Brian T. Hill, MD, PhD, sheds light on XPO1 as a target in diffuse large B-cell lymphoma, the emergence of selinexor in the treatment landscape, and exciting agents in the pipeline.
Brian T. Hill, MD, PhD
Selinexor (Xpovio) may serve as a favorable therapeutic option for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy or CAR T-cell therapy, according to Brian T. Hill, MD, PhD, who added that the agent is now being explored in combination as well as in earlier lines of treatment.
In June 2020, the FDA approved selinexor for the treatment of patients with relapsed/refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, following at least 2 lines of systemic therapy.
The regulatory decision was based on data from the phase 2b SADAL trial (NCT02227251), in which the agent elicited a 29% overall response rate (ORR; 95% CI, 22-38) in a total of 129 patients with DLBCL after 2 to 5 systemic regimens; this included a complete response rate of 13%. Notably, 38% of patients who achieved a partial response or CR had response durations of at least 6 months; 15% had response durations that persisted for at least 12 months. These responses were encouraging, noted Hill, especially for such a heavily pretreated population.
“Selinexor is an oral agent that can potentially be taken for prolonged periods of time with adequate supportive care and monitoring for adverse effects (AEs); that's new to the field and new to this disease,” said Hill. “All of the effective therapies we've had previously have been exclusively intravenous or rely on intravenous therapy. Particularly for older patients who are not candidates for intensive therapy such as autologous stem cell transplant or CAR T-cell therapy, [selinexor] may represent a viable treatment strategy.”
In an interview with OncLive, Hill, director of the Lymphoid Malignancies Program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, shed light on XPO1 as a target in DLBCL, the emergence of selinexor in the treatment landscape, and exciting agents in the pipeline.
OncLive: Could you start off by describing the challenges faced in managing heavily pretreated patients with DLBCL?
Hill: After [progression on] frontline therapy, patients with DLBCL are at high risk for [additional] treatment failure and poor survival. We had autologous stem cell transplant for appropriate candidates and now we have CAR T-cell therapy, as well. However, beyond those 2 relatively intense modalities of treatment, historically, we've had very few tools to treat patients who are in a deep relapsed or refractory state.
How has treatment evolved in recent years?
The major change in the treatment of [patients with] relapsed DLBCL was introduced a couple of years ago with the FDA approval of CAR T-cell therapy. Before this modality, we really did not have any good [methods for] achieving durable remission for patients who had relapsed after autologous stem cell transplant, or for those who could never achieve sufficient disease control or have enough chemosensitivity to make it to transplant.
We're now in this post–CAR T era, but the reality is that the rate of durable remission in the best of circumstances, even with CAR T-cell therapy, [ranges from approximately] 40% to 50% [of patients who go on to achieve] durable remission. That means that even with CAR T cells, over half of patients are still going to progress on their treatment. There's still an unmet need for effective therapies that can keep patients going beyond that.
Could you speak to XPO1 as a target in this disease?
XPO1 is a nuclear export protein, which shuttles various transcription factors and other regulatory proteins in and out of the cell nucleus. By inhibiting XPO1 with the selective nuclear export inhibitor selinexor, their cell undergoes apoptosis through a variety of mechanisms. This is a novel target we haven't had before in oncology.
Selinexor was recently approved by the FDA. Could you speak to the findings from the phase 2b SADAL trial that led to its approval?
Selinexor was previously FDA approved for use in heavily pretreated multiple myeloma and [the agent] recently gained approval for relapsed/refractory DLBCL based on findings from the SADAL trial. This [trial was done in] a heavily pretreated patient population, many of whom received multiple lines of previous therapy, including autologous stem cell transplant. In these patients, selinexor was given orally twice a week at a couple of different doses, either 100 mg or 60 mg. The toxicity seen at the high dose was significant in terms of cytopenia and gastrointestinal [AEs]. However, those AEs [were reduced when the drug was given] at the dose of 60 mg twice a week. The ORR was [around] 30%, which for a heavily pretreated patient population is very reasonable.
Is selinexor under examination in any other clinical trials?
As is frequently the case with new drug approvals, selinexor was shown to have activity in an extensively pretreated patient population. The natural progression of [research and] development is going to be to move the agent into earlier lines of treatment.
Right now, the drug is being [evaluated in] various second- and third-line platinum-based chemotherapy combinations that still have activity in DLBCL; the potential that this may be additive [in terms of] efficacy without additional toxicity is being examined, as well.
Beyond this agent, are any efforts examining XPO1 inhibition?
This target is now being explored in a wide variety of malignancies. In addition to multiple myeloma and DLBCL, [XPO1 inhibitors] now being combined with other pathway inhibitors, both for hematologic malignancies and for solid tumors.
Are any other notable agents coming down the pike that you wanted to highlight?
Just within the past year, we've had 3 drugs approved in the relapsed/refractory DLBCL setting. We have the antibody-drug conjugate polatuzumab vedotin (Polivy); the monoclonal antibody [targeted] against CD19, tafasitamab-cxix (Monjuvi), which is used in combination with lenalidomide (Revlimid); and selinexor.
[These agents are] welcome additions; [it’s important] to have more than 1 option [for] this patient population because it's unlikely that any of these [agents] are going to be curative. However, if we’re able to extend the patient's wellbeing and livelihood for a period of time following progression on curative intent therapy, [we’re] still clinically benefitting them.
FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed August 30, 2020. bit.ly/37VnEXd.