: Brian, I think this study GOG-258, which was first authored by Daniela Matei, MD, published in 

, of both—we’ve been talking radiation versus chemotherapy—but this is both versus chemotherapy. I think the reason it was published in 

 is because it did not show that chemotherapy and radiation was better than chemotherapy. It was published to encourage people to stop giving chemotherapy and radiation. But I don’t know. Brian, tell me what you think about GOG-258 and what’s the real interpretation.

: To Katie’s point, GOG-258’s really a group of high-risk individuals. In GOG-249, there was no difference because if you’re not going to recur, it doesn’t matter what you give. But GOG-258 was truly high-risk individuals. They gave the best chemotherapy that we thought at the time. The study made an assumption going in that Taxol/carbo [paclitaxel and carboplatin] was going to be the best chemotherapy, because it was prior to the publication of GOG-209. They compared it to a regimen of a heavy dose of cisplatin, 50 mg with radiation, followed by 4 doses of carboplatin and paclitaxel.

What they found is the addition of the radiation for the entire group did not have a superior outcome to those patients who just got chemotherapy alone. Now there’s a subgroup analysis in those patients that had a target to radiate. Meaning, if they didn’t give whole pelvic, if it was more target directed, those patients may benefit from some radiotherapy. But in general, the typical advanced-stage patient, node positive, node was resected, endometrial cancer, the study is definitive evidence that says chemotherapy alone is enough. We don’t need to radiate those patients.

: Thanks, Brian, that’s very succinct. I keep coming back to you, Krish. In your practice, when do you use chemotherapy and radiation in endometrial cancer?

: All right. Well, that’s pretty simple.

: I told you, if they’ve got advanced disease then chemotherapy. If they’ve got high-risk, early stage disease, it’s adjuvant radiotherapy.

: I love the practicality and quite frankly, I agree with you. Dave, there was this paper called PORTEC-3, which I don’t understand. I’m not even going to start. I’m turning it over to one of my smartest friends. Tell me what this trial is. It’s gotten a lot of attention. Put this PORTEC-3 into perspective.

: Well, PORTEC-3 was a European trial. It’s actually 2 publications. The first publication looked at the clinical outcomes in a very—you used the word heterogenous group earlier in this conversation. This was a very mixed bag. So stage I, grade 3 with deep invasion, or lymph vascularization, or both. As well as stage II, stage III or any patients with stage I to III serous or clear cell endometrial cancer. So, a very mixed group of patients. Basically, what they compared was whole pelvic radiation versus chemotherapy plus whole pelvic radiation. We were having a conversation….

: Wait, Dr Tewari said if I got a positive node, the control arm is chemotherapy.

: Well, you have a very strong argument with regard to data that we’ve already reviewed, that the control arm should have been chemotherapy. In some of these patients, the control arm should have been nothing or vaginal cuff brachytherapy to support the previous PORTEC trials. So when we look at this, we call into question, but when you bring in stage III, it’s a diverse group of patients, to say the least. But interestingly, they showed improvements with the chemotherapy. As we’ve already talked about, that should have been no surprise. To the radiation therapist on the clinical trial, I think it was.

So 5-year overall survival benefits by about 7%. The hazard ratio was about 0.7. Failure-free survival, the same thing, about a 6% improvement. When we look at those groups of patients, the addition of chemotherapy to radiation showed improvement in this entire population. We can talk more about the population, the molecular changes, but I’ll stop there.

: I think I’m going to keep moving. To your point, and thank you for being so good natured, it shows that chemotherapy works when used in the adjuvant setting, which is what Dr Tewari said. He said it when he subanalyzed GOG-122 and he practices it, as all of you do, and Dr Slomovitz says that the addition of radiation doesn’t do much to it. I think we’ve set the standard.

Videos

GOG-258 and PORTEC-3 Studies in Endometrial Cancer

: Krish, you had mentioned this high-risk, high-intermediate risk GOG-99 group, deeply invasive, maybe limited to the uterus, serous tumors, cervical involvement. You had participated and been an advocate for this study led by Scott McMeekin, MD, FACOG, FACS until his untimely death, GOG-249. Tell us what the intention was of GOG-249 trying to beat pelvic radiation as the standard in that high-risk limited to the uterus subgroup.

: It was taking a riff on what was done in cervical cancer and trying to see if chemotherapy could make the radiation work a little better and also eradicate distant metastases. There was a lot of thought that even serous cancers are going to respond better to this treatment approach because of the chemotherapy. But it really didn’t pan out. They had a good percentage of serous cancers in the study. But right now, if I have a high-risk, early stage endometrial cancer, I’m treating them with adjuvant radiotherapy.

