ADCs for Relapsed/Refractory DLBCL: Next Steps

Tycel Jovelle Phillips, MD: A fair number of the antibody-drug conjugates are being combined with other standard chemotherapy options of some novel agents to see if we can improve upon the efficacies of these patients. Especially with loncastuximab, there’s an ongoing combination study combining that with ibrutinib in patients with relapsed/refractory large-cell lymphoma and mantle cell lymphoma. There are several studies looking at utilizing polatuzumab in combination with standard chemotherapy, other than bendamustine and rituximab, based on the fact that bendamustine and rituximab isn’t normally utilized in patients with relapsed/refractory large-cell lymphoma for most US academic practices. It will be interesting to see if we get an improvement, or if the toxicity profile is any different with combinations like GEMOX [gemcitabine in combination with oxaliplatin].

Other studies are trying to add on to this. For example, Selinexor had a study where they were trying to combine Selinexor with some of the agents that are approved—polatuzumab, lenalidomide and tafasitamab. There is also an upcoming study from BMS [Bristol Myers Squibb] Celgene that is looking to add a novel oral agent to these antibody-drug conjugates, or even tafasitamab, given the recent FDA approval. Thus, combinations are what we will explore in detail next to try to pull out and see if there are any improvements we can make in this patient population, especially in patients who are failures of CAR T [chimeric antigen receptor T-cell therapy] or who are ineligible for CAR T and have primary refractory disease. That is something we’ll look forward to.

The upcoming phase 3 study will look to cover what we touched on earlier as far as evaluation of loncastuximab in the phase 2 setting, comparing it to a standard agent of R-GEMOX [rituximab plus gemcitabine and oxaliplatin]. I’ll be curious to see what that data pulls out, and the breakdown between the response rates in those who are primary refractory, who you would anticipate to have a poor response to R-GEMOX. How that looks with loncastuximab plus rituximab, versus those who are what we would consider relapsed, I’d be curious to see if there’s any difference in the outcomes between those two arms. The fact that they’re including patients with transformed disease and patients with double-hit lymphoma will give us a better readout of whether loncastuximab is better in these higher-risk patient populations. The double-hits, depending on when they transform, especially if they’ve seen chemotherapy before the transformation, are also considered difficult to treat. Additionally, double-hit lymphomas, if in a relapsed/refractory setting, are overall difficult to treat. Thus, we’ll get a true assessment of where loncastuximab fits in a second-line setting, and compared to what we have on len-tafa [tafasitamab plus lenalidomide], the planned patient enrollment is more difficult to treat because they include primary refractory patients. I’ll be interested to see this study readout and whether it is a benefit, and whether we can move this treatment into the second-line setting versus where it is right now.

We have a plethora of options now. The FDA has recently approved more agents for large-cell lymphoma than we’ve had in a long time. While that does give options, it also makes it difficult to choose which option is best for certain patients in certain situations. Patient fitness and where they are in the treatment course should drive where you want to go and direct what agents you use. Also, tolerance-wise, if you have an elderly patient with relapsed/refractory disease and you’re concerned about toxicity, lenalidomide-tafasitamab is a better option given the tolerability of that regimen compared to some of the others. Loncastuximab can be considered, but you must be cognizant of the cardiovascular situation of the patient. I wouldn’t use that agent in a patient who had poorly controlled heart failure, or anything of that nature, where fluid shifts are common.

For primary refractory patients, loncastuximab and pola-BR [polatuzumab vedotin in combination with bendamustine and rituximab] are probably better options. Pola-BR may be harder to tolerate than loncastuximab, but both would be efficacious. Again, the role for Selinexor is in a patient who you’ve exhausted all options.

Moving forward, the bispecific [antibodies] and some of these combination studies will be helpful for us and hopefully continue to improve outcomes we have in this patient population. There's been a big shift in the patients we’ve been able to save and cure with CAR T. Hopefully, with some of the augmentation we’ll have with some of these newer agents, we’ll be able to capture and save more of these patients, and we’ll have less of these patients who eventually succumb and die from diffuse large B-cell lymphoma [DLBCL].

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