodiazepine.⁹ They call it a warhead, but [because of] the current bellicose international landscape, I’m going to say payload instead. Reminiscent of the previous study, there is a more intense induction, but it becomes easier for patients as we go along. Every 3 weeks, [patients] get a higher dose for 2 cycles, then a lower dose for 2 cycles, [and] then the dose is maintained every 12 weeks for up to 3 years.¹⁰ It is easier, better, [and] more patient friendly.

They had some bad actors, including double-hit lymphoma [and] prior CAR T-cell therapy failure, each [approximately] 10%. The median prior therapies was 3, so patients were slightly more heavily pretreated with LONCA-T than the other 2 agents.¹⁰

The CR is 24% and PR [partial response] is 24%, making an ORR of 48%.¹⁰ The CR may be a little lower than those of the other 2 agents, but remember, these patients were more heavily pretreated, so it’s a little unfair to try to compare just the numbers and say one is better than the other. The median DOR seems to be [approximately] 1 year in general, but for the patients [who] achieved CR—at least based on the last update—the median DOR had not been reached, which is important.¹⁰

If you’re among those 24% of patients [who] achieve CR, maybe you could have a long DOR, so don’t rule it out. Keep it on the table as a tool in your tool belt because there is a role for this medication.

This trial permitted transplant-eligible and transplant-ineligible patients. It had data for transformed DLBCL and double-hit lymphoma. This is included in the FDA indication, [which] makes it a bit unique. The ORR data for patients who did and did not receive prior CAR T-cell therapy seem similar, but of course, this was a small number of patients.¹⁰

How would you sequence these therapies?

These are the questions that keep me up at night, particularly sequencing of the anti-CD19 agents. We have anti-CD19 CAR T cells, anti-CD19 monoclonal antibodies, [and] anti-CD19 ADCs. Does sequencing matter? It is CD20 agents [like] rituximab that we keep hammering down through multiple lines of therapy, but it mostly does not seem to be an issue with CD20. We just keep recycling rituximab and patients usually do well, maybe because of the agent you’re combining rituximab with but rituximab probably has something to do with it, too.

Now remember, when you have a hammer, everything looks like a nail, and now we have the anti-CD19 hammer that is proving to be quite rewarding in these trials. Fourteen patients received CAR T cells after LONCA-T, they had an ORR of 46%, and fast responses were 1.4 months.¹⁰ It seems like not all is lost after you fail CAR T cells. Remember, CAR T cells’ FDA approvals occurred during this LONCA-T trial, [which] is why you started seeing some [patients with] CAR T-cell failure join the study. Sadly, cancer keeps giving us second chances to try other drugs.

Bad actors also respond; of 11 patients with high-grade B-cell lymphoma [HGBCL], 5 had CR, [which] gave LONCA-T the label for double-hit lymphoma. It’s amazing. It is such a bad disease that if you see a signal with 5 patients going into CR, you get an approval on your label. Interestingly, it may take a little longer to achieve that response in patients with HGBCL—79 days, to be exact, vs 43 days for the garden-variety DLBCL.¹¹

The best responses to LONCA-T after CAR T cells was a CR of 15% and PR of 30%.¹² It’s not a home run, but there are responses. The critics will point out the small numbers and short follow-up. They’re probably right, but there seems to be a signal there, and it’s a good weapon to have in the armamentarium.

For toxicity of LONCA-T, there is myelosuppression and peripheral edema, so keep an eye on those. The trial tested for GGT [gamma-glutamyl transferase]. I’m not sure how many of you test for GGT in the clinic, but if you ask the question, sometimes you will get an answer. What they saw in the trial is that GGT was increased. In my experience, this drug doesn’t cause PI3K inhibitor–level transaminitis, so I’m not concerned about an autoimmune hepatitis causing trouble.

In my eyes, you also see the alkaline phosphatase increased. It’s a little bit compared with what you see with GGT. I have not been too impressed just by following the GGT. Usually, the aspartate aminotransferase and alanine transaminase are not dramatically increased, but the peripheral edema is real, and patients can have weight gain and pleural effusions. It’s not only lower-extremity edema, so you need to pull the trigger there relatively quickly with diuretics. This trial encouraged the use of spironolactone [Aldactone].¹⁰

Comparison is truly the thief of joy, but it is so tempting to compare. Again, proceed with caution. These were not randomized trials. Remember [that] some were more complex than others. In the L-MIND trial, one could prescribe the agent until progression of disease. In LOTIS-2, it was 1 year, and POLA-BR was 6 cycles. POLA-BR was for the transplant-ineligible patients or those with treatment failure with prior ASCT. L-MIND was for the transplant-ineligible [patients], too. LOTIS-2 permitted those who received ASCT 30 days prior or allogeneic SCT 60 days prior. Also, the primary end points were different; it was CR for POLA-BR [and] ORR for TAFA-LEN and LONCA-T.

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_{9. 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}

_{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. Alderuccio JP, Ai WZ, Radford J, et al. Clinical characteristics and responses of patients with relapsed or refractory high-grade B-cell lymphoma treated with loncastuximab tesirine in the LOTIS-2 clinical trial. Blood. 2021;138(suppl 1): 3575. doi.org/10.1182/blood-2021-148730}

_{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}