Brem Looks at Multiple Treatments for Patients With DLBCL

Elizabeth A. Brem, MD

During a Targeted OncologyTM Case-Based Roundtable event, Elizabeth A. Brem, MD, an assistant professor in Division of Hematology/Oncology, Department of Medicine at UC Irvine Health in Los Angeles, CA, moderated a discussion about a 43-year-old woman with diffuse large B-cell lymphoma.

Targeted Oncology™: What therapeutic options would you consider at this point?

BREM: [Based on the NCCN (National Comprehensive Cancer Network) guidelines,] up-front chemotherapy with CHOP is an option.1 We will not have the CHOP vs EPOCH [etoposide (Toposar), prednisone, vincristine, cyclophosphamide, doxorubicin] discussion now. Unfortunately, when a patient progresses after that, you’re going to restage them and think about options such as chimeric antigen receptor [CAR] T-cell therapy. Now, with some of the newer agents being approved, the toxicity profile is getting a bit better, so the pool of [patients] who are eligible for CAR T-cell therapy is probably increasing. Furthermore, you’re going to think about a clinical trial if you had one available. If a patient only had 1 site of disease, you could think about palliative radiation, although in my experience you’re not going to reach for it often.

The question about whether you should consider transplant after some sort of salvage therapy with one of these novel therapies is very much up in the air. The revised NCCN guidelines [for treatment of patients with DLBCL] came out recently and I feel things have changed since they got published. The preferred regimens that are FDA approved are gemcitabine [Gemzar], oxaliplatin [Eloxatin] plus rituximab [R-GemOx] or polatuzumab [Polivy] plus or minus bendamustine [Treanda] plus or minus rituximab [polaBR]. I’ve never used CEPP [cyclophosphamide, etoposide, prednisone, procarbazine (Matulane)], CEOP [cyclophosphamide, etoposide, vincristine, prednisone], or EPOCH in this situation. GDP [gemcitabine, dexamethasone, cisplatin], [is a treatment that] I’m not necessarily sure is that different from R-GemOx. I’ve never given vinorelbine [Navelbine] and I would not give single-agent rituximab.

Now we have tafasitamab [Monjuvi] plus lenalidomide [Revlimid]—tafasitamab being an anti-CD19 antibody, lenalidomide being the immunomodulatory drug that we know and love from multiple myeloma.

Others that are useful in certain circumstances are brentuximab vedotin [Adcetris] for CD30-positive disease. There are some more ongoing data in this situation; however, I don’t use bendamustine plus rituximab much because it doesn’t work for very long. Ibrutinib [Imbruvica] has activity of about 30% in nongerminal center B-cell [nGCB] DLBCL and in times of desperation I have reached for that. Lenalidomide plus rituximab was used for a fair amount before tafasitamab plus lenalidomide was approved and I feel we’re going to move away from that now.¹

There are important footnotes in the NCCN guidelines. We have 3 anti-CD19 CAR T-cell therapies that are technically FDA approved only after 2 prior chemoimmunotherapy regimens, so that’s something to keep in mind. This patient had both CHOP and R-ICE, so [she] would potentially be a candidate. Loncastuximab [Zynlonta] is a conjugated anti-CD19 that has a [tesirine] linked to it and is approved after 2 or more lines of systemic therapy.

What’s not clear is this idea of bridging people to CAR T-cell therapy when a patient has a lot of symptoms and you want to get them feeling better but you know that CAR T-cell therapy is going to take time. It’s going to take time to [do leukapheresis] on them, send it off to get made, and then time to get a response. Sometimes you do something else while you get that going. Some of these other drugs we mentioned target CD19, so should you be doing 2 drugs that target CD19? The jury is very much still out on that.

Please discuss the poll results.

We’re not supposed to compare single-arm phase 2 studies, but we don’t have any randomized studies comparing CAR T-cell therapies. The ZUMA-1 study [NCT02348216] used axicabtagene ciloleucel [axi-cel; Yescarta],. Overall response rate [ORR] was 83%, CR [complete response] rate was 58%. There’s going to be a recurring theme in novel agents in DLBCL, which is that if you achieve a CR, you do better. There is a plateau, but some of these patients who achieved a CR might be cured, so it is important to look at the CR rate. Toxicity was about 11% for grade 3 and 4 cytokine release syndrome and about 32% for neurotoxicity.^2,3

Maybe it is because it was the first construct, and we were still getting used to it and maybe that’s why some of the other ones do better with neurotoxicity. The newest treatment, lisocabtagene maraleucel [liso-cel (Breyanzi)], is being pushed as the safer option and the evidence for that is based on the grade 3 and 4 neurotoxicity [of 11%], and the CR rate is still quite good at 53%.⁴

What are you most likely to recommend for this patient?

