Recent Clinical Trial Updates Shift DLBCL Treatment Paradigm

Gilles Salles, MD, PhD

Although progress in the development of new treatment regimens for the management of patients with diffuse large B-cell lymphoma (DLBCL) has been relatively slow overall, recent developments in both the frontline and relapsed/refractory spaces have stirred optimism amongst clinicians in the field, according to a presentation given by Gilles A. Salles, MD, PhD, at the 41st Annual CFS.¹

“We all know that [approximately] 20 years ago, we combined rituximab [Rituxan] with CHOP and we improved the results [seen with] CHOP in the vast majority of patients with DLBCL,” Salles, the chief of the Lymphoma Service and the Steven A. Greenberg Chair at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “[However, it only cures 60% to 70%] of patients. When we tried in the last decade to move the needle forward [by] changing the anti-CD20 antibody, transplanting patients in first remission, or using different types of drugs in maintenance, [we found that] none of these trials were positive. R-CHOP has remained the standard of care [SOC] for these patients.”

Emerging Frontline Treatment Options

Salles began his presentation by discussing updated findings from the phase 3 POLARIX trial (NCT03274492). The double-blinded study enrolled patients aged 18 to 80 years with previously untreated intermediate- or high-risk DLBCL and randomly assigned them in a 1:1 manner to receive 6 cycles of a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin-piiq (Polivy), or standard R-CHOP, plus 2 cycles of rituximab monotherapy at a dose of 375 mg/m2. The primary end point was progression-free survival (PFS) by investigator assessment and secondary end points included overall survival (OS) as well as safety.²

At a median follow-up of 28.2 months (range, 0.1-43.4) patients in the pola-R-CHP arm (n = 440) experienced a 27% reduction in the relative risk of disease progression, relapse, or death, compared with patients in the R-CHOP arm (n = 439; HR, 0.73; 95% CI, 0.57-0.95; P = .02). The 2-year PFS rates were 76.7% vs 70.2%, respectively.

“The primary end point was achieved, and pola-R-CHP showed a 27% reduction of the risk of progression, relapse or death, translating into a 6.5% [PFS] benefit at 24 months,” Salles said. “These were encouraging results. Obviously not a revolution, but a change in [an area where] we hadn’t seen any positive results in the last 20 years.”

Additionally, treatment with pola-R-CHP conferred a benefit in terms of disease-free survival among patients who achieved a complete response (CR) compared with standard R-CHOP (HR, 0.70; 95% CI, 0.50-0.98). The CR rates were 86.6% vs 82.7%, respectively, and the partial response (PR) rates were 9.3% vs 11.4%, respectively. There was not a significant difference regarding OS between the 2 arms (HR, 0.94; 95% CI, 0.65-1.37; P = .75).

A subgroup analysis revealed that pola-R-CHP was favored over standard R-CHOP in most of the key subgroups examined. Salles highlighted that there was an approximate 10% difference in 2-year PFS rate in favor of pola-R-CHP among patients with an IPI score of 3 to 5 (HR, 0.7; 95% CI, 0.5-0.9). There was also a 15% difference in 2-year PFS rate in favor of the pola-R-CHP regimen among patients with activated B-cell DLBCL (HR, 0.4; 95% CI, 0.2-0.6).

In terms of safety, no new safety signals were observed with pola-R-CHP and the safety profile of the regimen was consistent with the known profiles of the individual agents. In the safety population of the ploa-R-CHP arm (n = 435) the most common any-grade adverse effects (AEs) included peripheral neuropathy (52.9%), nausea (41.6%), and neutropenia (30.8%). Comparatively, the most common any-grade AEs in the R-CHOP arm (n = 438) also included peripheral neuropathy (53.9%), nausea (36.8%), and neutropenia (32.6%).

On April 19, 2023, the FDA approved pola-R-CHP for the treatment of adult patients with previously untreated DLBCL, not otherwise specified, or high-grade B-cell lymphoma (HGBL) who have an IPI score of at least 2. The approval was supported by findings from POLARIX.³

Salles concluded his discussion of POLARIX by noting that pola-R-CHP significantly prolongs PFS vs R-CHOP in patients with intermediate- and high-risk treatment-naive DLBCL and that the safety profiles of the 2 regimens were comparable. Exploratory analyses of various subgroups and other prognostic classification systems are ongoing and findings from POLARIX support the use of pola-R-CHP in the initial management of patients with DLBCL, he said.

New Options in the Second Line and Beyond

Salles then transitioned into discussing updates regarding treatment options for patients with relapsed/refractory DLBCL. “You cure approximately 60% to 70% of patients, but there are still more than 25% of patients who fail first-line therapy,” Salles said. “In 2021, the situation was simple. Half of your patients [will be] eligible for salvage therapy and autologous stem cell transplant [ASCT]. If you are eligible for ASCT, you do a platinum-based salvage therapy—half of the patients respond and go to transplant the other half are refractory and go to third line [therapy]. What changed in 2022 was a presentation at ASH and the publication of 3 studies.”

