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Key Studies in Lymphomas: CCO Independent Conference Highlights of the 2020 Virtual ASH Annual Meeting

John M. Burke, MD
Jeff P. Sharman, MD
Released: February 26, 2021

Aggressive Lymphomas

Glofitamab for R/R B-Cell Lymphomas

John M. Burke, MD:
Data from studies of several emerging investigational therapeutics for more-aggressive lymphomas were also presented at ASH 2020. Glofitamab is a novel bispecific antibody with a 2:1 molecular configuration: 2 CD20 binding sites and 1 CD3 binding site, which gives it a higher potency compared with other bispecific antibodies.[19,20] However, this agent has been associated with substantial CRS in earlier trials.[21]

At ASH 2020, results were presented from an ongoing phase I dose-escalation and expansion study of glofitamab in R/R CD20-positive B-cell NHL (N = 52).[22]  This study used obinutuzumab as a pretreatment and added step-up dosing in an attempt to minimize the risk of CRS while enabling a higher target dose of glofitamab.[23] Treatment began with obinutuzumab 1000 mg administered for 7 days before starting glofitamab. In cycle 1, glofitamab step-up doses were given on Days 1 (2.5 mg) and 8 (10 mg). In subsequent 3-week cycles (maximum: 12 cycles), glofitamab was given at target doses starting on cycle 2, Day 1 (2.5/10/16 mg or 1.5/10/30 mg). The primary endpoint was safety, with other objectives including pharmacokinetics, efficacy, MTD, and recommended phase II dose.

The median age of patients in this study was 68 years, and patients had received a median of 3 previous lines of therapy (range: 1-12). Approximately 31% of patients had diffuse large B-cell lymphoma (DLBCL) or transformed FL (ie, aggressive NHLs) and 46% had grade 1-3a FL (indolent NHL). Most (77%) were refractory to their most recent therapy and 73% were refractory to any previous CD20-targeted therapy.

Glofitamab for R/R B-Cell Lymphomas: Efficacy

John M. Burke, MD:
In patients who received glofitamab at fixed doses of at least 10 mg, the ORR in indolent NHL was 67% and 49% in aggressive NHL. In the step-up dosing cohort, the ORR in aggressive lymphoma was 61%, and the ORR in the indolent group was the same as in the fixed-dose cohort (67%). Of note, in the step-up dosing group, 12 patients with indolent lymphoma (53.6%) and 15 with aggressive lymphoma (54.2%) achieved a CR.

Glofitamab for R/R B-Cell Lymphomas: CRS

Jeff P. Sharman, MD:
In terms of toxicity, the step-up dosing schedule reduced the frequency and severity of CRS. The median time to CRS was 14 hours and the median duration approximately 1 day. Only approximately 4% of patients who received step-up dosing experienced grade 3/4 CRS, and approximately 60% of patients experienced grade 1/2 CRS.

Glofitamab for R/R B-Cell Lymphomas: Conclusions

John M. Burke, MD:
In summary, in this early-phase study, step-up dosing of glofitamab achieved high CR rates (~ 50%) in patients with refractory, aggressive large‑cell lymphoma. The use of step-up dosing appeared to reduce the severity and frequency of CRS, thereby allowing administration of a higher target dose of 30 mg. This probably contributed to higher response rates and deeper responses. Although it is still too early for an approval in aggressive large‑cell lymphoma, I am optimistic that glofitamab will continue to show promise and be approved for the treatment of patients with NHL.

Jeff P. Sharman, MD:
This drug class is going to be exciting to watch. Although bispecific antibodies have not yet been approved for aggressive lymphomas, I expect that they will become available in the next several years pending positive results from pivotal, practice-changing studies.

John M. Burke, MD:
I agree and also think these drugs are not going to be limited to single‑agent treatment. Bispecific antibodies appear to combine well with chemotherapy drugs and with other targeted drugs, so I encourage healthcare professionals to watch for those combination studies in aggressive lymphomas. 

Epcoritamab in R/R B-Cell NHL

John M. Burke, MD:
Epcoritamab is a novel bispecific mAb that targets CD3 and CD20.[24,25] CAR T-cells are effective in many different forms of relapsed B‑cell lymphomas, but they can be expensive and challenging to produce. By using bispecific antibodies, the hope is to have an off-the-shelf product that can be administered quickly and with high efficacy. Of note, epcoritamab is administered subcutaneously.

