Mosunetuzumab induces remissions in advanced non-Hodgkin lymphoma after CAR-T fails
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ORLANDO — About 20% of a cohort of patients with aggressive relapsed or refractory non-Hodgkin lymphoma experienced complete response to treatment with the investigational agent mosunetuzumab, according to updated data from a phase 1/phase 1b dose-escalation and dose-expansion study presented during the plenary session of ASH Annual Meeting and Exposition.
Mosunetuzumab (Genentech) also appeared effective among those who failed previous chimeric antigen receptor T-cell therapy, with a 22% complete response rate among these patients.
Mosunetuzumab is a humanized, T-cell bispecific antibody designed to engage T cells and redirect their cytotoxic activity against malignant B cells. It simultaneously binds to CD3-epsilon, a component of the T-cell receptor complex, and to CD20, a protein expressed on the cell surface of most B-cell malignancies.
“There are no standard-of-care treatment options for patients who do not respond to CAR T-cell therapy. Survival of these patients is usually short, measured in months,” Stephen J. Schuster, MD, director of the lymphoma program at Abramson Cancer Center of the University of Pennsylvania, and one of the study’s co-authors, told Healio.
“The University of Pennsylvania has been one of the primary sites of development of CAR T-cell therapy,” he added. “We opened this trial specifically because they allowed enrollment of patients who had previously received CAR T cells, but with an unsuccessful outcome.”
The study included 270 patients (median age 62 years; range 19-96; 63.7% men) with relapsed or refractory B-cell non-Hodgkin lymphoma. Most of the patients (66.7%; n = 180) had aggressive NHL, and 31.5% (n = 85) had indolent NHL. Patients had a median three (range, 1-14) previous systemic therapies, including 30 patients (11%) who underwent CAR T-cell therapy.
The subset of patients who had previous CAR T-cell therapy had a median five (range, 3-14) previous lines of therapy. Twenty-nine patients (96.7%) in the CAR-T subgroup were refractory to previous anti-CD20 therapy, and 22 patients were refractory to previous CAR T-cell therapy.
Patients in group B of the study, for which the researchers presented data, received IV mosunetuzumab with step-up dosing on days 1, 8 and 15 of the first cycle, followed by a fixed dose on the first day of each subsequent 21-day cycle. Initial treatment continued for eight cycles. Those who achieved complete response discontinued treatment. Patients who had partial response or stable disease continued treatment for up to 17 cycles. Retreatment with mosunetuzumab was permitted for patients whose disease relapsed after an initial complete response.
Researchers evaluated best objective response rate according to revised International Group Working criteria, maximum tolerated dose of mosunetuzumab and tolerability.
Results showed an ORR of 37.1% among 124 efficacy-evaluable patients with aggressive NHL, including 24 complete responses (19.4%). Seventeen of the complete responders remained in remission up to 16 months after initial treatment.
The ORR among 67 efficacy-evaluable patients with indolent NHL was 62.7%, including 29 complete responses (43.3%). Twenty-four of the complete responders remain in remission up to 26 months following initial treatment.
The ORR in the previous CAR T-cell therapy subgroup was 38.9%, with four patients (22%) demonstrating a complete response to therapy.
Treatment-related adverse events included cytokine release syndrome (CRS), which 78 patients (28.9%) experienced. These included three cases of grade 3 CRS, one of which occurred in a patient who had received previous CAR T-cell therapy.
Researchers reported neurotoxicity among 118 patients (43.7%), including 13 patients in the previous CAR T-cell therapy subgroup. One patient in that subgroup had grade 3 immune effector cell-associated neurotoxicity syndrome.
“Mosunetuzumab has a very acceptable toxicity profile and efficacy in a very difficult-to-treat patient population,” Schuster told Healio. “This agent can potentially fulfill an unmet need in B-cell lymphoma as either therapy for patients failing to respond to CAR T cells or maybe even as a bridge therapy to reduce tumor burden prior to CAR T cells.”
Nevertheless, Schuster warned interested clinicians that there are cell-mediated immune class effects when using mosunetuzumab that mirror those seen with CAR T-cell therapy, including CRS and neurotoxicity, “although these side effects appear to be much milder and more easily managed with mosunetuzumab,” he said.
