Novel Approaches Gain Ground in Diffuse Large B-Cell Lymphoma

Craig Moskowitz, MD

Despite advances made in the treatment of patients with diffuse large B-cell lymphoma (DLBCL), investigators are on a quest to move more novel agents through the pipeline, said Craig Moskowitz, MD, in a presentation during the 24th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma.

Following first-line chemotherapy comprised of an anthracycline and rituximab (Rituxan), patients with DLBCL will typically achieve an overall response rate (ORR) of 60% and a long-term event-free survival of 50%. Despite this initial promise, 30% to 40% of patients will eventually relapse, and 10% are primary refractory.¹

Although these patients have the option to receive salvage chemotherapy, including autologous stem cell transplant (ASCT) and monoclonal antibodies, the prognosis of these patients remains poor. Furthermore, only half of patients with relapsed/refractory disease are able to proceed to ASCT.

Although these patients are eligible for clinical trials, they do not tend to perform well. The emergence of CD19-targeted CAR T-cell therapies into the treatment paradigm, however, has led to high response rates and generated excitement within the space.

CAR T-Cell Therapy Offers Hope in Relapsed/Refractory Disease

CAR T-cell therapy is a "designer-treatment," and their use will largely be restricted to transplant centers, said Moskowitz, physician in chief, Oncology Service Line, Sylvester Comprehensive Cancer Center, and professor of medicine, University of Miami Health System Miller School of Medicine. "Each center is convinced that their CAR T-cell therapy is the "'best.'"

Currently, 2 CAR T-cell products are approved for use as third-line treatment in patients with relapsed/refractory DLBCL: axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah).

Axi-cel received approval from the FDA in October 2017 for use in adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after ≥2 prior lines of therapy. The product has been found to induce a median overall survival (OS) of 25.8 months for patients with refractory large B-cell lymphoma, according to data from a 3-year analysis of the pivotal phase II ZUMA-1 trial.²

At a median follow-up of 39.1 months, axi-cel boasted a 3-year OS rate of 47%, with approximately 60% of patients having relapsed or progressed. Prior findings from a 2-year analysis of the trial showed that treatment with the agent led to an ORR of 83% and a complete remission rate of 58%. At 2 years, the OS rate was 51% with axi-cel and the progression-free survival (PFS) rate was 39%.

Tisagenlecleucel received approval from the FDA the following year, in May 2018, for use in adult patients with relapsed/refractory large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The regulatory decision was based on data from the pivotal phase II JULIET trial, which showed that treatment with the product led to an ORR of 50% (95% CI, 38%-62%) in those with relapsed/refractory DLBCL.³

Updated data from the trial, which were published in the New England Journal of Medicine, showed a best ORR of 52%, with 40% of patients achieving complete responses (CRs) and 12% achieving partial responses (PRs).⁴ The estimated rate of PFS at 12 months with the product was 83% among those who had experienced a CR or PR at 3 months. Moreover, the estimated probability of survival at 12 months was 40%.

The ongoing phase III ZUMA-7 trial (NCT03391466) is evaluating whether treatment with axi-cel will improve the clinical outcomes for patients with relapsed/refractory DLBCL compared with standard-of-care second-line therapy, which is comprised of platinum-containing salvage chemotherapy followed by high-dose therapy and ASCT in responders.⁵

Despite the promise seen with CAR T-cell products, more work is needed to improve outcomes with this approach, according to Moskowitz. For one, smarter, more controllable CAR T cells must be developed. Additionally, pairing these products with additional agents, such as checkpoint inhibitors or BTK inhibitors, might boost responses in patients. More research should also be dedicated to the development of universal CAR T cells-potentially available off-the-shelf products, which would allow treatment to be more convenient for patients.

Lastly, Moskowitz mentioned antibody-coupled T-cell receptor (ACTR) therapy as one that might serve as another promising approach. ACTR is an autologous engineered T cell therapy designed to combine with tumor-targeting antibodies to employ strong antitumor immune responses to kill tumor cells.

Despite these advances, Moskowitz predicts that "the end is not year" when it comes to the role of ASCT in the treatment of these patients. "As far as I know, patients in CR have a 60% cure rate with ASCT," said Moskowitz. "It is unclear whether patients benefit from CAR T cells in CR after salvage therapy."

As such, he advised that patients receive 3 cycles of salvage therapy on clinical trials. If they achieve a CR, they should go to ASCT and consider a post-ASCT research study. If they achieve a PR after salvage therapy, they should receive CAR T cells with bridging chemotherapy.

Outcomes for patients with relapsed/refractory DLBCL who are ineligible for transplant remain poor. To this end, a multicenter, open-label study, referred to as GO29365, is evaluating the use of intravenous polatuzumab vedotin (Polivy) in combination with standard doses of bendamustine and either rituximab (BR) or obinutuzumab (Gazyva) in this patient population.

