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Targeted therapy combinations may be able to be used alone before chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), researchers reported.

As described in the (JCO), the enrolled 60 patients with newly diagnosed non–germinal center B-cell-like DLBCL in a single-arm phase II trial of rituximab, lenalidomide, and ibrutinib with the sequential addition of chemotherapy. After two cycles of targeted therapy, standard chemotherapy was added for six additional cycles.

The results indicate the potential for a "new screening strategy paradigm to more rapidly identify efficacy of rational targeted therapies in biologically defined subsets of this disease," JCO Editor-in-Chief Jonathan W. Friedberg, MD, wrote in a published note about the relevance of the findings.

In the following interview, Jason Westin, MD, leader of the DLBCL research team at the University of Texas MD Anderson Cancer Center in Houston, elaborates on the team's study, which was first presented in abstract form at the 2019 ASCO annual meeting.

What does the study add to the literature?

Westin: Smart Start is the first trial to evaluate novel combinations with the potential to affect previously untreated aggressive lymphomas. We know targeted therapies work in previously treated patients, but they have never been evaluated in untreated patients. We took a bold approach to use not 1970s chemotherapy, but modern targeted therapies instead. There is a potential for cure with chemotherapy, so we did not want to be too aggressive. We wanted to get an uncontaminated view of what targeted therapies can do in the absence of chemotherapy.

Effectively, this is a proof-of-concept study to show that we can treat patients upfront and still obtain a curative potential. The two-cycle targeted therapy lead-in resulted in an 86% response rate and was safe. With a median follow-up of 31 months, the progression-free survival rate was 91.3% and overall survival was 96.6% at 2 years. We can now launch induction trials that evaluate de-escalating or replacing chemotherapy with various combinations.

Anecdotally, one patient chose not to start chemotherapy after two cycles of targeted therapy and achieved a complete response (CR). More than 4 years out from targeted therapy, the patient has still not relapsed.

Were there any surprises in the data?

Westin: We were pleasantly surprised with the high response to the lead-in phase. This data plus ct [circulating tumor]DNA data show that a number of patients had deep responses early on prior to chemotherapy. We know from other studies that this type of response usually has the potential for a cure. These are not minor or transient responses.

How could this be used as a new screening strategy paradigm in biologically defined subsets of this disease?

Westin: In a relapse population -- more specifically, a molecularly defined subset -- if we have a hint that this may be promising in specific subtype, we can do a lead-in study with targeted therapy. We could do this in a genetically defined subtype with more precision and biological rationale. If the data hold up in the frontline setting, this may lead to randomized studies in genetically defined subsets.

How do you account for the depth of response with rituximab, lenalidomide, and ibrutinib?

Westin: This is a potent therapy. We know from cell line models that this combination has strong synergy. The depth of response and ctDNA depth of response speaks to the synergy and potency. We should not keep novel targeted therapy in reserve if cytotoxic chemotherapy does not work, if we use it in the right combination with the right patient.

What is the next step in this research?

Westin: The Smart Stop trial will evaluate whether we can de-escalate or stop chemotherapy if patients have a good response to lead-in targeted therapy. This trial expands the lead-in to four cycles and uses a different BTK [Bruton's tyrosine kinase] inhibitor, acalabrutinib, and the CD19 antibody tafasitamab, in response-adaptive therapy.

If the patient achieves a CR, instead of six cycles of chemotherapy, we will explore de-escalating to two cycles of chemotherapy alone while continuing the targeted therapy combination. In another cohort, if patients reach targeted thresholds and achieve CR with lead-in targeted therapy, they will receive no chemotherapy.

We hope the Smart Stop trial will move beyond the "R-CHOP plus X" approach for these patients and further validate this targeted therapy concept.

What is your main message for practicing oncologists?

Westin: Clinical trials can move the needle in ways that are surprising and not always incremental improvements, and may change the way we practice. I advise referring appropriate lymphoma patients to seek out clinical trials that may move the field forward.

I would not recommend using this targeted therapy combination in clinical practice in place of R-CHOP since this is a proof-of-concept trial. However, the future is bright for chemotherapy-free approaches.

Read the study here and expert commentary about it here.