Tafasitamab: Final Results of Five-Year Safety and Efficacy Study (Phase II L-MIND) Prof. Kalakonda

Tafasitamab: Final Results of Five-Year Safety and Efficacy Study (Phase II L-MIND) Prof. Kalakonda

By Professor Nagesh Kalakonda

Thank you for this opportunity to talk about the L-MIND study. The study itself was initiated in 2016 and targeted relapsed refractory patients with diffuse large B-cell lymphoma. It was an open-label phase 2 study conducted in 10 countries and at 39 sites. The study was specifically targeted towards patients who were not eligible for an autologous stem cell transplantation, either with one previous line of therapy or multiple previous lines of therapy. This represents a population with an unmet need and where there is no standard of care. When the study was first initiated in 2016, there was a clear gap in clinical practice for physicians and patients, making it a timely study. The study ran for 5 years, including the follow-up phases.

 

What were the primary and secondary endpoints of the study, and how were they measured?

So, I think the primary endpoint, as with other studies in this space, was overall response rate to the treatment. This response rate was judged by an independent review committee, so it wasn’t left to the sites to decide, making it fairly tight in terms of examining outcomes for the study. Secondary endpoints included progression-free survival, duration of response, overall survival, and, of course, safety. Since this was a phase 2 study involving a novel combination of a CD19 targeted antibody (Tafasitamab) with Lenalidomide, safety was a critical secondary endpoint during the course of the study.

 

The ORR reported in the final 5-year analysis was 57.5%. How does this compare to previous analyses? 

So, I think this was the most telling outcome of the study: it had an excellent overall response rate at the 1-year analysis. The overall response rate was 60%, and at the 3-year analysis, which have both been published, it was again 57.5%. The 5-year analysis actually maintained that overall response rate at 57.5%.

 

So, it’s an excellent outcome for the study. I should have pointed out earlier that the study recruited 81 patients in total, and 80 patients were eligible for the analysis. It clearly shows that the combination is very effective in a very difficult-to-treat population. Additionally, the complete remission rates at the primary analysis at 1 year were 43%, but as was maintained at 41% at the 3-year analysis. This was sustained again at the final 5-year analysis, which was presented at the AACR meeting last weekend.

 

The median duration was not reached after a median follow-up of 44 months. What implications does this have for the long-term efficacy of tafasitamab, and how might it impact clinical practice?

I think it just shows that this is a very viable treatment option for patients, as I pointed out earlier, who have relapsed or recurrent diffuse large B-cell lymphoma. The fact that the median duration of response is not being reached even after 5 years suggests that at least a subset of patients are probably cured by this combination and derive long-term benefits. So, overall, I think the results are very positive.

 

The incidence of adverse events (AEs) declined after the transition from combination therapy to tafasitamab monotherapy and again after more than 2 years of monotherapy. Can you explain why this might have occurred, and what implications it has for patient safety? 

I think this again because this was a novel combination of the CD19 monoclonal antibody, which is Tafasitamab. And you have to remember that this is an engineered NFC-enhanced antibody that has never been combined with Lenalidomide in the past. But in this study, clearly, the adverse event profile was higher, as would be expected with the first-year combination treatment.

 

But patients then progressed to monotherapy after 12 months, and I think it was important to note that during the monotherapy phase, for 12 months on and beyond, there were very few adverse events. In fact, the adverse event profile was significantly improved.

 

So it suggests that, yes, there are challenges with the combination, which may have led to some dose reductions and the majority of adverse events could probably be linked to Lenalidomide. But the investigational drug, which is the CD19 antibody, is clearly very well tolerated, with very few short or long-term adverse events and no safety concerns.

 

What were the exploratory analyses of efficacy endpoints by prior lines of therapy (pLoT), and what do they suggest about the effectiveness of tafasitamab in different patient populations?

So, I think the analysis was performed to see if there was a difference in the overall response rates and, in fact, the complete remission rates based on how many prior lines of therapy patients had experienced. I think there was a clear difference, and again, understandably, the outcomes were better in patients who had only had one prior line of therapy compared to those who had had 2 or more prior lines of therapy.

