In this video interview, Manali Kamdar, MD, Clinical Director of Lymphoma Services, University of Colorado Cancer Center, summarized her presentation from the 2023 ASCO Annual Meeting titled “Therapeutic options for patients with primary refractory/early relapse of diffuse large B-cell lymphoma.”

Transcript:

Manali Kamdar, MD: My name's Manali Kamdar. I'm an associate professor of medicine within the division of hematology and bone marrow transplantation at the University of Colorado Cancer Center. I'm going to go through some of the therapeutic options for patients with primary refractory and early relapsed diffuse large B-cell lymphoma. As the audience here very well knows, that auto transplant was the standard of care based on the PARMA study, which was a study done in the pre-rituxan era, comparing conventional treatment, salvage treatment, versus transplantation in relapse transplant-eligible diffuse large B-cell lymphoma. And this study showed that auto transplantation was significantly superior compared to just salvage chemotherapy with regards to event-free survival as well as overall survival. And thus, auto transplant became the standard of care for second-line chemosensitive, relapsed aggressive, B-cell non-Hodgkin lymphoma. Now, auto transplant has about a potential to cure 40% of patients based on this study, but as you can imagine, 60% of patients will either not respond to salvage chemo or will relapse after an auto transplant.

And this unmet need was fulfilled by chimeric antigen receptor T-cell therapies, also called CAR T-cell therapies. And the FDA-approved CAR T-cell therapies for patients with relapsed refractory large B-cell lymphoma in the third-line setting based on pivotal phase II studies, namely ZUMA-1, TRANSCEND, and JULIET. And these studies explored constructs directed against CD-19, called axi-cel or axicabtagene ciloleucel, liso-cel or lisocabtagene maraleucel, or tisagenlecleucel  also called tisa-cel. Important to also figure out in terms of the long-term follow-up of these studies, which we now have, based on the ZUMA-1 as well as the JULIET studies, that the five-year overall survival is now anywhere between 30 to 40%, which means that 40% of patients who would've otherwise succumbed to their disease now can be salvaged and potentially cured by CAR T-cell therapy in the third-line setting.

So way back in 2021, the algorithm for relapsed/refractory diffuse large B-cell lymphoma for transplant-eligible patients would be salvage chemotherapy, and if patients identified chemosensitivity, they were taken to an auto transplant. On the other hand, if they did not demonstrate chemosensitivity or if they relapsed after an auto transplant, they were then taken to CAR T-cell therapy.

However, we also know that not all relapses are created equal. So not all patients who go through auto transplant, the 40% of patients who can get cured, are not primarily considered the same. And we know that based on the CORAL study, wherein patients who relapsed within a year of receiving initial chemoimmunotherapy, if they received previous rituximab, their survival was very, very poor. We also know based on a meta-analysis by Crump and colleagues, called a SCHOLAR-1 analysis, that patients who relapsed within the first one year off chemoimmunotherapy or auto transplant or primary refractory, their overall survival was less than six months.

There are also certain unique subtypes of diffuse large B-cell lymphoma, that if these subtypes even demonstrate chemosensitivity and are taken to an auto transplant, they actually historically have poor outcomes. And these subtypes were relapsed/refractory double hit lymphoma. This was demonstrated in a multicenter retrospective study led by Alex Herrera and colleagues, that even if these patients did show chemosensitivity, if they did harbor double hit lymphoma relapse, the four-year overall survival was only 25%. There was another retrospective multicenter study that was led by Luciano Costa and colleagues called the refined analysis that looked at certain risk factors, and if patients had those then their survival after an auto transplant, even if they then did demonstrate chemosensitivity, was very poor. And the REFINE study basically identified a risk set called the ultra-high risk diffuse large B-cell lymphoma, meaning patients who harbored MYC rearrangements, or primary progression of disease, or patients who had an interim or high-risk NCCN-IPI. If they had all three risk factors, then their two-year overall survival was 11%.

So clearly, this was the unmet need, which was primary refractory disease of patients who relapsed within one year of receiving upfront R-chemoimmunotherapy, because in these patients, even if they did have chemosensitivity, their survival post auto transplant has been historically poor, and thus was born the three randomized trials of CAR T-cell therapy versus salvage chemotherapy, followed by an auto, inpatients who are transplant-eligible diffuse large B-cell lymphoma with early relapse of primary refractory disease. These three studies were ZUMA-7, comparing axi-cel versus standard of care, TRANSFORM comparing liso-cel versus standard of care, and BELINDA, comparing tisa-cel versus standard of care. All of these three studies had the primary endpoint as event-free survival. The net is that BELINDA was a negative study, which means standard of care was equivalent to tisa-cel.

On the other hand, ZUMA-7 and TRANSFORM were positive studies. The primary endpoint of event-free survival was met, and the event-free survival was statistically significant and superior on the CAR T-cell therapy arm versus the auto transplant arm. In fact, a later follow-up that was presented at ASCO by Dr  Weston and colleagues showed that on the ZUMA-7 study, axi-cel also showed overall survival benefit. Based on the positive studies, the FDA approved axi-cel and liso-cel as now the new standard of care for patients who relapse which are primary refractory or relapse within the first year after receiving rituximab plus chemoimmunotherapy. So this is clearly the new standard of care for transplant-eligible patients. It's also important to identify that patient-reported outcome studies and cost-effectiveness analysis was also conducted, and it does appear that PROs, and proven that PROs, are much more clinically meaningful, and it did improve quality of life for patients who received CAR T-cell therapy versus auto transplant.

