Sequencing Challenges Arise Amid New Approvals in DLBCL Paradigm

Andrew M. Evens, DO, MSc

The approvals of 3 new regimens have reformed the treatment paradigm of relapsed/refractory diffuse-large B-cell lymphoma (DLBCL), said Andrew M. Evens, DO, MSc, who added that among these new options, sequencing and treatment selection challenges have become more apparent.

“In terms of sequencing, there is not 1 right standard of care,” said Evens. “It becomes individualized in terms of assessing the different agents’ efficacy and safety signals. How does that apply to the individual patient? Do patients have any preexisting conditions that might overlap in a negative way with 1 of the recently approved agents? Then, we try to sequence through.”

On June 22, 2020 , the FDA approved the first-in-class XPO1 inhibitor selinexor (Xpovio) for the treatment of patients with relapsed/refractory DLBCL after at least 2 prior lines of systemic therapy.¹ The regulatory decision was based on findings from the phase 2b SADAL trial, in which selinexor induced a 29% overall response rate (ORR), including a 13% complete response (CR) rate.²

Then, on July 31, 2020, the combination of tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid) was granted accelerated approval for patients with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplant (ASCT).³ Data from the phase 2 L-MIND trial served as the basis for the approval, wherein the combination led to an ORR of 55%, with a CR rate of 37%.⁴

Additionally, back in June 2019, polatuzumab vedotin-piiq (Polivy) was granted an accelerated approval by the FDA for use in combination with bendamustine and rituximab (Rituxan; BR) for patients with relapsed/refractory DLBCL who have received at least 2 prior therapies. The antibody-drug conjugate (ADC) demonstrated a 40% CR rate versus 18% with BR alone (P = .026).⁵

Among these additions to the armamentarium, Evens explained that CAR T-cell therapy remains an exciting option in relapsed/refractory DLBCL, as 2 products, axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah), are currently approved.

In an interview with OncLive®, Evens, associate director for clinical services and director of the Lymphoma Program at Rutgers Cancer Institute, as well as medical director for the Oncology Service Line and Robert Wood Johnson Barnabas Health, discussed the clinical impact of these approvals, sequencing and treatment selection challenges that have emerged, and future directions for research in the relapsed/refractory setting.

OncLive®: What is the goal of frontline therapy, and how does initial response impact subsequent treatment decisions?

Evens: DLBCL is one of many different subtypes of non-Hodgkin lymphoma (NHL). It is the most common subtype and accounts for approximately one-third of all cases [of NHL] diagnosed in the United States. DLBCL is the subtype we think about as being very treatable and curable. That, frankly, is our goal: to get all patients into a CR and cure.

With initial diagnosis, we hope to achieve [a CR] with frontline therapy, whether that is with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], or other chemotherapy backbones.

There are a proportion of patients who have primary refractory disease where initial therapy does not work, and patients never go into an initial remission. There is also a small subset of patients who [go into remission] and [their disease] comes back. [In those cases], treatment becomes somewhat individualized in terms of thinking of the different options we have for patients.

What factors do you consider when selecting treatment for patients?

For patients with relapsed/refractory DLBCL, the initial consideration is whether the patient is a candidate for more aggressive therapy, such as ASCT. Also, of course, we have CD19[-directed] CAR T-cell therapy on label. The commercial product is approved for [use in patients with] prior failure of 2 previous treatments. Those are probably the tip of the spear for relapsed/refractory DLBCL.

However, not all patients are candidates for ASCT, or even CAR T-cell therapy. Also, unfortunately, there are some patients where those therapies do not work and they still relapse.

What challenges remain in terms of sequencing currently available options?

In terms of sequencing for patients who are not eligible for CAR T-cell therapy or if they relapse afterward, there are now a host of new treatment options available for patients. These include polatuzumab vedotin, which is an ADC, tafasitamab, which is a CD19-directed antibody, in combination with lenalidomide, and selinexor, which is a first-in-market inhibitor of the nuclear transport protein XPO1.