: That would be the ASTRO [American Society for Radiation Oncology] guidelines. Katie Moore, so what it was is pelvic radiation, limited to the uterus, but still serious cancer, versus vaginal brachytherapy in 3 doses of chemotherapy, trying, as you said Krish, to get a systemic effect. Is the reason that that study did not show superiority of vaginal brachytherapy in chemotherapy because we only gave 3 cycles? What do you think?

: No, I don’t think so. I think we have a lot to learn from this study. I’m hopeful we’ll do some subgroup analyses from it. But I think the same problem plagued this study as has plagued other stage I endometrial cancer studies, is that we’re just not great at predicting that group of patients who are really high risk. The GOG-99 criteria, I respect them and the time, but I think they’re not the criteria that really identify the patients who need therapy. It’s probably all 3 risk factors. If you look at the breakdown, and I think we’ll see this from the GOG-249 exploratory. But if you look at those who have deep invasion, high grade and are of older age, all 3, that may be the group who benefits from chemotherapy. They’re all clinical factors. We haven’t incorporated the pathologic factors we’ve talked about, as well, to really identify that 15% who need more help. Then the rest probably don’t need it.

: Yes. Krish, you wrote a very nice subset paper of GOG-122, chemotherapy versus radiation in node-positive disease. You said, “Well, what if there’s just 1 node? Maybe radiation is good enough.” But your findings suggested even where there’s 1 node, that 3C1 tumor, that chemotherapy is better, right?

: That’s right. It’s exploratory. But you’d think that a single positive node, radiation should be just as effective. But we found that if it was a single positive node, chemotherapy is still better. We also found, even if there was just isolated cervical involvement, chemotherapy is better.

: Again, to Brian and Dave’s point, chemotherapy works. It works regardless of the cell type as Dave was saying.

GOG-249 Study in Early-Stage Endometrial Cancer

 Krish, I’m going to come back to you. You said, “Let’s treat the patient.” What are some of the challenges you have in treating in an adjuvant setting, so after hysterectomy? Or do you have it all worked out in your mind? In other words, who should get adjuvant treatment? I’m not going to ask you to get into the studies. We’re going to that next. But just summarize, in a statement or 2, who needs adjuvant treatment for endometrial cancer.

 You’ve got a well surgically staged patient; you can use the GOG-99 criteria to determine if they adjuvant radiotherapy. If you’ve got a surgically staged patient with a positive node, they need chemotherapy.

 I love it. See, we’re getting simple here, guys. If you have a deeply invasive or a grade 3 tumor or cervical extension, you give them pelvic radiation. In other words, it’s a chemotherapy world. I love it. Let’s talk now, Katie Moore, about what the standard chemotherapy is, published this year by our friend David Miller. Tell us about GOG-0209.

 Right. We’ve been waiting for this publication. We saw the abstract for it in 2011 or 2012, and we’ve been waiting for this paper for a long time. The reason it took so long is actually not laziness. It’s just that the patients did really well. It took a long time to reach the end points. This is how long it takes to do trials. This was a really important study. It’s very different from preceding studies that had set the standard of care in the past, which had been Adriamycin and cisplatin, after a series of studies done in stage IV recurrent disease. GOG-0209, led by Dr David Miller, had those patients, but also had adjuvant patients. You just referred to that, Dr Monk. For these patients who are fully staged and apparently stage I, then you find a node. Now we call stage IIIC1 or IIIC2. They were all included as well. It’s a very different prognostic group of patients included in GOG-0209. It took what was the community standard at that time—paclitaxel and carboplatin, which is identical to what we do in ovarian cancer—and compared it with what had been the preceding winning arm in endometrial cancer, which was a triplet: paclitaxel, Adriamycin, and cisplatin, which requires GCSF support to give. It was a noninferiority study. No one thought it was going to be better, but it is as good and certainly far more convenient and less toxic. GOG-0209 showed us that, indeed, it is noninferior. It’s pretty much identical if you look at the overall end point, which was overall survival. Why it took so long? If you look at overall survival, it’s completely noninferior and almost identical. If you look at the paper, the curves basically sit on one another with medians of 37 and 41 months.

Probably the most interesting part—and really why I wanted to see the paper—is that they did break out the adjuvant group from the measurable disease group. Because I’m interested to see what that looks like in a nonbiologic therapy era. We’re going to talk about the biologic therapies coming up. But if you use just chemotherapy, what do you get? These are benchmarking data. If you look at the measurable disease—identical, 20 to 22 months median—that’s better than what we’ve seen in the past.

 PFS for the nonmeasurable—basically, these patients are cured. They just never reached it. We had like 112 months vs nonreached. They had a lot of patients in this group cured with chemotherapy. It gives us standard toxicity comparisons that I don’t think we need to belabor here. We all know that paclitaxel-carboplatin is well tolerated and certainly better tolerated than the triplet. I believe we all moved to this many years ago. But if there was any question of what the superior regimen or backbone should be, it should be well established now that it’s paclitaxel-carboplatin.