With regards to cost-effectiveness analysis, based on some of the studies that we have, we do know that CAR T-cell therapy appears more cost-effective as compared to auto transplant, and the costs were higher on the CAR T-cell therapy initially. But, however, for patients on the standard of care arm because they relapsed more, the subsequent treatment cost basically negated it as a result. Eventually the incremental cost-effectiveness ratio was somewhere around 66,000 quality of adjusted life years. So in terms of transplant-eligible patients who are primary refractory and early relapse, now being CAR T-cell therapy as the standard, it definitely asks the question: what for patients who are transplant ineligible? And as you know, most of our patients who do relapse after rituximab plus chemotherapy are either older or they're transplant-ineligible because of comorbidities. And this is where the PILOT study came into play, which is a phase II open label pivotal study, with the primary endpoint of overall response rate.

Seventy-four patients were enrolled in this study; 61 received liso-cel. And the goal of this study was to test liso-cel in the second-line study for auto transplant-ineligible patients. Of these 54% of patients were primary refractory, and patients who had relapsed within the first one year, 21% made up for that set and 33% of these patients had double hit lymphoma. And this study was a positive study. The primary endpoint of overall response rate was about 80% with a complete response rate of more than 50%. And it's important to identify that the overall survival for this study was not reached, and in patients who had a complete response, it was not reached. And based on the positive outcome of the PILOT study in 2022, FDA approved liso-cel after one line of chemoimmunotherapy in transplant-ineligible patients. So now, CAR T-cell therapy is the new standard of care for patients who are transplant-eligible with primary refractory and early relapsed DLBCL.

It is also now one of the standards of care in the second-line setting for patients who are transplant-ineligible and have relapsed diffused large B-cell lymphoma. So the big question then is: is this CAR T for all? And the answer is no, because there are patients who may not be eligible for CAR T-cell therapy, and that could be because of the burden of tumor, where, as a result of the burden of disease, manufacturing delays may impede the ability to take these patients to CAR T.

Lack of predictive factors to anticipate efficacy or toxicity is another barrier. But besides that, the most important barrier would be surrounded around logistics and financial toxicity. Logistics such as referral to an academic CAR T-cell therapy center, insurance approval, caregiver needs, access. We clearly are aware of the rural versus urban discord. We are aware of the racial disparity, and I think these are the factors that may make patients CAR T-cell therapy ineligible.

So, what for these patients if they have primary refractory or early relapse disease? And I think there are some options that are available for these patients in the second-line setting, and this was tested in what we call the phase II L-MIND trial, which tested tafasitamab, which is an anti-CD19 antibody in combination with lenalidomide. The primary endpoint was overall response rate. Only 18% of patients had primary refractory disease. The majority had relapsed, but at median follow-up of 13.2 months, the overall response rate was around 57%, the CR rate was 43%. And most interestingly, for patients who achieved a complete response, the median PFS and the median overall survival was not reached. The safety profile was very manageable, with most common adverse events being neutropenia thrombocytopenia, about 12% of patients had febrile neutropenia. Based on the positive outcomes of this study, the FDA has approved tafasitamab and lenalidomide for patients with relapsed refractory diffuse large B-cell lymphoma who are not eligible for an auto transplant after failure of one line of treatment.

Of course, there are other options that we could consider for patients who are CAR T-cell therapy ineligible. For example, polatuzumab plus bendamustine rituximab. We could use salvage chemos, such as are R-GemOx, but as we all know, the median PFS is only five months, so we need something better. Loncastuximab is a CD-19 antibody drug conjugate, and loncastuximab is now FDA-approved in the third-line setting. So it's not available in the second-line setting, but sometimes for patients who don't have any other options, that could be one of the strategies. Overall response rate with single agent lonca in a heavily pretreated population was 48% and a CR rate of 24%.

The median PFS at a short follow up was 4.9 months. At the median, overall survival was about 10 months. The bigger question at this point is about the new drug approvals that have come way in 2023, with the bispecific T-cell engagers targeting CD-20. We call them BITEs. And there are two BITEs that are now FDA approved in third-line setting. One is epcoritamab and the second one is glofitamab. Epcoritamab is given sub-Q and it's given until progression, whereas glofitamab is given with obinutuzumab for the first cycle to mitigate cytokine release syndrome. It's given IV. But the biggest advantage, as I see it, with glofitamab is that it's only given for 12 cycles. So it's a time-limited treatment. Both of these agents are extremely efficacious. Their overall response rate is upwards of 60%, complete response rate of about 39%. And most interestingly, patients who have failed CAR T-cell therapy, they did demonstrate efficacy in patients who received BITEs later.

In the glofitamab study, interestingly and importantly, 78% of the complete responders continue to be in a complete response without treatment after 12 cycles of glofitamab. And the one-year progression-free survival for both of these agents is somewhere around 40%. So clearly these are the drugs that are now FDA approved in the third-line setting and could be considered for patients who are CAR T ineligible.

So overall, I do believe that the algorithm for patients who have primary refractory and early relapsed diffuse large B-cell lymphoma has undergone a sea change since the approvals of some great novel agents, which have shown efficacy as well as less toxicity. The top contenders, in my mind, would be CAR T-cell therapy based on the key data that I talked about. Bi-specific T-cell engagers are certainly off-the-shelf products approved now in the third-line setting. They're being currently investigated in the earlier lines of treatment. At the end of the day, I do believe that shared decision making is the key to a successful patient outcome.

So with that, I come to the end of this talk. Thank you very much for your patient listening.