Salles highlighted findings from the phase 3 ZUMA-7 trial (NCT03391466) which compared the CAR T-cell therapy axicabtagene ciloleucel(axi-cel; Yescarta) with SOC therapy in patients with DLBCL that was relapsed/refractory no more than 12 months after chemoimmunotherapy. The primary end point was event-free survival (EFS) and secondary end points included overall response rate (ORR), OS, and safety.⁴

At a median follow-up of 24.9 months, the median EFS in the axi-cel arm (n = 180) was 8.3 months (95% CI, 4.5-15.8) compared with 2.0 months in the SOC arm (n = 179; 95% CI, 1.6-2.8) and the 2-year EFS rates were 40.5% vs 16.3%, respectively (HR, 0.398; 95% CI, 0.308-0.514; P < .0001). Moreover, axi-cel provided an EFS benefit over SOC in all of the key subgroups examined, with the most pronounced benefit being reported in patients who were aged 65 years or older (HR, 0.276; 95% CI, 0.164-0.465) and those with HGBL-double/triple hit disease (HR, 0.285; 95% CI, 0.137-0.593).

Salles noted that in a 2023 update to ZUMA-7 published in the New England Journal of Medicine, axi-cel was also found to significantly extend OS compared with SOC. The median OS was not reached (NR; 95% CI, 28.6-not estimable [NE]) vs 31.1 months (95% CI, 17.1-NE), respectively (HR, 0.73; 95% CI, 0.54-0.98; P = .03). The respective estimated 4-year OS rates were 55% vs 46%.⁵

In another phase 3 trial, TRANSFORM (NCT03575351), investigators compared the CAR T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) with SOC for the second-line treatment of patients with primary refractory or early relapsed large B-cell lymphoma. The primary end point was EFS.⁶

At a median follow-up of 17.5 months, patients in the liso-cel arm (n = 92) achieved a median EFS of NR (95% CI, 9.5-NR) compared with 2.4 months (95% CI, 2.2-4.9) in the SOC arm (n = 92; HR, 0.356; 95% CI, 0.243-0.522). The 18-month EFS rates were 52.6% (95% CI, 42.3%-62.9%) vs 20.8% (95% CI, 12.2%-29.5%), respectively. The median PFS was NR (95% CI, 12.6-NR) vs 6.2 months (95% CI, 4.3-8.6), respectively (HR, 0.400; 95% CI, 0.261-0.615; P < .0001). The respective 18-month PFS rates were 58.2% (95% CI, 47.7%-68.7%) vs 28.8% (95% CI, 17.7%-40.0%).

In the phase 3 BELINDA trial (NCT03570892), investigators evaluated the CAR T-cell agent tisagenlecleucel (tisa-cel; Kymriah) compared with SOC in patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. The primary end point was EFS.⁷

However, findings from BELINDA showed that tisa-cel was not superior to SOC therapy; at a median follow-up of 10.0 months, the median EFS was 3.0 months in both arms (HR, 1.07; 95% CI, 0.82-1.40; 2-sided P = .61). The ORR at 12 weeks in the tisa-cel arm (n = 162) was 46.3%, with a 28.4% CR rate, compared with 42.5%, with a 27.5% CR rate, in the SOC arm (n = 160).

Salles finished his presentation by touching on novel agents that are under investigation for the treatment of relapsed/refractory DLBCL. The antibody drug conjugate loncastuximab tesirine (Zynlonta) plus rituximab is being evaluated in the phase 3 LOTIS-5 study (NCT04384484); initial findings presented at the 2023 SOHO Annual Meeting showed promising initial efficacy and the study is expected to complete enrollment in 2024. Loncastuximab tesirine is also being combined with other anti-cancer agents in the phase 1b LOTIS-7 trial (NCT04970901). Other bispecific antibodies being examined in relapsed/refractory DLBCL include mosunetuzumab (Lunsumio), odronextumab, and glofitamab (Columvi).¹

“I believe what we have here are new agents for patients who are not eligible for transplant or for CAR T,” Salles said in conclusion. “We don't know when these new agents [will be available] for those patients. What's the optimal way to sequence them? How do we potentially combine them? Are we curing some patients with relapsed/refractory DLBCL? [We definitely are] with CAR T and maybe we will with some of the other agents as we continue to move forward.”

References

1. Salles GA. Paradigm changes in the management of DLBCL. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
2. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304
3. FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma. News release. FDA. April 19, 2023. Accessed November 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not
4. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
5. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-Cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
6. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730
7. Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596