Starting with selinexor, could you speak to the rationale of targeting the XPO1 protein?

Selinexor is a first-in-class agent. It is a small molecule compound that goes by the acronym of SINE, or selective inhibitor of nuclear export. There are many reasons why cancer cells grow. One reason in particular for lymphoma, as well as other blood cancers, is that there are proteins inside the nucleus of lymphoma cells that export tumor suppressor genes.

We all have tumor suppressor genes in the body, such as p53, p21, and p73, that hopefully are able to suppress tumors. One way in which lymphoma cells survive is that through the protein XPO1, they are able to export those proteins out of the cell, [preventing] the cells from doing the protective work they normally would. Inhibiting [XPO1] keeps these tumor suppressor genes, and hopefully all of the favorable antitumor effects, within the cell.

The agent was approved based on findings from the phase 2b SADAL trial. What did you find interesting about the activity of selinexor in that study?

The SADAL trial was a pivotal study that ultimately led to the FDA approval of selinexor. It was a single-arm, multinational, multicenter, open-label, phase 2 clinical trial done in nearly 60 sites, across 19 countries. Patients had to be 18 years of age or older with relapsed DLBCL. Patients had to have received 2 to 5 previous lines of therapy and progressed after or were not candidates for stem cell transplant.

The study initially [evaluated] 2 dosing levels [of selinexor:] 60 mg and 100 mg twice weekly. Ultimately, the 100 mg dose was discontinued, and patients continued on the 60-mg dose given orally on days 1 and 3.

There were 267 patients enrolled on the study; 175 patients received the 60 mg dose. In terms of efficacy, for all patients on the 60 mg dose, the ORR was [29]%, with 17% of those [responses] being a partial response.

Interestingly, there are a couple of small subsets that we could maybe glean a slight benefit [with selinexor] versus not. First, patients with germinal center cell of origin seemed to have a slightly higher response rate of approximately [34]% versus [21]% for patients with non–germinal center.

What safety signals were observed with selinexor, and what options are available to treat toxicities that may emerge for patients receiving the therapy?

As with any agent, the balance of efficacy is always the safety signals and adverse effects (AEs). In the SADAL study, the most common grade 3/4 AEs were hematologic, including thrombocytopenia, neutropenia, and anemia. Now, most of those were manageable with dose reductions or other supportive care measures, such as granulocyte stimulating factor for neutropenia.

In terms of non-hematologic toxicities, the signals to look out for and that we saw are fatigue, nausea, asthenia, and anorexia. Thankfully, they were uncommon in terms of severe AEs. They were also manageable with dose reductions and other supportive care measures.

How would you characterize the activity of tafasitamab in the relapsed/refractory setting?

Tafasitamab is another first-in-class approval. It is a CD19[-directed] antibody, approved in combination with the oral agent lenalidomide, which is already FDA approved in mantle cell lymphoma and follicular lymphoma. Tafasitamab was approved as a combination therapy.

The ORR [with the combination] was 55%, and it was seemingly quite active and tolerable. The safety signals, if anything, relate back to the known events that we see with lenalidomide. So, [tafasitamab] is another active agent that is new to the space. [Tafasitamab and selinexor] were approved within a 2-month period of one another.

We are going to learn how to use [these therapies] in terms of which patients to use them in and how to sequence them.

How have you seen the June 2019 approval of polatuzumab vedotin impact the relapsed/refractory space?

Polatuzumab vedotin was FDA approved [in June 2019] for relapsed/refractory DLBCL. Although it has activity as a single agent, [polatuzumab vedotin] was approved in combination with bendamustine, on days 1 and 2 as we would typically give it, and rituximab.

The ORR with the combination was 63%, so the [combination] is pretty active from that standpoint. In terms of AEs, [we saw] what we would expect with BR, mainly hematologic AEs and some infection issues.

