Checkpoint Inhibitors and Bispecifics Build Momentum Throughout Lymphoma

Stephen J. Schuster, MD

Although checkpoint inhibitors and bispecific antibodies have come to represent clinical oncology’s fourth leg of treatment—immunotherapy—there remains much to explore, according to Stephen J. Schuster, MD, who stated that although each treatment class has shown respectable single-agent activity throughout lymphoma, combinations thereof represent the path forward.

“When I was in training, immunotherapy was a theoretical consideration, and I’ve had the opportunity to watch it become a reality throughout my career,” Schuster, a professor of medicine at the Perelman School of Medicine and director of the Lymphoma Program & Lymphoma Translational Research at the Abramson Cancer Center of the University of Pennsylvania, said in a presentation during the 26th Annual International Congress on Hematologic Malignancies^®, an event hosted by Physicians’ Education Resource, LLC.¹

“However, we’re still doing single-agent studies [with bispecifics], and we need to study these [agents] in combination with checkpoint inhibitors, and those studies are in progress,” he added.

The first approval for immunotherapy in oncology came in the form of ipilimumab (Yervoy) in 2011, which was followed by nivolumab (Opdivo) and pembrolizumab (Keytruda) in 2014. Since then, nivolumab and pembrolizumab have received approvals in relapsed/refractory classical Hodgkin lymphoma and have been evaluated in primary mediastinal large B-cell lymphoma (LBCL) and follicular lymphoma.

In the phase 1 KEYNOTE-013 (NCT01953692) and phase 2 KEYNOTE-170 (NCT02576990) trials, pembrolizumab was evaluated in patients with relapsed/refractory primary mediastinal LBCL. In KEYNOTE-013 (n = 21), the objective response rate (ORR) with pembrolizumab was 48% (95% CI, 26%-70%), with a complete response (CR) rate of 33% and a partial response rate (PR) of 14%.² The median progression-free survival (PFS) was 10.4 months (95% CI, 3.4–not reached [NR]), and the median overall survival (OS) was 31.4 months (95% CI, 4.9-NR).

In KEYNOTE-170 (n = 53), the ORR was 45% (95% CI, 32%-60%), with a CR and PR rate of 19% and 26%, respectively.³ The median PFS and OS was 5.5 months (95% CI, 2.7-15.1) and 22.3 months (95% CI, 7.3-NR), respectively.

In June 2018, the FDA granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal LBCL, or who have relapsed after 2 or more prior lines of therapy based on findings from KEYNOTE-170, making it a standard of care in clinical practice, Schuster said.

In follicular lymphoma, nivolumab was evaluated in the phase 2 CheckMate 140 trial (NCT02038946). The single-arm study enrolled 92 patients with relapsed/refractory disease following failure of at least 2 prior lines of therapy that included a CD20-dircted antibody and an alkylating agent.⁴ The ORR per independent review was 4% (95% CI, 1%-11%), with a CR rate of 1% and a PR rate of 3%. The median PFS was 2.2 months (95% CI, 1.9-3.6). 

Shifting focus, Schuster turned his attention to the 60-plus-year-history of bispecific antibodies, which culminated in the first-in-class approval of blinatumomab (Blincyto) in 2014. Now, several bispecific antibodies are in development, including mosunetuzumab, glofitamab, odronextamab, and epcoritamab.

In a phase 1/2 study (NCT03625037), epcoritamab was evaluated in patients with relapsed/refractory B-cell lymphomas. Across the target doses of 12 mg to 60 mg, 48 mg—the recommended phase 2 dose—and 60 mg, the results demonstrated an ORR of 68% (95% CI, 45%-86%), 88% (95% CI, 47%-100%), and 100% (95% CI, 29%-100%), respectively, in the diffuse large B-cell lymphoma (DLBCL) cohort.⁵ The CR rates were 45%, 38%, and 100%, respectively; the PR rates were 23%, 50%, and 0%, respectively.

The median PFS in patients who received at least 12 mg of epcoritamab was 9.1 months (interquartile range, 1.6–not estimable). The median PFS in patients who received at least 48 mg of epcoritamab was NR at data cutoff.

Among patients with follicular lymphoma, the ORR was 90% (95% CI, 55%-100%) between doses of 0.76 mg and 48 mg. The CR and PR rates were 50% and 40%, respectively.

The agent is now under evaluation in the randomized phase 3 EPCORE DLBCL-1 trial (NCT04628494) vs investigator’s choice of rituximab (Rituxan), gemcitabine, and oxaliplatin, or bendamustine and rituximab, in adults with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Moreover, Schuster called attention to a phase 1/2 study (NCT02500407) with mosunetuzumab that demonstrated encouraging responses in patients with NHL who had received prior CAR T-cell therapy.⁶ Across the DLBCL (n = 9), transformed follicular lymphoma (n = 5), and follicular lymphoma (n = 4) cohorts, the ORR was 22.2% (n = 2), 20.0% (n = 1), and 100% (n = 4), respectively; 2 CRs each were seen in the DLBCL and follicular lymphoma cohorts.

“As single agents, bispecific antibodies exhibit a promising benefit-risk profile in patients with relapsed/refractory B-cell lymphomas, but combination studies, including with CAR T-cell therapy, are ongoing,” concluded Schuster.

References

1. Schuster SJ. Non-CAR T-cell engagers: checkpoint inhibitors and bispecific agents. Presented at: 26th Annual International Congress on Hematologic Malignancies®; February 24-27, 2022; Miami, FL. Accessed February 25, 2022.
2. Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol. 2019;37(34):3291-3299. doi:10.1200/JCO.19.01389
3. Zinzani PL, Melnichenko V, Bouabdallah K, et al. Pembrolizumab monotherapy in relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL): 3-year follow-up of the Keynote-170 study. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-137080
4. Armand P, Janssens A, Gritti G, et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma Blood. 2021;137(5):637-645. doi:10.1182/blood.2019004753
5. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8
6. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and Is active in treatment through multiple lines. Blood. 2019;134(suppl 1):6. doi:10.1182/blood-2019-123742