On July 31, 2020, the FDA granted accelerated approval to the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant.1
The approval was granted based on findings from the phase 2 L-MIND trial that assessed the safety and efficacy of the combination of tafasitamab and lenalidomide in patients with relapsed/refractory DLBCL who had received 2 prior lines of therapy, including a CD20-directed therapy, and who are ineligible for high-dose chemotherapy and autologous stem cell transplantation.
In this trial, the trial induced an objective response rate of 60%, with complete responses in 43%. The median duration of response was 21.7 months and 72% had a response lasting at least a year.2
The median progression-free survival (PFS) was 12.1 months with a 50% PFS rate at 1 year and 46% at 18 months. The median overall survival was not reached but 74% were alive at 1 year and 64% at 18 months.
With the observational Re-MIND study, the investigators confirmed the benefit that tafasitamab added to the combination by comparing real-world responses with lenalidomide alone to those in the L-MIND trial. Patients who received lenalidomide alone comparatively had an objective response rate of 34.2% with complete responses in 13.2%. The median PFS was 4.0 months with the monotherapy and the median overall survival was 9.4 months.3
I think its great news for patients with lymphoma and we hope we can offer this form of therapy to them soon and I think this is real progress in the field, Gilles Salles, MD, PhD, told Targeted Oncology about his perspective on the recent approval.
In an interview with Targeted Oncology, Salles, who is professor at the University of Lyon and chair of the Department of Hematology at Centre Hospitalier Lyon-Sud in France, and who will soon be moving to Memorial Sloan Kettering Cancer Center in New York as chief of the Lymphoma Service, explained the unmet needs in DLBCL that may be filled by this new option in the treatment armamentarium and the findings that led to the approval of the combination.
Targeted Oncology: Could you describe the unmet needs in DLBCL that led to the investigation of this combination?
Salles: So DLBCL is the most frequent lymphoma entity. Now more than 30,000 patients are affected [with DLBCL] each [year in the United States].
For patients that are younger and without comorbidities, salvage chemotherapy followed by a stem cell transplant is a standard of care. However, about half of the patients do not respond to salvage chemotherapy. And even after autologous transplant, half of the patients will relapse. And for the other patients that are not transplant eligible, we usually use palliative chemotherapy such as rituximab (Rituxan) and bendamustine or other rituximab and cytotoxicbased regimen. And if those patients fail this salvage regimen, we usually cant go on too long with other regimens, since we are hampered by the cytotoxicity of these different regimens. So there is a real need to improve the outcome of patients that have failed the first line of therapy in DLBCL.
Obviously in the field we have seen CAR T-cell therapy emerging in the recent years. And this has been a major progress, but its a progress that is also hampered by the difficulty of accessing CAR therapy, you need to have this treatment in specialized centers, a significant amount of grade 3/4 adverse effects that are specific to CAR T-cell therapycytokine release syndromes, neurological events, and cytopenias may occur. And it’s also not necessarily a treatment for which all patients can be eligible because for patients with a rapidly growing disease there is a waiting time to get the CAR T reinfused and some patients cannot [wait through the manufacturing process]. So, there are clearly some unmet needs.
We have seen polatuzumab vedotin (Polivy), which can be combined with bendamustine and rituximab, and was approved recently and selinexor (Xpovio) also recently [was approved], but they don’t necessarily fulfill the whole unmet need in the field.
Could you give some background on the mechanism of action for tafasitamab and why this combination was explored in this setting?
So, tafasitamab is a CD19 fFc-enhanced monoclonal antibody that will mobilize the effector cells such as NK cells and macrophages and enhance their cytotoxic activity against tumor cells. As a single agent, it has demonstrated safety and modest efficacy, but there was a rationale based on this mechanism of action to combine it with lenalidomide, which has been shown previously to enhance the NK activity and in vitro studies have demonstrated the potential of this combination.
The L-MIND study was a study evaluating [this combination] in patients with relapsed/refractory DLBCL that were non-transplant eligible. The combination of lenalidomide administered in 21 out of 28-day cycles, with tafasitamab injected, initially weekly, and then every 2 weeks. This combination period lasted one year then tafasitamab alone was then administered every 2 weeks in patients that benefited from this combination.
What did the L-MIND study show?
The main results of the studies that have been published recently in Lancet Oncology had shown that there was a response rate of around 60%. So, the majority of patients responded to this form of combination, and 43% of the patients achieved a complete response, which was usually rapidly achieved at the time of the third cycle of therapy. What was really meaningful is the duration of response, which has been reported recently is in the range of 21 months, which is remarkable for this kind of therapy in this population of patients.