Polatuzumab vedotin is a monoclonal antibody targeting CD79b, which is one of the components of the B-cell receptor pathway. It’s conjugated to a payload, in this case MMAE [monomethyl auristatin E], which is one of those conjugated antibodies where the idea is that you only deliver the payload to the malignant cell because that’s what’s expressing the marker. The payload inhibits tubulin polymerization, leading to growth arrest and apoptosis.⁵

We have phase 2 data looking at pola-BR. It was for patients who had biopsy-confirmed relapsed/refractory DLBCL after at least 1 prior line of therapy. For some of the patients, this was their second line of therapy. One of the toxicities of polatuzumab is peripheral neuropathy, so a patient couldn’t have had greater than grade 1 neuropathy going into the study. These were patients who at the investigator’s discretion were felt to not be eligible for transplant or had previously failed transplant. The 80 patients who had DLBCL were randomized to BR vs pola-BR given once every 21 days for 6 cycles.⁶

The baseline characteristics of the study were a median age of late 60s or early 70s; a little bit unbalanced IPI [International Prognostic Index] risk score, with slightly higher IPIs in the BR arm; most patients had Ann Arbor stage III or IV disease; the median lines of therapy in both arms were 2; most patients had greater than 3 prior lines of therapy; most had less than 12 months of response to their last therapy; and most were considered refractory to the last therapy with only a small percentage who got stem cell transplant. Because some drugs work better in GCB DLBCL vs non–GCB DLBCL, this group of patients tended to be non–GCB DLBCL.⁶

The primary end point was CR rate assessed by PET scan. In the pola-BR arm by investigator response, the ORR, which was the CR plus the PR, was 45% and that was obviously significantly better than the BR alone arm, [which was 17.5%].⁶

There was an improvement in the median progression-free survival [mPFS] for the pola-BR vs BR arm both by IRC [independent review committee] and by investigator. [The mPFS by IRC was 9.5 months for pola-BR vs 3.7 months for BR (HR, 0.36; 95% CI, 0.21- 0.63; P < .001)].⁶

The overall survival [OS], which is not the primary end point but something we always think about in DLBCL because we want this to be a curable disease, had a plateau in its curve as you get out to 2-plus years, which can be encouraging. [The median OS was 12.4 months for pola-BR vs 4.7 months for BR (HR, 0.42; 95% CI, 0.24- 0.75; P = .002)].⁶

What is your reaction to the efficacy data for polatuzumab vedotin plus BR? Which data stand out to you?

It’s worth keeping in mind that prior to the approval of polatuzumab in 2019, these patients had an mOS of 6 months. It’s kind of amazing how far we’ve come and that we have options for this patient population.

Do you have data for just using polatuzumab vedotin with rituximab and without the bendamustine if you have unfit patients with an ECOG score of 2 to 3?

This is a debate that I have listened to people talk about, because obviously as you’re pointing out, it was pola-BR vs BR but do you really need the B, and for that matter do you really need the R? There were some earlier phase 1 studies looking at just polatuzumab and I think just pola-R, and the response rates weren’t that much lower. There are some [patients] who, because the bendamustine can cause cytopenia, if you are going to eventually, for example, try to take a patient to a CAR T-cell therapy, you must be able to collect their cells. Because there’s some concern that bendamustine might impair stem cell collection, there are [patients] who use polatuzumab either alone or just pola-R and skip the B. A couple of times when I’ve been in the hospital, we had 1 or 2 [patients to whom] we gave single-agent polatuzumab. They had a response, improved symptom burden, and we were able to get them out of the hospital.

What toxicities should clinicians be aware of?

Anytime we’re talking about these therapies, we need to talk about their toxicity. Although BR is not the most effective drug in DLBCL, it’s well tolerated outside of the cytopenia. When you add in the polatuzumab, you do have more anemia, more thrombocytopenia, but not more febrile neutropenia. The amount of grade 3 and 4 anemia and neutropenia is not all that much worse than the BR alone. In terms of GI [gastrointestinal] disturbances, you see them on both sides, maybe slightly more low-grade diarrhea in the polatuzumab arm, but there is similar fatigue and decrease in appetite. Obviously, peripheral neuropathy, a toxicity associated with the payload, is higher in the pola-BR arm, but interestingly there was no grade 3 or 4 peripheral neuropathy. They were all low grade. Grade 3 and 4 infections were similar in both arms. Even though there is more cytopenia when you add the polatuzumab, you didn’t have more infections or febrile neutropenia.

What other therapeutic options are available?