At ASH 2020, updated data from an ongoing phase I/II trial of epcoritamab for patients with R/R B-cell NHL (including those with previous CAR T-cell therapy and exposure to CD20 antibodies) were presented (N = 68).[26] Split (step-up) dosing was again used to decrease the incidence of CRS and to allow for safer administration of the drug. The primary objectives were to determine the recommended phase II dose and the MTD. Secondary objectives included an evaluation of antitumor activity (investigator-assessed ORR per Lugano criteria) and tolerability.

The baseline characteristics are typical of this heavily pretreated population, with a median of 3 previous therapies (range: 1-6) in patients with large‑cell lymphoma (n = 46) and a median of 5 previous therapies in patients with FL (range: 1-18) (n = 12). All had been exposed to chemoimmunotherapy. Nearly 90% of patients were refractory to their last therapy; this is important to remember when interpreting the results. At the time of data analysis, median follow-up was short at 10 months and 25% of patients remained on treatment.

Epcoritamab in R/R B-Cell NHL: Safety

John M. Burke, MD:
The primary toxicity of concern, CRS, was seen in 60% of patients, but all cases were grade 1/2 and nearly all occurred during cycle 1. The median time to resolution of CRS was 2 days. Even with the subcutaneous administration, injection-site reactions were seen in one half of the patients. A total of 4 patients experienced neurotoxicity. There was no febrile neutropenia and no treatment‑related deaths.

At the time of data reporting, 66% of patients had discontinued due to disease progression and only 1 patient discontinued due to toxicity.

Epcoritamab in R/R B-Cell NHL: Efficacy

John M. Burke, MD:
The efficacy of epcoritamab in B-cell NHL has been impressive. In patients with DLBCL who received a dose of 48-60 mg, the ORR was 91%, with CRs observed in 55%. In patients with DLBCL who received 12-60 mg, the ORR was 68%, with 46% achieving CRs. The ORR in the FL group was 80% to 90%, with approximately one half of patients achieving a CR (although there were only 12 patients in this group). Responses were even seen in patients who had failed previous CAR T‑cell therapy. The median time to response was approximately 1.4 months—basically, the first time patients get a scan, they are usually already responding.

Epcoritamab in R/R B-Cell NHL: Conclusions

John M. Burke, MD:
In conclusion, the bispecific antibody epcoritamab appears to have excellent activity in both FL and DLBCL in this early study. Phase III trials are planned in this setting with monotherapy and combination regimens. I hope these will be positive and this agent will become available in the clinic in the next few years.

Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin for R/R HL

John M. Burke, MD:
Finally, results were presented from a single-arm phase II study of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin for patients with R/R classical Hodgkin lymphoma following 1 previous line of therapy (N = 39).[27] Patients received 2-4 cycles of pembrolizumab plus GVD therapy; those with a CR proceeded to autologous stem cell transplant. The primary endpoint of this study was CR after 2-4 cycles of therapy.

Overall, 95% of evaluable patients achieved CR after 2-4 cycles of therapy, with 92% achieving CR after 2 cycles. Almost all patients in CR proceeded to transplant, and with a median post–autologous stem cell transplant follow-up of 11.2 months, no progressions were observed.

To my knowledge, this CR rate is the highest that has been seen with a salvage regimen in patients with relapsed Hodgkin lymphoma. There is no single standard regimen in this space, and acceptable regimens include things like ICE, DHAP, brentuximab vedotin plus chemotherapy, and brentuximab vedotin plus nivolumab. Use of all of these regimens is based primarily on data from phase II studies. Although the number of patients treated with pembrolizumab plus GVD was relatively small at 39, I am planning to change my practice based on these results until I larger or additional comparative datasets become available. Furthermore, this regimen could be useful in the growing population of patients treated with brentuximab vedotin plus AVD in the frontline, as these patients have already by exposed to brentuximab vedotin and may therefore be less responsive to it in the relapsed setting.

Final Thoughts

Jeff P. Sharman, MD:
Within the next year, important and pivotal studies will be reading out, including:

  • POLARIX: frontline R-CHOP vs R-CHP plus polatuzumab in large‑cell lymphoma[28]
  • GLOW: first-line ibrutinib/venetoclax plus obinutuzumab/chlorambicil in CLL/SLL[29]
  • CLL13: first-line venetoclax plus rituximab, venetoclax plus obinutuzumab, or venetoclax plus ibrutinib plus obinutuzumab vs chemoimmunotherapy for fit patients with CLL without del(17p) or TP53 mutation[30]
  • ELEVATE‑R/R: ibrutinib vs acalabrutinib for previously treated high-risk CLL[31]

We are also anticipating additional approvals of CAR T‑cell therapies in various different niches of B‑cell malignancies.

John M. Burke, MD:
I concur that the future is very bright with these highly promising agents with novel mechanisms of action.

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