Comparisons of treatment outcomes of epcoritamab versus chemoimmunotherapy, polatuzumab-based regimens, tafasitamab-based regimens, or chimeric antigen receptor T-cell therapy, in third-line or later relapsed/refractory large B-cell lymphoma

Abstract

Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL.

To the editor

Although current frontline therapies for large B-cell lymphoma (LBCL) have curative potential, 30–40% of patients have refractory disease or relapse following treatment with standard chemoimmunotherapy (CIT) [1]. A number of these patients present with challenging-to-treat disease and suboptimal treatment outcomes [2]. Still, CIT remains the most commonly used therapy among patients with relapsed/refractory (R/R) LBCL and diffuse LBCL (DLBCL) after ≥ 2 lines of therapy (LOTs). Newly approved treatments include chimeric antigen receptor T-cell (CAR T) therapies, polatuzumab vedotin plus bendamustine and rituximab, and tafasitamab plus lenalidomide [3]. Epcoritamab is an off-the-shelf subcutaneous CD3xCD20 bispecific antibody therapy being developed as a core therapy across various lymphoma subtypes. It is currently approved for R/R DLBCL after ≥ 2 LOTs, based on strong efficacy and manageable safety data from EPCORE NHL-1 (NCT03625037) [4,5,6].

In the absence of head-to-head trials, statistical methods such as inverse probability of treatment weighting (IPTW) can adjust for confounding and assess comparative effectiveness [7]. We report the results of an IPTW analysis comparing outcomes of patients treated with epcoritamab in EPCORE NHL-1 versus clinical practice cohorts receiving third-line or later treatment with CIT or novel therapies from COTA, a US-based electronic health records database. Comparisons were conducted in LBCL or DLBCL depending on each therapy’s US FDA approval indication. Methodological details are in the Supplemental Material.

Epcoritamab versus chemoimmunotherapy

A total of 157 epcoritamab-treated patients with LBCL were compared with 179 CIT-treated patients with LBCL. Median follow-up times were 8.5 months and 5.4 months for the epcoritamab and CIT cohorts, respectively. The adjusted cohorts were balanced on clinical and demographic characteristics: age, sex, previous treatment with CAR T, previous stem cell transplant, number of prior LOTs, primary refractory status, refractory to last LOT status, and time since discontinuation of last LOT (Supplemental Material). After adjustment, complete response (CR) rate was significantly higher with epcoritamab (38.9% [95% CI: 31.2, 46.5]) versus CIT (9.4% [95% CI: 4.7, 14.2]), with an adjusted odds ratio (OR) of 4.1 (95% CI: 2.4, 7.1; P < 0.0001) (Table 1). Median overall survival (OS) was not reached with epcoritamab and was 4.9 months (95% CI: 4.1, 10.9) with CIT, corresponding to an adjusted hazard ratio (HR) of 0.5 (95% CI: 0.4, 0.7; P < 0.0001), indicating significantly better survival with epcoritamab than with CIT (Fig. 1).

Table 1 Adjusted clinical outcomes of epcoritamab compared with CIT and novel therapies

Fig. 1

Hazard ratios for OS outcomes. Epcoritamab vs A CIT (LBCL); B CAR T (LBCL); C Pola (DLBCL); and D Tafa (DLBCL). CAR T, chimeric antigen receptor T-cell; CI, confidence interval; CIT, chemoimmunotherapy; DLBCL, diffuse large B-cell lymphoma; Epco, epcoritamab; HR, hazard ratio; LBCL, large B-cell lymphoma; NE, not estimable; NR, not reached; OS, overall survival; Pola, polatuzumab; Tafa, tafasitamab

Epcoritamab versus novel therapies

A total of 96 CAR T-naive epcoritamab-treated patients with LBCL were compared with 55 CAR T-treated patients with LBCL. One hundred thirty-nine epcoritamab-treated patients with DLBCL were compared with 37 patients with DLBCL treated with polatuzumab-based regimens and 20 patients with DLBCL treated with tafasitamab-based regimens. Median follow-up times were 10.0, 6.6, and 4.3 months for the CAR T, polatuzumab-based, and tafasitamab-based cohorts, respectively. Polatuzumab-based regimens included polatuzumab combined with other agents including bendamustine, rituximab, obinutuzumab, or bendamustine plus rituximab; tafasitamab-based regimens included tafasitamab with or without lenalidomide. The adjusted cohorts were balanced on clinical and demographic characteristics: age, sex, previous treatment with CAR T, previous stem cell transplant, number of prior LOTs, primary refractory status, refractory to last LOT status, and time since discontinuation of last LOT (Supplemental Material).

The CR rate (95% CI) was 38.9% (30.8, 47.0) with epcoritamab versus 10.7% (5.1, 16.5) with polatuzumab-based and 11.2% (5.5, 16.8) with tafasitamab-based regimens. The adjusted ORs (95% CI) for achieving a CR were 3.6 (2.0, 6.4; P < 0.0001) for epcoritamab versus polatuzumab-based regimens and 3.5 (2.0, 6.0; P < 0.0001) for epcoritamab versus tafasitamab-based regimens (Table 1). The median OS was not reached for epcoritamab and was 5.6 (95% CI: 3.6, 10.2) months for polatuzumab-based regimens and 6.6 (95% CI: 1.6, 16.2) months for tafasitamab-based regimens. Adjusted HRs (95% CI) for OS events were 0.4 (0.3, 0.6; P < 0.0001) for epcoritamab versus polatuzumab-based regimens and 0.5 (0.4, 0.8; P = 0.0003) for epcoritamab versus tafasitamab-based regimens, indicating significantly better survival with epcoritamab (Fig. 1).

The adjusted CR rate (95% CI) with epcoritamab was 41.7% (31.8, 51.5) versus 36.5% (26.4, 46.5) with CAR T; the corresponding adjusted OR (95% CI) for achieving a CR was 1.1 (0.8, 1.6; P = 0.472) (Table 1). Median OS was not reached with epcoritamab and was 15.0 (95% CI: 9.5, 31.1) months with CAR T. The adjusted HR was 1.1 (95% CI: 0.7, 1.7; P = 0.724), indicating no significant difference in survival between epcoritamab and CAR T (Fig. 1).

Conclusions

Epcoritamab demonstrated better efficacy than CIT in R/R LBCL, significantly increasing the likelihood of CR and reducing risk of mortality by half. Compared with polatuzumab-based and tafasitamab-based regimens in R/R DLBCL, epcoritamab significantly increased the likelihood of achieving CR and reduced the risk of mortality by half. No difference in efficacy was found between epcoritamab and CAR T in R/R LBCL. Findings are subject to limitations, including the potential for residual confounding due to unmeasured characteristics and small sample sizes in the real-world novel treatment cohorts.