That’s understandable, so I think it suggests that the combination, if one was considering it for patients, should be used early on in their patient journey rather than waiting until they have had more than 2 lines of treatment. Now, some exploratory analysis was done to see if there were other factors that influenced remission rates.

 

One of the most impressive was that they looked at NK cell counts in patients at baseline, as it was hypothesized that NK cells would be critical for responses. It suggests that anyone with an NK cell count of less than a hundred cells per microliter didn’t do as well as those who had a good NK cell count at baseline.

 

So, I think that’s an interesting observation in the exploratory analysis. And again, there may be other exploratory analyses going on that may give us a bit more insight into which patients benefit. There’s clearly a subset of patients who benefit much more, and I think our challenge is to identify who is most likely to benefit from this combination because not all patients do well.

 

Can you discuss any limitations or challenges? 

I guess this was directed towards the treatment itself, which was directed to patients who undergo autologous stem cell transplant. So it excludes patients who do not meet that criterion. Another challenge to point out is that it is not being tested in other sets of patients.

 

It would be interesting to see whether this combination still has efficacy in a wider group of patients. Therefore, I suppose that is one of the limitations of the study because the eligibility criteria were fairly strict, and only targeted a subset of patients. Additionally, just listening to my colleagues and various other people who have also seen this data, it is not very clear whether in the patients who do well, one can stop Tafasitamab monotherapy because some of these patients may be cured. The trial itself, the way it was designed, required patients to continue on Tafasitamab until the end of the study, as long as they maintained their response.

 

The question, I suppose, can be challenging in clinical practice because patients have to come back every two weeks to receive an infusion. At present, it is unclear whether one can stop the monotherapy after a period of time. Newer efficient technologies, such as ctDNA, may help us in this regard to determine whether one can stop the treatment without any potential future recurrence in that cohort of patients.

 

Therefore, I think that could be seen as potentially difficult, especially for this group of patients, to keep coming back to the hospital every two weeks to have these infusions.

 

What do the final 5-year results of the L-MIND study suggest about the potential to offer curative benefits to patients with R/R DLBCL ineligible for ASCT?

I think the trial clearly shows that this is a definite option that should be considered for this group of patients. Not surprisingly, the study itself gained FDA approval and market authorization from the European Medical Agency as well. This attests to the efficacy and safety of this novel combination in a group of patients who are very difficult to treat, giving physicians another therapy option. It will be of interest to physicians who treat patients with relapsed refractory DLBCL (diffuse large B-cell lymphoma), and there are multiple ongoing studies. Currently, there is a study called Frontline, which is trying to move Tafasitamab to improve outcomes in newly diagnosed patients. Additionally, efforts are being made to see whether there are any synergies that can be gained from combining it with other treatment options in the second line and beyond.

 

Are there any plans to conduct further studies, and if so, what research questions will they aim to address?

I am aware of multiple studies that are ongoing around the world, trying to combine it with other treatments that also have potential activity for this group of patients to try and improve their outcomes. The outcomes for relapse refractory DLBCL (diffuse large B-cell lymphoma) have remained poor for a very long time.

 

Just to add, I think the drug has probably been used in post-CAR T settings because CAR T therapy was established after this study was initiated. So, there are groups of patients who do progress after CAR T, and again, there seems to be evidence to suggest that this combination, with Tafasitamab, can be an option for those patients as well.

 

What are the key takeaways from the L-MIND study for clinicians and patients, and how might they inform treatment decisions going forward?

I think the data clearly shows that this is a very well-tolerated combination, and it also has clear activity in a group of patients with relapse-refractory diffuse large B-cell lymphoma. For a space in which there are limited options, it addresses the needs of patients who are specifically ineligible for an autologous stem cell transplant.

 

So, I think it will clearly gain attention from physicians and patients alike, and hopefully, it will give us more evidence as to which group of patients might benefit the most when people start using it in the real-world setting.

 

Final Thoughts About the L-MIND Clinical Trail?

