Antibody-drug Conjugates Change the Standard of Care for Both B- and T-cell Non-Hodgkin Lymphoma

This year we saw the U.S. Food and Drug Administration (FDA) approval of antibody-drug conjugates in combination with chemotherapy for both relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and for previously untreated CD30⁺ peripheral T-cell non-Hodgkin lymphoma (T-NHL), marking practice changing therapy for two diseases with limited therapeutic options. Polatuzumab vedotin, an anti-CD79b antibody with a monomethyl auristatin E (MMAE) payload, was combined with bendamustine and rituximab (BR) and compared with BR alone in DLBCL, with an improvement in not only response rates and duration of response, but also overall survival (OS).¹  Brentuximab vedotin, an anti-CD30 antibody also conjugated to MMAE and previously approved by the FDA for the treatment of R/R Hodgkin lymphoma and R/R anaplastic large-cell lymphoma (ALCL), was combined with CHP (cyclophosphamide, doxorubicin, prednisone) and compared with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in previously untreated CD30⁺ T-NHL; the novel combination similarly demonstrated an improvement in both progression-free survival (PFS) and OS compared with the previous standard of care.²  These studies further solidify this class of therapies in our anti-cancer armamentarium and improve outcomes for lymphoma populations with unmet needs.

Chemotherapy-resistant DLBCL, as defined by insufficient response or relapse after two or more lines of chemoimmunotherapy, has limited treatment options. Before the approval of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy for these lymphomas, the best options yielded responses in fewer than one-quarter of patients, and median OS was approximately six months. CAR-T therapy has improved options for some, but not all, of these patients. CAR-T therapy takes time to manufacture the cells and has a unique toxicity profile, which can limit application to patients without rapidly proliferative disease or significant comorbidities. Furthermore, not everyone responds to CAR-T therapy, and up to 20 to 30 percent of patients who do respond subsequently relapse. So, there is still work to be done. Given the activity of polatuzumab monotherapy and polatuzumab combined with anti-CD20 antibody therapy in R/R DLBCL, polatuzumab combined with BR (pola-BR) was compared with BR alone in a pivotal randomized phase II study following a phase Ib safety run-in of six patients treated with pola-BR. Eighty patients were randomized in a 1:1 manner, and 39 patients were treated in each arm. The groups were evenly matched by age, performance status, cell of origin, stage, and International Prognostic Index (IPI). Overall and complete response rates were superior following pola-BR compared with BR alone (70% vs. 33% and 58% vs. 20%, respectively). Responses were more durable following pola-BR (12.6 months vs. 7.7 months), and both median PFS and OS were improved as well (PFS, 9.5 months vs. 3.7 months; OS, 12.4 months vs. 4.7 months, respectively). These benefits of pola-BR over BR were seen across all risk groups where there were adequate numbers to study. Grade 3 or higher cytopenias were more common following pola-BR, but rates of febrile neutropenia were similar. There was a considerable increase in peripheral neuropathy with the addition of polatuzumab (44% vs. 8%), but this was all grade 1 or 2. Based on these results, the FDA granted approval of pola-BR for R/R DLBCL in the third line and beyond in June of  2019. A double-blind randomized trial of polatuzumab in combination with rituximab-CHP compared with rituximab-CHOP for previously untreated DLBCL has completed approval, and we await the results to learn if this drug may be the first since the addition of rituximab to CHOP to improve outcomes following frontline therapy for the most common lymphoma diagnosed in the United States and Europe.

T-NHL represents a heterogeneous collection of diseases, the majority of which have very low cure rates and relatively short survivals. Much of our current strategy in treating these lymphomas is based on what we have learned from B-cell NHLs, but deeper analysis of the molecular and genetic underpinnings of these diseases is sure to improve outcomes going forward. Brentuximab vedotin is approved as a single agent for the treatment of R/R ALCL as well as previously untreated CD30⁺ peripheral T cell lymphoma. Following a successful phase I study combining brentuximab with CHP chemotherapy in previously untreated CD30⁺ T-NHL, the randomized, double-blind phase III ECHELON-2 study was conducted.²  Patients with tumors with at least 10 percent positivity for CD30 were included and randomized to brentuximab vedotin plus CHP (A-CHP) or CHOP in a 1:1 manner. In total, 452 patients were randomized, and 226 patients were treated in each arm. The groups were well matched by performance status, T-NHL subtype, disease stage, and IPI. Response rates were improved following A-CHP (overall response, 83% vs. 72%; complete response, 68% vs. 56%), but more importantly, PFS and risk of death were improved as well (median PFS, 20.8 months vs. 48.2 months; risk of death hazard ratio, 0.66; 95% CI, 0.46-0.95). The biggest survival benefit was seen among the 98 patients with ALK⁺ ALCL, followed by the 218 patients with ALK^- ALCL; other T cell histologies did not seem to show a similar benefit. Additionally, patients with IPI 4 to 5 did not seem to benefit significantly nor did patients with a performance status greater than 1. Rates of grade 3+ adverse events were similar in each arm overall, but patients receiving A-CHP had higher rates of diarrhea and vomiting. Rates and grades of peripheral neuropathy were similar between groups. Although brentuximab is now FDA approved in combination with CHP for the front-line treatment of CD30⁺ T-NHL, the group that derives the maximum benefit from A-CHP overlaps with the group that benefits most from CHOP plus etoposide, and so it is unclear how practice changing or permeating this regimen will become.

Although antibody-drug conjugates have led to substantive improvements for multiple cancer types ranging from solid tumors to hematologic malignancies, it is not clear that we understand exactly how they work. They are likely to work by additional mechanisms than those for which they were designed, but whether these mechanisms are consistent across this class of drugs or specific to the tumor target and/or payload remains to be discovered. Understanding how these drugs work will be pivotal to understanding how best to combine and sequence them to further improve outcomes in cancers and patients with limited options.