Leo Gordon, MD: First-line treatment in diffuse large B-cell [lymphoma]: First of all, chemotherapy is potentially curative in the majority of patients with DLBCL. There have been a number of decades-long comparisons of different chemotherapy regimens. I remember we looked at a combination of, before Rituxan [rituximab], CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], compared with what was popular at the time in the early 1990s. We did a roughly 400-patient randomized study comparing CHOP with MB-CART that showed more toxicity with CHOP, no improvement in outcome. There have been many, many studies comparing CHOP and R-CHOP [Rituxan-CHOP] with other chemotherapy regimens, and I think it still remains the standard. More recently there are 2 studies that I think were important. One is the PHOENIX trial, which looked at the addition of the BTK inhibitor ibrutinib to patients with diffuse large B-cell lymphoma, [randomly assigned] to receive or not receive ibrutinib. While there wasn’t a striking difference between the 2 arms, there might have been some subgroup differences suggesting [that] younger patients [and] women did a little better with the burden of it.

One of the problems we have with clinical trials is [that] when we have subgroups of patients, but they’re kind of diluted when you put them all together in a large clinical trial,…you may miss important clinical observations that apply to certain subgroups. That happened with the PHOENIX trial, and also more recently, the addition of polatuzumab, the substitution of polatuzumab for vincristine, showed a slightly improved progression-free survival advantage to polatuzumab, which is an anti-CD79 antibody-drug conjugate, but no difference in survival. When you look at subgroups, recent data suggests that patients with nongerminal center-type diffuse large B-cell lymphoma had 3 to 4 times improvement in outcome in progression-free survival compared to standard R-CHOP. So I would say the standard first line is either R-CHOP, R-polatuzumab [Rituxan plus polatuzumab], CHP [cyclophosphamide, doxorubicin, and prednisone], [and] R-EPOCH [Rituxan plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin]. We have not included ibrutinib as part of the guidelines, but maybe we should rethink that at some point. I’m sure we’ll be discussing that.

For patients achieving remission, most patients, if their remission lasts for 2 years, the majority, not all of them, are probably cured. There are some late relapses, but most of the relapses happen in the first 2 years. Second-line treatment has for decades been a combination of a second regimen, [a] chemotherapy regimen, either rituximab-ICE [ifosfamide, carboplatin, etoposide], or gemcitabine and oxaliplatin, or a regimen called DHAP [dexamethasone ara-C and cisplatin]. There are a host of second-line regimens, and those are given for 2 or 3 cycles. Then people get an autologous stem cell transplant, and that’s been the standard of care. What we’ve noticed is that during the Rituxan era, which dates to the early ’90s until now, the results of transplant really haven’t been as good as they were pre-Rituxan. The reason for that, I think, is because you’ve selected out [the] patients who are resistant even to Rituxan, and they’re not going to do as well with the second-line bone marrow transplant. The main observation during this time was that [for] people who relapsed early, like within a year, or never achieve remission and then go to transplant, the outcome is very poor. Maybe 10%, 15% of patients have long-term good outcome or long-term survival. So, during this time, [new treatments were developed] for patients in the third, fourth and fifth lines, and that was the development of immunotherapy, specifically T-cell therapy, or CAR T [chimeric antigen receptor T-cell] therapy. And based on the TRANSCEND study with liso-cel [lisocabtagene maraleucel], and the ZUMA-1 study with axi-cel [axicabtagene ciloleucel], that became a standard of care for patients with the third- and fourth-line large-cell lymphoma. The question became, and this happens in oncology all the time, when there’s a good third- or fourth-line treatment, should you move it up to second line and, ultimately, should you move it up to first line? So for patients in the second line who relapsed early within a year or never achieved remission, there were 3 randomized studies that looked at standard of care, which is stem cell transplant preceded by 2 cycles of ICE or any one of a number of regimens, and then randomized to go ahead to transplant or go right to CAR T therapy. There were 3 studies that looked at that. Two of the 3 showed a statistically significant improvement in progression-free survival, and 1 already showed now overall survival improvement using CAR T therapy. Those studies were the ZUMA-7 study, which we participated in. [The ZUMA-7 study] looked at axi-cel and now compared with standard of care [transplant], and that showed progression-free survival; the more recent manuscript both published in the New England Journal [of Medicine] showed a survival advantage.

The other was the TRANSFORM study using liso-cel, again, showing a statistically significant improvement in progression-free survival, and we are waiting to see about improvement in overall survival. I think we’ll see it in time. That study was a little behind ZUMA-7. The third study was the BELINDA study, published also in the New England Journal [of Medicine]. That was a negative trial that looked at tisa-cel [tisagenlecleucel] or Kymriah, which is the Novartis product, compared with standard-of-care transplant. That did not show an advantage to CAR T over transplant. It’s not clear what the reason for that is, whether it’s the product, I don’t know. I can’t say it was or whether it’s just that those patients were a different group, and it took a little bit longer to manufacture the CAR T [cells], so there was a long delay before people got treated. There were lots of potential possible reasons for all that. That’s a long way of saying [that] based on those studies, randomized trials, CAR-[T-cell therapy] is now second-line treatment for people that relapse early.

We then did a trial, the PILOT study, looking at patients who may have relapsed at 2, 3, 4, 5 or 6 years but were perhaps older—over 70 [years old] or had compromised renal or cardiac function and for whatever reason were judged not to be good candidates for transplant. We studied 70 patients in that in that trial in the phase 2 study. Again, we had similar results with CAR T that we saw in the other studies and that led to FDA approval. So now we have FDA-approved CAR [T-cell] therapy for both patients who recur within a year and also for older patients who can recur any time, even 3 or 4 years later, but are not great candidates for transplant. Now we have…CAR-[T-cell] therapy approved for those patients. Those are second-line treatments.

Third-line treatment remains CAR T if patients haven’t gotten that previously [or] other regimens that are out there; there’s a drug called selinexor, loncastuximab [tesirine-lpyl], combinations of Rituxan and Revlimid [lenalidomide]. But, more recently, the bispecific antibodies have been approved, mosunetuzumab for follicular lymphoma, which I know we’re not talking about, but 2, epcoritamab and glofitamab, for a diffuse large B-cell lymphoma in the third line. And I think that the data there look pretty promising, and [referring to epcoritamab] based on 2 studies published maybe a year apart. The first was in the Lancet, and then about 70 patients. And then the more recent study in the Journal of Clinical Oncology, Catherine Thieblemont [Hôpital Saint-Louis, Paris, France] looked at 157 patients with diffuse large B-cell lymphoma and treated with epcoritamab. The bottom line was that the overall response rate was about 60% to 61%, complete response rate about 38%, and with less toxicity than you might see with CAR [T-cell] therapy. That’s our current third-line regimen. Sort of a very relevant question because we do this in oncology, [we ask,] should these drugs be moved to second line, or should they be moved to first line? That’s the theme in clinical oncology research, that you have drugs that work later. Will they work better if you do them earlier?

Transcript is AI-generated and edited for clarity and readability.