I have [seen] some very durable responses in patients who we were initially using [polatuzumab vedotin] as a bridge to CAR T-cell therapy. Patients ended up going into a very deep remission and have maintained that [remission] for quite a long period of time.

Shifting to CAR T-cell therapy, how have the two approved products been utilized in the clinic, and what are the next steps with this modality?

In terms of CD19[-directed] CAR T-cell therapy, there are currently 2 products approved and on the market: tisagenlecleucel and axi-cel. Both products are quite active in the space of relapsed/refractory DLBCL. For most of us treating these patients, [CAR T-cell therapy] is becoming a standard of care for patients, on label, who have received 2 prior therapies.

The first pivot is to look at whether a patient is eligible. Are we able to get [CAR T-cell therapy] approved for them under these conditions? For most patients, the answer is yes, including older patients. Some interesting real-world analyses have been done, comparing older patients over the age of 60 or 65 years with younger patients. Efficacy and safety signals are not markedly different.

With that said, not all patients are eligible. There may be some insurance or social barriers [that limit CAR T-cell therapy from being obtained].

What challenges remain in the treatment of patients with relapsed/refractory DLBCL? Where should future research efforts be focused?

In terms of the future of DLBCL, we all of a sudden have a multitude of novel targeted agents for patients. These agents are mostly intravenous (IV), but are also oral.

[Future directions] are severalfold. Number 1 is understanding the proper sequencing [method] and which patients should receive which treatments. Of course, we are always looking for biomarkers as there is a lack of true, actionable, predictive biomarkers in this space to try to enrich the prediction of who will respond to what. Hopefully that research will continue.

Also, to dovetail on that, translational research [is important]. Of course, we always like to think of novel combination therapies, and there are a number of studies ongoing in terms of CAR T-cell therapy. Are there agents that we can add to CAR T to make it more effective? The same goes for the recent approvals of polatuzumab vedotin, tafasitamab, and selinexor. Yes, they are active on their own, but are there smart strategies to combine or sequence these agents? Is there a maintenance therapy for these different agents?

Lastly, of course, these agents are all approved for patients with relapsed/refractory DLBCL. How can we move [these therapies] closer to the frontline setting? Ongoing studies with CAR T-cell therapy are going head-to-head with transplant at first relapse. Those data are eagerly awaited. Then, how can we move these agents to the frontline setting to try to cure more patients up front without initial treatment?

What specific impact could oral agents like selinexor have compared with traditional IV therapies given the ongoing coronavirus disease 2019 (COVID-19) pandemic?

That is a good point. In terms of managing DLBCL during the COVID-19 pandemic, what impact do these new agents have? To date, most therapy had been IV, and there is no way around having to come into the clinic every 2, 3, or 4 weeks. Now, with some oral agents like lenalidomide and selinexor, if there was a concern from the patient or provider to socially distance and avoid having to come into the clinic, [oral agents] could be leveraged as an option. Of course, how do we manage all of these if a patient has COVID-19? That is another difficult issue that has to be very individualized.

References:

1. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. June 22, 2020. Accessed October 2, 2020. bit.ly/37VnEXd.
2. Maerevoet M, Vermaat J, Canales MA, et al. Single agent oral selinexor demonstrates deep and durable responses in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in both GCB and non-GCB subtypes: the phase 2b SADAL study. Blood. 2018;132(suppl 1677):626. doi:10.1182/blood-2018-99-116868
3. FDA approves Monjuvi (tafasitamab-cxix) in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. July 31, 2020. Accessed October 2, 2020. https://bwnews.pr/3jZhE5g.
4. Maddocks KJ, Duell J, Barca EG, et al. Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): response rates in patient subgroups with poor prognosis. J Clin Oncol. 2019;37(suppl 15):7521. doi:10.1200/JCO.2019.37.15_suppl.7521
5. Sehn LH, Herrera AF, Matasar MJ, et al. Polatuzumab vedotin (pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Blood; 2018;132(suppl 1):1683. doi.org/10.1182/blood-2018-99-118551