Schuster said single-agent and combination studies with mosunetuzumab are ongoing, including studies among patients with previously untreated diffuse large B-cell lymphoma.
“We obviously need longer follow-up to see what the durability of these complete remissions will be, as well as biomarker studies that will help us identify patients most likely to benefit from this therapy,” Schuster said. – by Drew Amorosi
Reference:
Schuster SJ, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure s : Schuster reports consultant roles with and honoraria and/or research funding from AbbVie, Acerta, AstraZeneca, Celgene, Genentech, Gilead, Loxo Oncology, Merck, Nordic Nanovector, Novartis, Pfizer and Pharmacyclics, and patents and royalties for combination CAR-T and PD-1 inhibitors from Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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John P. Leonard, MD
CAR T-cell therapy provides meaningfully durable remissions for about one-third of patients with recurrent diffuse large B-cell lymphoma — a group with limited other effective options. Mosunetuzumab is a bispecific monoclonal antibody targeting CD20 on B-cell tumors and CD3 to engage host T cells. This agent is one of several bispecifics in clinical development. How these therapies compare with CAR T cells in efficacy and safety remains to be established, although the principle of trying to better engage or activate host T cells and direct them against tumor cells is quite promising and has demonstrated activity when applied to patients.
The report by Schuster and colleagues describes an update of a previously presented large dose-escalation study of mosunetuzumab among patients with recurrent B cell-lymphoma (indolent, aggressive and transformed) showing meaningful activity and reasonable tolerability in this setting. Some of the interest in this report presumably relates to the activity noted among patients with disease progression after CAR T-cell therapy. At this point, the limited follow-up and relatively small number of patients necessitate further study. However, how bispecific antibodies will be used — before, after or as an alternative to CAR T therapy — will be of interest given that their activity and efficacy are noted in the context of greater feasibility (“off the shelf”) and potentially broader applicability than cell-based therapies for this patient population that generally needs additional useful treatments.
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Andre H. Goy, MD, MS
Bispecific T-cell engager (BiTE) antibodies are really starting to get traction, with close to 300 abstracts at this year’s ASH. This anti-CD20/CD3 BiTE antibody has demonstrated several remarkable things. First, it conferred a very high complete response rate for this population, including among those who had received prior CAR T-cell therapy, and the responses were very durable. Some of these longer durations were unexpected in this setting. There really are no other treatment options for patients who have failed CAR T-cell therapy; having a complete response that lasts for these patients is impressive.
Second, the treatment appeared tolerable, even among patients previously treated with CAR T cells. This is a dose-finding escalation study, but the maximum tolerated dose has not been reached. There was very minimal occurrence of CRS and minimal neurotoxicity. This was surprising, because with evolution of a novel therapy that is very active we would expect toxicity, such as what we have seen with CAR T cells and blinatumomab (Blincyto, Amgen). The therapy depends on activation of T cells. For instance, with CAR T, the phenomenon is acute, with a huge wave of T-cell implication. This needs to occur for response, but it also causes the patients to get sick with neurotoxicity. Perhaps this effect is a bit more progressive when you use the BiTE antibody; this agent might be a less aggressive way to activate the immune system.
These are very impressive data, especially considering that we have all been struggling with the CAR T patient who relapses, because there have been no real treatment options. The only option we had for these patients was to give them a small dose of radiation for 2 days, which has an abscopal effect, with a checkpoint inhibitor. With that dose of radiation, we’ve had several patients who converted back into complete remission. But, otherwise, there were no real options for this setting. These patients are profoundly immunosuppressed, so chemotherapy is not an option.
Outside of this trial population, in the real world, there are many patients too unstable or whose disease is too advanced for CAR T-cell therapy. Could this be an option as a bridging therapy? The responses are so impressive that it’s not clear we would even need the CAR T-cell therapy afterward. For patients who are doing very poorly and for whom CAR T-cell therapy is not an option, mosunetuzumab could potentially be a much easier solution earlier on, especially considering how well-tolerated it is.
I think mosunetuzumab is going to be very appealing as a treatment option earlier in the relapsed/refractory setting for large-cell lymphoma. We could potentially combine BiTE antibodies and CAR T-cell therapy. This study represents a platform from which to build.
Hackensack University Medical Center
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