Results from the trial showed that the median duration of response (DOR) was significantly longer with polatuzumab vedotin plus BR versus BR alone, at 10.3 months versus 4.1 months (HR, 0.44; 95% CI, 0.20-0.95; P =.0321).⁶ The same held true for PFS; treatment with the polatuzumab vedotin combination led to a PFS of 7.6 months versus 2.0 months with BR (HR, 0.34; 95% CI, 0.20-0.57; P <.0001). By independent review, the median PFS was 11.1 months with polatuzumab vedotin and 3.7 months without (HR, 0.36; 95% CI, 0.21-0.63; P = .0002).

Looking Ahead: Emerging Antibody Therapies Show Early Promise

Several novel antibody therapies are under investigation in DLBCL, according to Moskowitz.

One such therapy is the Hu5F9-G4 antibody (5F9), which is a macrophage immune checkpoint inhibitor that is designed to block the CD47 that produces tumor-cell phagocytosis. The antibody synergizes with rituximab to kill B-cell non-Hodgkin lymphoma cells.

In a phase Ib study, the combination of 5F9 and rituximab was evaluated in 22 patients with relapsed/refractory non-Hodgkin lymphoma; 15 patients had DLBCL and 7 patients had follicular lymphoma. Patients received a median of 4 prior lines of therapies and 95% were rituximab-refractory.

Results showed that half of the patients experienced an objective response with the combination, with 36% having a CR. Among patients with DLBCL, the ORR was 40%; in those with FL the ORR was 71%.⁷ At median follow-up of 6.2 months among those with DLBCL and 8.1 months among those with FL, 91% of the responses were ongoing.

Another antibody generating excitement in this space is tafasitamib (MOR208), an Fc-enhanced, humanized, anti-CD19 monoclonal antibody that has shown single agent activity in patients with relapsed/refractory DLBCL. In the single-arm phase II L-MIND trial, tafasitamib is being explored in combination with lenalidomide (Revlimid) in patients with relapsed/refractory DLBCL.

Results from the primary analysis of the trial showed that treatment with the combination led to an ORR of 60%, with a CR rate of 43% in this patient population.⁸ Median PFS with the combination was 12.1 months with a median follow-up of 17.3 months, suggesting that many of the patients are experiencing durable treatment effects. The median DOR reported with the treatment was 21.7 months.

Lastly, mosunetuzumab is a CD20/CD3 bispecific antibody that is designed to direct T cells to engage and kill malignant B cells. In a phase I/IIb trial, the antibody was shown to induce promising response rates in patients with DLBCL and follicular lymphoma.⁹ In those with DLBCL or transformed follicular lymphoma, the ORR was 34.0% with the agent, while the CR rate was 19.1%; the ORR and CR rates were 69.2% and 38.5%, respectively, in those with relapsed/refractory follicular lymphoma.

"Why am I still passionate about the Hodgkin lymphoma and DLBCL research programs?" Moskowitz asked during his presentation. "[They're our chance to] mentor the future leaders in lymphoma."

References

1. Hopfinger G, Jager U, Worel N. CAR-T cell therapy in diffuse large B cell lymphoma: hype and hope. HemaSphere. 2019;3(2):e185. doi: 10.1097/HS9.0000000000000185.
2. Neelapu SS, Rossi JM, Jacobsen CA, et al. CD19-loss with preservation of other B cell lineage features in patients with large B cell lymphoma who relapsed post-axi-cel. Blood. 2019;134(suppl 1):203. doi: 10.1182/blood-2019-126218.
3. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of JULIET: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory large B-cell lymphoma. Blood. 2017;130(suppl 1):577. doi: 10.1182/blood.V130.suppl_1.577.577.
4. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi: 10.1056/NEJMoa1804980./
5. Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7). bit.ly/3957f1P. Updated December 9, 2019. Accessed February 27, 2020.
6. 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: 10.1182/blood-2018-99-118551.
7. Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma. N Engl J Med. 2018;379(18):1711-1721. doi: 10.1056/NEJMoa1807315.
8. MorphoSys AG: primary endpoint of L-MIND, a combination study of tafasitamib (MOR208) and lenalidomide, has been met, confirming previously published activity [news release]. Planegg/Munich, Germany: MorphoSys. Published May 16, 2019. bit.ly/32x1M1m. Accessed February 27, 2020
9. Budde LE, Sehn LH, Assouline S, et al. Mosunetuzumab, a full-length bispecific CD20/CD3 antibody, displays clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL): interim safety and efficacy results from a phase 1 study. Blood. 2018;132(suppl 1):399. doi: 10.1182/blood-2018-99-118344.

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