The adverse events after receiving this treatment were essentially hematologic, a few rashes, a few gastrointestinal symptomswhich are usual when you administer lenalidomide to patients. We had about 50% of the patients experiencing grades 3/4 neutropenia, about 20% experiencing thrombocytopenia, and a few other adverse events and they were manageable for the majority of patients. Furthermore, while this event occurs essentially during the first year of the treatment for those responders that continued on tafasitamab alone, there were very few events that were observed in these patients showing that the majority of these events were really linked to the administration of lenalidomide.
The patients in the study had a prolonged overall survival also, demonstrating that there was a benefit for this population. So it’s an interesting combination, which is a chemotherapy-free combination that can be used in those patients that are non-transplant eligible, according to the approval label, and are already at their first failure after R-CHOP, and obviously at later lines if needed.
How did the observational Re-MIND study contribute to the findings for the benefit achieved by the combination in this setting?
The Re-MIND study was a comparison of observational data regarding the use of lenalidomide as a single agent in the same populations as the L-MIND study. A comparison was made then between the patients recruited in the trial and the patients that received lenalidomide in real life. And what the Re-MIND study has shown was that clearly, there was an increase over response rates, CR rates, and PFS for those patients that received the combination, clearly showing that tafasitamab was adding a potential therapeutic benefit compared to those patients that received lenalidomide alone, further confirming the synergy of the combination.
What are some of the safety concerns that you’ve seen with this combination? And how can these adverse events be managed?
The adverse events that we see are essentially hematologic with about 50% of patients experiencing a grade 3 or 4 neutropenia, and about 20%, thrombocytopenia. Most of them are reversible and we have recently updated the trial showing that the frequency of neutropenia during the first year of treatment is around 1.1 per patient year, and the frequency of thrombocytopenia is about 0.2 per patient year.4 It’s events that we know how to manage and in most cases, they don’t require hospitalization, they don’t require transfusion. This is clearly an ambulatory treatment. The other adverse effects are those relating to lenalidomidea few rashes, gastrointestinal symptoms, but nothing that we can’t manage easily in these patients. Obviously, I will say that this regimen is well tolerated. There are very few febrile neutropenias, a few infections. And I think it’s a regimen that is particularly suitable for those patients that are non-transplant eligible.
Given the safety profile of this combination of tafasitamab plus lenalidomide, this regimen is particularly suitable for a large proportion of patients with DLBCL. We do know that the median age of occurrence of DLBCL is in the late 60s and there are many, many patients that are over 70 and that are not usually transplant eligible. Clearly this is a great opportunity for patients to receive this non cytotoxic regimen.
What is your perspective of how this combination will fit into the overall treatment paradigm for relapsed/refractory DLBCL, and what do you think is the overall impact of this approval?
I think it will be a new treatment option for patients with non-transplant eligible DLBCL and those patients could be offered to receive this regimen either at first relapse after R-CHOP or if they fail the first salvage conventional chemo. This treatment then can be proposed to many patients. And there are also those patients that were transplant eligible but will fail to respond to salvage therapy or those who relapse after transplant and then became eligible to receive this combination.
So, I am confident there is a large proportion of patients that can benefit from this option. And I see it as one of the major options in the relapsed/refractory setting for those patients who are not designated to go down the path of transplant or who have failed this path. And I think this is important.
What is unknown at this time is how this regimen will be combined or how it will sequence with CAR T programs. We have no experience, or very limited experience, of patients receiving this regimen before CAR T. But there is anecdotal evidence that this can be achieved. So, whether it can be used or bridging or not, I think we have insufficient data and because it targets the same antigen at CAR T, which is CD19 there clearly should be some precaution in order to use this regimen before CAR T. But, we need to have more data in this field. For those patients that had failed CAR T-cell therapy, substantial proportions, about 30% of them, may have lost CD19 expression and then may not be eligible anymore for this regimen. There is, however, a substantial proportion of patients that retains CD19 and in whom tafasitamab/lenalidomide can be used as a treatment option.
So, I believe it will be one of the regimens that will be rapidly used by many physicians and proposed to patients as one of the options that we have in this setting.
1. FDA Approves Monjuvi (tafasitamab-cxix) in Combination With Lenalidomide for the Treatment of Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL). News release. MorphoSys AG and Incyte. July 31, 2020. Accessed August 7, 2020. https://bit.ly/3fgyqZZ
2. Salles G, Duell J, Barca EG, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4
3. Zinzani PL, Rodgers T, Marino D, et al. RE-MIND study: Comparison of tafasitamab + lenalidomide (L-MIND) vs lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma. Presented at: European Hematology Association Virtual Congress; June 11-21, 2020. Abstract S238.
4. Salles G, Duell J, Gonzlez-Barca E, et al. Long-term outcomes from the phase II L-MIND study of Tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: European Hematology Association Virtual Congress; June 11-21, 2020. Abstract EP1201.