Just to say, I think I’m following the presentation at the Clinical Trials Plenary at AACR. I am aware that there is a manuscript that’s going to be submitted in due course and probably has a lot more detail that may be of interest to clinicians in the field and also to patients. I would certainly suggest that folks look out for the presentation when and if it’s finally published.

 

What is Tafasitamab?

Tafasitamab is a type of medication known as a monoclonal antibody that is used to treat certain types of cancer. Specifically, it is used to treat a type of cancer known as diffuse large B-cell lymphoma (DLBCL).

DLBCL (diffuse large B-cell lymphoma) is a type of cancer that affects a type of white blood cell called B cells. Tafasitamab works by targeting and binding to a protein on the surface of these cancerous B cells known as CD19. This binding helps to activate the immune system to attack and destroy the cancerous cells (B-cell lymphoma cells).

Tafasitamab is administered through intravenous infusion, which means it is given directly into the bloodstream through a vein. The dosage and duration of treatment will depend on various factors, such as the individual’s age, overall health, and the severity of their cancer.

Clinical trials have shown that tafasitamab can be effective in treating DLBCL, either alone or in combination with other chemotherapy drugs. It has been approved for use in the United States and Europe, and is considered a promising option for patients with this type of cancer.

As with any medication, there can be side effects associated with tafasitamab. Common side effects include fever, chills, nausea, and fatigue. However, more serious side effects can also occur, and patients should speak with their healthcare provider about any concerns or questions they may have about their treatment with this medication.

 

10 Key Takeaways from the L-MIND Clinical Trial In Relapsed or Refractory DLBCL

The L-MIND clinical trial is a study focused on the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), a type of cancer that affects white blood cells called lymphocytes. The study was designed to evaluate the safety and effectiveness of a combination therapy involving two drugs, lenalidomide and tafasitamab.

1. The combination therapy of lenalidomide and tafasitamab demonstrated significant efficacy in treating relapsed or refractory DLBCL patients.

2. The overall response rate (ORR) in patients treated with lenalidomide and tafasitamab was 60%, with 43% of patients achieving a complete response (CR).

3. The median progression-free survival (PFS) was 12.1 months, indicating that patients treated with lenalidomide and tafasitamab had a longer period of time before their disease progressed compared to patients treated with other therapies.

4. The combination therapy was generally well-tolerated, with few serious adverse events reported.

5. The most common adverse events were neutropenia, thrombocytopenia, and anemia.

6. The study included patients who had received multiple prior therapies, including stem cell transplant, and demonstrated efficacy in this population.

7. The combination therapy showed consistent efficacy across multiple subgroups of patients, including those with high-risk disease.

8. The L-MIND trial provides evidence supporting the use of lenalidomide and tafasitamab as a viable treatment option for relapsed or refractory DLBCL.

9. The study findings were consistent with the results of a previous phase 1/2 study, which evaluated the safety and efficacy of the combination therapy in patients with relapsed or refractory DLBCL.

10. The results of the L-MIND trial have led to the approval of lenalidomide and tafasitamab by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory DLBCL.

 

Professor Nagesh Kalakonda, MBBS, MRCP, FRCPath, PhD – About The Author, Credentials, and Affiliations

Professor Nagesh Kalakonda is a highly accomplished medical professional with extensive training and expertise in the field of haemato-oncology. Having earned an MBBS degree in India, he trained in haematology in the UK and gained membership of the Royal College of Physicians (MRCP) and a fellowship of the Royal College of Pathologists (FRCPath).

He also holds a PhD in Oncology from the University of Manchester in the UK. He is currently a valued faculty member (Chair of Experimental Haematology) at the University of Liverpool and haemato-oncologist at the Clatterbridge Cancer Centre in Liverpool, UK. Professor Kalakonda’s research interests lie in the areas of hemato-oncology and cancer epigenetics, and he has published numerous articles in reputable scientific journals.

Throughout his career, Professor Kalakonda has earned recognition and accolades for his contributions to the medical field. He is widely respected as an expert in his field, and his work has helped to advance our understanding of blood disorders and improve patient care.