About 3 to 4 years ago we had nothing approved in this space and were making stuff up by giving more chemotherapy, giving ibrutinib [Imbruvica] off label, or giving rituximab plus lenalidomide. We then got pola-BR followed by tafasitamab plus lenalidomide. Tafasitamab is an anti- CD19 monoclonal antibody, and we combine it with lenalidomide, an immunomodulatory drug that has a lot of explanations on how it works in vivo, but it’s all very [uncertain]. Theoretically, it turns the [bone marrow] into an antitumor environment.

What data support the use of tafasitamab?

Phase 2 data from the single-arm L-MIND study [NCT02399085] are what we have, so we’ll work with that. It is what led to the FDA approval of tafasitamab plus lenalidomide. This was a slightly different population of patients who had at least 1 but up to 3 prior regimens compared with the pola-BR data, where patients had more prior lines of therapy. Patients were those felt to not be eligible for transplant. Interestingly, primary refractory patients were explicitly excluded from this study. In the beginning, they defined this as patients who progressed within 3 months of therapy, but they ended up having a few patients who progressed within 6 months of therapy, which some people would consider primary refractory. Anyway, just worth noting that primary refractory patients were excluded from this study, as opposed to the pola-BR study where there were patients who had a less than 12-month response to prior therapy.⁷

Tafasitamab is a monoclonal antibody delivered intravenously [IV] and given more frequently in the beginning and then spread out. The lenalidomide dose was relatively high here at 25 mg, which is a bit different than what we do, for example, in follicular lymphoma. Patients who had stable disease went on tafasitamab maintenance. The patients got 1 year of the combination and then if they had stable disease or better, they got the tafasitamab as a maintenance. The primary end point was ORR, which is again different from pola-BR where the primary end point was CR.⁷

Can you discuss the relevant data regarding tafasitamab?

The primary end point was ORR. With a median follow-up of 17 months, the ORR was 60% and after 35 months it was still close to that at 57.5%. Nearly three-quarters of patients had achieved disease control, meaning stable disease or better. About 30% of patients achieved a CR.

The [mPFS and mOS] were not reached for patients who achieved a CR. Now again, these were not primary end points, so these are just exploratory and nice to look at but also intriguing. The survival was significantly better for the patients who achieved a CR vs the total population and those who achieved only a PR.⁷

For toxicities—as you can imagine, because you’re using 25 mg of lenalidomide—you’re seeing a lot of cytopenia.

Still, not a ton of febrile neutropenia, at just about 12% for grade 3 or 4. There were no grade 5 AEs [adverse events].⁷

For the nonhematologic AEs, again, you’re using lenalidomide, so expect fatigue, diarrhea, a little bit of grade 1 or 2 peripheral edema, decreased appetite, all these things that we know and love from many of our oncology drugs.

Are there any other treatment options to highlight for this patient population?

The new kid on the block is loncastuximab, which is also a CD19-targeted agent, but unlike the [oral] tafasitamab that is FDA approved with the IV lenalidomide, loncastuximab is a single-agent IV drug. That’s one thing it’s got going for it. It’s also an antibody-drug conjugate; in this case, it is a different payload, SG3199. I think this is the first drug approved with this payload, and it has its own AE profile because of this payload.⁸

The [LOTIS-2 (NCT03589469) is again] a single-arm phase 2 study, but that’s what we have and that’s what led to the FDA approval of the agent. This study population had 2 or more prior lines of therapy, which is different from the other 2 studies we talked about where they could potentially have had only 1 prior line of therapy. In this case, unlike with the tafasitamab data, if somebody had prior anti-CD19 therapy, they had to have another biopsy to show they were still CD19 positive. If somebody had CAR T-cell therapy and they wanted to get this agent, they had to still be CD19 positive. For the first 2 cycles, the patients got a slightly higher dose of loncastuximab followed by a slightly lower dose. The dosing could continue for up to 3 years.⁹ For duration of therapy, pola-BR was 6 cycles; tafasitamab plus lenalidomide was 1 year of combination, then ongoing maintenance; and for loncastuximab, it was potentially up to 3 years of treatment but with only a single drug. In this study, the primary end point was ORR, like the tafasitamab plus lenalidomide one.

The ORR was the primary end point and it turned out to be 48%. Median duration of response for the responders was about 10.3 months but was longer if you achieved a CR, so it was out to 13.4 months. They did [subgroup analyses] for some of the high-risk subgroups such as [patients] with transformed disease, or [patients] with double and triple hit and they had good responses. In this study, 15 patients got CAR T-cell therapy after, so loncastuximab was used as a bridge and the ORR to the CAR T-cell therapy was 46.7%. This was a small number, so we can’t make too many assessments about it, but you could argue that this is close to what the CAR T-cell ORR is. A few patients also got transplant after loncastuximab.⁹

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