Always be prepared for success

In this issue of Blood, Ward et al¹ report the promising efficacy and manageable toxicity profile from an investigator-initiated phase 1 trial combining brentuximab vedotin and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had received or were ineligible for autologous stem cell transplantation (ASCT).

For patients with relapsed or refractory DLBCL, second-line treatment algorithms have historically categorized patients based on their fitness for potential high-dose chemotherapy and ASCT, or, to state this more succinctly, either curative or palliative intent. Patients who were ineligible for or relapsed after ASCT potentially benefit from additional therapy; however, results were often transient and toxic. Thankfully, this paradigm is shifting.

Brentuximab vedotin, an antibody drug conjugate targeting CD30, and lenalidomide, an immunomodulatory drug targeting cereblon, are both Food and Drug Administration approved for various hematologic malignancies. As single-agent therapy for patients with relapsed DLBCL, both drugs have resulted in modest efficacy, with brentuximab vedotin achieving an overall response rate (ORR) of 44% and complete response rate (CRR) of 17%,² and lenalidomide achieving an ORR of 28% and CRR of 15%.³ Based on the nonoverlapping drug targets, manageable toxicities, and single-agent efficacy, the combination of brentuximab vedotin and lenalidomide was evaluated by Ward and colleagues.

In total, 37 patients with DLBCL were enrolled with 3 median prior lines of therapy, of which 46% were refractory to initial therapy and 54% were refractory to most recent therapy. Patients were treated in 3 dose levels, identifying the maximum tolerated dose of the combination to be 1.2 mg/kg of brentuximab vedotin IV every 21 days and 20 mg of lenalidomide orally. Contrary to the commonly used lenalidomide dosing strategy of a dosing period followed by a rest period, the investigators on this trial used a continuous dosing strategy, which may have contributed to the 84% of patients requiring growth factor support and with 55% requiring lenalidomide dose reductions. Toxicities were generally similar to previous data with either brentuximab vedotin and lenalidomide, with only 10% of patients discontinuing therapy because of an adverse event.

The combination of brentuximab vedotin and lenalidomide resulted in an ORR of 57% (95% confidence interval [CI]: 39.6% to 72.5%) and CRR of 35% (95% CI: 20.7% to 52.6%), which compares favorably to the historical single-agent efficacy. Responses generally occurred quickly with a median time to response of 1.4 months and were durable with a median duration of response of 13.1 months for all patients who responded. The median progression-free survival was 10.2 months, and median overall survival was 14.3 months. To confirm these results, a randomized phase 3 study comparing the CD20 targeting monoclonal antibody rituximab and lenalidomide with and without brentuximab vedotin is currently enrolling (NCT04404283).⁴ 

With the caveats of this being a relatively small phase 1 trial, the efficacy results are comparable to several other clinical trials recently conducted in similar patients with relapsed DLBCL (see table). Lenalidomide-based combinations, with dosing of 25 mg for 21 days on followed by 7 days off, have impressive efficacy when combined with the CD19 targeting monoclonal antibody tafasitamab,⁵ and with the BTK inhibitor ibrutinib and rituximab (although improved efficacy was observed in the nongerminal center subtype).⁶ Antibody drug conjugates including the CD79B targeting polatuzumab vedotin in combination with bendamustine and rituximab⁷ and the CD19 targeting loncastuximab tesirine have also had promising activity.⁸ 

With all of these intriguing combinations, including lenalidomide and/or antibody drug conjugates, what is the treating physician to do? How to choose a particular therapy for a particular patient? Ideally, a large, randomized study would be conducted to directly compare various treatment options in the same population, but with multiple novel treatments emerging for patients with relapsed DLBCL, or potentially moving to first-line therapy, such a trial would be prohibitive and potentially out of date prior to completion.

The legendary clinical investigator, Emil J. Freireich, who recently died at age 93, helped develop essential concepts, including combination chemotherapy, platelet transfusions, and plasmapheresis, but also was known to turn a phrase (or ten).^9,10 Freireich’s law number 2 is “Always be prepared for success. Failure creates few problems.” This sage advice speaks volumes regarding the current situation for treatment of patients with relapsed DLBCL: we have several recent successful trials, with a high probability of many more to come. We must be prepared to catch this growing wind in our sails whichever way it blows, to help treating physicians to select the optimal therapy for each patient.

Ward and colleagues have taken an important first step along these lines by conducting a detailed analysis of both tumor tissue and dynamic changes in the peripheral blood immune cell subsets. Actionable baseline clinical factors that may be predictive for response with brentuximab vedotin and lenalidomide were not identified in this trial, perhaps because of the relatively small sample size or assays used. However, the intention of the investigators was laudable and should represent an expected norm for future such trials.

As a field, we should work to harmonize our approaches for patients with DLBCL, starting with plans for the analysis of baseline and dynamic factors, including tumor tissue, immune cell subsets, circulating tumor DNA, and microbiome samples that could be compared across trials. These data would not replace the need for future randomized trials but could allow for greater cross-trial comparisons and eventually improved precision in treatment selection.

In conclusion, the combination of brentuximab vedotin and lenalidomide is impressive in this phase 1 trial, and a confirmatory randomized phase 3 trial is now ongoing. The results of this and other similar trials highlight a large and increasingly urgent need: let’s prepare for success.