Mosunetuzumab Maintains Efficacy/Survival Benefit in Elderly Patients With DLBCL

Adam J. Olszewski, MD

Promising efficacy, durable responses, and a manageable safety profile were seen with mosunetuzumab (Lunsumio) among elderly/unfit patients who were previously untreated for their diffuse large B-cell lymphoma (DLBCL), according to findings from a phase 1b/2 study (NCT03677154).

The trial enrolled 54 patients aged ≥ 80 years, or 60-79 years with ≥ 1 activity of daily living with DLBCL. Patients were administered step-up dosing mosunetuzumab given intravenously on days 1 at 1mg, 8 at 2mg, 15 at either 13.5 or 30mg, and at 13.5mg or 30 mg mosunetuzumab on day 1 of each subsequent 21-day cycle 1/2/13.5mg and 1/2/30mg.

If patients achieved a complete response (CR), mosunetuzumab was stopped after 8 cycles. Additionally, patients with a partial response (PR) or stable disease (SD) were able to mosunetuzumab up to 17 cycles. Investigators evaluated the primary end points of objective response rate (ORR) and CR rates.

Findings showed that the best ORR and CR rates were 56% in 30 of the 54 patients, and 43% in 23 of the 54, respectively. The median duration of CR was 15.8 months (95% CI, 8.5-not estimable), and 11 of 23 patients who reached a CR maintained it for >12 months. Further, the 12-month progression-free survival rate was 39% (95% CI, 25.8-52.8).

Regarding safety, there were no new safety signals observed. A total of 98% of patients had ≥ 1 adverse event (AE), and 48% had a grade 3/4 AE. AEs that led to treatment discontinuation was reported in 1 patient, and fatal AEs were seen in 3 pts. Moreover, there was 1 death attributed to natural causes and 2 resulting from COVID-19 pneumonia.

In an interview with Targeted Oncology^TM, Adam J. Olszewski, MD, associate professor of medicine at Brown University, lymphoma clinician at Rhode Island Hospital in Providence, Rhode Island, discussed mosunetuzumab and the rationale and findings of this phase 1b/2 study assessing the agent in DLBCL.

Targeted Oncology: Can you provide an overview of the phase 1b/2 study evaluating mosunetuzumab in DLBCL?

Olszewski: We presented updated results of an ongoing phase 1b/2 study which uses immunotherapy alone without any chemotherapy exposure for the treatment of older patients with diffuse large B-cell lymphoma. These patients are previously untreated, so it's a first-line therapy, but they are of age or impairment of functional status or medical issues, ineligible to receive standard chemotherapy. These patients on the trial are treated using mosunetuzumab, which is a bispecific antibody and is a form of immunotherapy, which stimulates the T cells, the natural immune cells to engage and destroy the malignant B cells.

What was the rationale behind the study?

The main rationale is that currently available treatments for this group of patients, so those who cannot receive stellar treatment, are very limited. We know that patients have inferior outcomes, both in terms of response rate and survival, but also their quality-of-life is majorly impaired when they receive attenuated forms of chemotherapy. These treatments, such as R-mini CHOP [rituximab [Rituxan] and reduced dose CHOP [cyclophosphamide, doxorubicine, vincristine, and prednisolone]] or as used in some centers, rituximab and bendamustine, are not curative and they cause a significant amount of toxicity for other patients, especially those who are already compromised by their disease.

These patients do not have a good treatment options, and by good, I mean with a curative potential, but also that would let them preserve their own quality-of-life that they already have without causing further impairment, potential for loss of independence, nursing home admissions, hospitalizations, taking time away from their life, which is often the last 2 years of their life because diffuse large B-cell lymphoma is a is an aggressive form of cancer that needs to be treated immediately. These patients are often up against the wall making choices about undergoing aggressive therapy, which could shorten their life vs leaving the disease untreated or treated positively.

Mosunetuzumab is a novel agent. It has a curative potential, it causes immune destruction of lymphoma itself, and it's an experimental agent, so we do not know how these promises will play out in future, but it does appear that in studies of relapsed/refractory disease, patients who achieve complete responses, maintain it for a long time with minimal toxicity, mostly related to the cytokine release syndrome and occasional neutropenia, which is often asymptomatic. This was an interesting population where this treatment could be tested as a first-line treatment. There is a natural course of drug development where every drug is given to patients who have relapsed and refractory disease. But in fact, the potential of immune agents may be highest before administration of cytotoxic immunosuppressive therapies and this trial tested this hypothesis. It's interesting that a population of patients who have limited treatment options and that are generally not fit to receive aggressive therapies can provide scientific and biologic information for us to understand how immune therapy can affect diffuse large B-cell lymphoma for people with an immune system that hasn't has been untouched by prior chemotherapy.

It is an interesting experiment biologically, but also, it was a great treatment option for my older patients with diffuse large B-cell lymphoma who presented over the past couple of years and were able to take this opportunity. Most of our patients, even though it's an experimental therapy, we're enthusiastic about it.

What are the findings from the study?

The treatment is quite safe. It was administered as an outpatient for most patients.

It causes CRS, or cytokine release syndrome, in about a quarter of patients, but this is often a low-grade CRS that can be managed with acetaminophen or fewer suppressing agents. Very few patients required hospitalization. Only 1 person required corticosteroids to suppress the CRS, and no patients required intensive care admissions or administration of tocilizumab [Actemra]. It's a safe treatment and many patients did have neutropenia, but it was asymptomatic with only febrile neutropenia. Only 1 of these 54 very elderly patients up to the age of 100 stopped therapy because of treatment-related adverse effects; only 1 in 54.

In terms of the efficacy, it turns out that for many patients who experienced progression early during the first 2, 3 weeks of treatment, these patients moved down to standard treatment, it was available to them without any detriment to their other treatment options. Fifty-six percent of patients achieved the response, and 43% of patients achieved complete response, so 4 out of 10 patients achieved complete response with complete disappearance of lymphoma, typically, after within 3 months of treatment, without any exposure to chemotherapy. These responses are built to be durable. Right now, the median duration of complete response is up to 3 years, and we will find out if these patients ever experienced a relapse. Four out of 23 patients have had a complete response and only 3 experienced relapse.The other 20 are continuing with complete responses.

Out of 54 patients, 20 elderly patients in my practice and other practices from investigators who participated in this trial live without any evidence of lymphoma. Some have passed away from natural causes because it's an elderly population. We have faced challenges related to the COVID pandemic. Mosunetuzumab is a depleting therapy, which can increase the risk of serious COVID complications, but we have learned how to manage it, especially using the prophylactic measures and available treatments. Altogether, a year after starting this therapy, 3 quarters of his patients were alive, and about 38% of patients were alive without any evidence of disease.

Are there any ongoing studies in this space that you are excited to learn more about?

We knew that this was the first experiment in this space and we would like these responses to be even higher without compromising the safety of this treatment because during this time, data accumulated on the combination of mosunetuzumab with polatuzumab vedotin [Polivy], which is the antibody drug conjugate that is generally safe and widely used currently in clinical practice for second- and third-line treatment for other patients with lymphoma. We opened a larger cohort of older patients using similar criteria who received the combination of mosunetuzumab with polatuzumab vedotin. The data from this cohort probably will be available within next year.

REFERENCE:

Olszewski AJ, Avigdor A, Babu S, et al. Mosunetuzumab monotherapy continues to demonstrate promising efficacy and durable complete responses in elderly/unfit patients with previously untreated diffuse large B-cell lymphoma. Blood. 2022;140(1)1778–1780. doi:0.1182/blood-2022-157768