Max S. Topp, MD, highlights the rationale for studying bispecific antibodies in newly diagnosed diffuse large B-cell lymphoma, how the safety profile of glofitamab plus R-CHOP contributes to its potential for outpatient administration, and where future directions with this research may lead.
Max S. Topp, MD
The combination of glofitamab and R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) elicited encouraging response rates and manageable toxicities in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to Max S. Topp, MD.
Findings from the safety run-in and expansion stages of the ongoing phase 1 NP40126 study (NCT03467373) showed that patients who received the combination experienced a complete metabolic response rate of 75.5% and an overall response rate (ORR) of 86.8%. Additionally, glofitamab plus R-CHOP was well tolerated, with 23.2% of patients experiencing grade 3 or 4 adverse effects (AEs) related to glofitamab.1
“Overall, the safety profile is favorable, and there were no specific higher-grade toxicities related to glofitamab,” Topp said in an interview with OncLive® at the 2022 ASH Annual Meeting.
In the interview, Topp, head of hematology and a professor of internal medicine, hematology, and oncology at the University Hospital of Wurzburg in Germany, highlighted the rationale for studying bispecific antibodies in newly diagnosed DLBCL, how the combination’s safety profile contributes to its potential for outpatient administration, and where future directions with this research may lead.
Topp: Glofitamab has shown remarkable efficacy in patients with relapsed/refractory large cell lymphoma, [eliciting] a complete response rate around 40%. Most of these patients remain in complete remission, even at long-term follow up.
The quest of our study was to bring this interesting compound into frontline therapy in patients with untreated aggressive lymphomas. We designed a clinical trial in which the first part, which was presented last year, [evaluated] glofitamab in patients with relapsed/refractory indolent lymphoma plus R-CHOP to understand how we can combine this compound with R-CHOP. We had 13 patients in the safety run-in phase presented [at the 2021 ASH Annual Meeting]. [We now have data in] 56 patients with aggressive lymphomas. The question was: What is the safety and efficacy of this combination in patients with aggressive lymphomas?
Glofitamab is a bispecific antibody targeting CD20 on the surface of lymphoma B cells. [It also targets] CD3. It interacts with every kind of T cell, including CD4 cells, CD8 cells, and all the other prodigies. [It has an] unusual 2:1 format, which means it has 2 VL regions targeting CD20 and 1 region targeting CD3. It’s distinct in its construct in comparison with the other bispecific antibody constructs currently in clinical development.
Once a T cell engages with the lymphoma cell via this bispecific antibody, it gets activated and starts to produce cytokines and proliferate. It also leads to direct lysis of the aggressive lymphoma cell.
We looked for patients with an International Prognostic Index [IPI] score of 2 to 5, because for those patients, R-CHOP is insufficient when compared with patients with an IPI score of 0, where there’s a response and a long-time cure rate of close to 95%. We focused on the patient cohorts that clearly have room for improvement.
The 3 topics we [aimed to study] were efficacy, safety, and the degree to which we can give our patients R-CHOP in combination with glofitamab. In over 90% of patients, the dose intensity of R-CHOP could be applied, with most patients receiving cortisone, rituximab, anthracycline, and cyclophosphamide. The only drug where we had a reduced exposure, as expected, was vincristine, because of the development of polyneuropathy, which led to a reduction or even complete abolishment of vincristine in some patients.
Considering efficacy, 56 patients were recruited [and comprised the safety population], and 53 were exposed to glofitamab plus R-CHOP [and comprised] the efficacy population. Of the 53 patients who were exposed to glofitamab, the ORR was 86.8%, and the complete metabolic response rate was 75.5%.
AEs occurred in virtually every patient, and serious AEs occurred in 32.1% of the patients, although just 8.9% [of patients had serious AEs] related to glofitamab. [Some of] the most common AEs were neutropenia, thrombocytopenia, and infections. Importantly, the rate of cytokine release syndrome [CRS] was in the single digits. Only 6 patients developed CRS out of 53 patients, 4 with grade 1 and 2 with grade 2 CRS.
AEs occurred in 3 patients during the second cycle of R-CHOP when glofitamab was added on day 8. On day 15, when the dose of glofitamab increased to 10 mg, 3 additional [cases of grades 1 and 2 CRS] were seen. Only 1 [instance of] grade 1 CRS was seen in cycle 3, when glofitamab was added at the full dose of 30 mg.
The safety profile regarding CRS is favorable and will likely allow this combination to be given during outpatient treatment. We removed the mandatory hospitalization after the safety run-in phase upon seeing the safety profile.
Regarding other AEs of interest, neurotoxicity was seen in many patients, all because of vincristine, and all leading to polyneuropathy. There were 9 serious infections, 8 from COVID-19. We lost 3 patients to COVID-19. Additionally, 1 patient had septic anemia.
Currently, we are recruiting another arm with Pola-R-CHP [polatuzumab vedotin-piiq (Polivy) plus rituximab, cyclophosphamide, doxorubicin, and prednisone], because that is the recommended frontline therapy in many regions of the world. Once we have a readout of that safety profile and efficacy dataset, the next step will be to design a global phase 3 trial answering the question: Can glofitamab be added in a patient population similar to what we have been recruiting, with an IPI score of 2 to 5? We are still discussing whether it can add benefit in that population, and our primary end point [will probably be] overall survival or event-free survival. However, these are questions that we’re still discussing amongst investigators, Roche, and the sponsor.
We can safely add a bispecific antibody targeting lymphoma as a frontline therapy with low toxicity, making this a doable outpatient treatment. [This will hopefully] help many patients in the future.
Topp MS, Tani M, Dickinson M, et al. Glofitamab plus R-CHOP induces high response rates and a favorable safety profile in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): results from a phase 1b study. Blood. 2022;140(suppl 1):1775-1777. doi:10.1182/blood-2022-157732