 Very succinct. Thank you. Global standards. Dave, I’m going to ask you a tough question. I think I know the answer. I’m not sure. Are the endometroid tumors or the serous tumors more chemotherapy sensitive? Or you don’t know? Or they’re the same? Does it matter? Are the endometroid tumors less sensitive or more sensitive than the serous tumors?

We’re seeing across time that both of them respond to chemotherapy almost equally. As we look at some of the other challenges with the poor prognosis of serous cancers, they are usually explained by other risk factors. As we look at these trials, we see that both types respond to chemotherapy. Maybe it’s slightly more in serous, but it’s not enough to deny anybody chemotherapy based on their histology.

I like speaking after Dave because I get to look smarter. I agree. The only other thing is that the chemotherapy is the same for grade 3 endometrioid cancers. Grade 1 and 2 are more hormonally responsive. Fewer cells are in the cell cycle. The low-grade endometrioid cancer doesn’t respond as well to chemotherapy as high grade. But high-grade endometrioid, serous, and carcinosarcomas are in the same category.

The PFS for those patients with tumor is worth repeating. It’s measurable disease. What’s the PFS from GOG-0209?

You guys have done such a great job teaching the world that these cervical and endometrial cancers are chemotherapy sensitive. That’s what I was trying to get you to say, Dave. And that’s probably the right answer. With PFS of over 20 months, they both work.

GOG 0209 Study in Advanced Endometrial Cancer

 Surgery is important. Anatomic, typical FIGO [International Federation of Gynecology and Obstetrics] staging is important. The molecular biology of the tumor is important. Dave, bring us back to practicality. I do a robotic hysterectomy as I did yesterday. What does the pathologist do with that tissue? What are the typical biomarkers that are the global standard in endometrial cancer?

 First of all, we need to assess the nodes. Most of us are doing sentinel lymph nodes at this point, and we think that adds to this dividing into stage III, which obviously is a higher risk. We have that. Let’s get the information we need surgically with the hysterectomy and at least sentinel lymph nodes, at the very least, mismatching pair proteins through IHC [immunohistochemistry] at the time of diagnosis. At this point, I would advocate—based on prognostic factors and potential treatment options, as well as identification of people with Lynch syndrome potentially or families with Lynch syndrome—that we do that as a baseline.

What is an evolution? Even though the NCCN [National Comprehensive Cancer Network] Guidelines changed last year, looking at this molecular classification based on the PORTEC trial that is still having a difficult time getting payers to reimburse and thus having my pathologist do these extra tests. What are some of the other things? Well, MSI [microsatellite instability]. Should we be doing that PCR [polymerase chain reaction] test if the MMR [mismatch repair] proteins are all intact? We’re not doing that yet, but that’s something I do on recurrence. How about the IHC for 

 that Katie and Brian have mentioned? That should probably be done routinely, but we need to make sure the payers are paying that. As we look at the 

 and the next generation sequencing, as well as additional mutational analysis, there are some other subgroups that maybe will identify their predictive in the future.

But at diagnosis, particularly in early stage disease, that’s not routinely being done, and we’re having trouble getting reimbursed. We really need to look and work with our pathologists as well as the payers to make sure these things are reimbursed so that we are able to perform those tests. I personally don’t think PD-L1 testing should be done. I see that frequently, especially in patients who are coming in for a referral, because we really haven’t seen that it is a marker in endometrial cancer. Don’t do a test if you don’t know what to do with the results.

 [human epidermal growth factor receptor 2] and ER [estrogen receptor], PR [progesterone receptor]?

 Great question. As we look at these, as 

 moves from the serous cancer where we have data, where it makes the clinical significance, clearly it should be done in all advanced-stage serous cancers. We’re not doing it at our institutions for the local or stage I or II disease, but it’s a consideration as we move forward. We’re not doing ER-PR routinely, but it’s really interesting information. I would argue that anybody with a grade 1 is going to be ER-PR positive. For that grade 2 and 3, you may bring a new set of treatments in that you otherwise wouldn’t use.

 I called you my brother when I introduced you. That’s way too complicated. If you tell your pathology what you just said, it isn’t going to work. Krish, I need you to boil it down here. Then I’ll get Brian. Boil it down—just a bite size. Go ahead. What biomarkers do you want done?

 I want TILs [tumor-infiltrating lymphocytes]. That’s what I want to know. Because that’s going to make a difference in whether immunotherapy is going to be effective for advanced disease.

 All right. Brian, help us. Come on, man.

 I appreciate that earlier you said we come from esteemed universities and that we’re all really smart, but I like to keep it simple. The advantage of molecular profile in these tumors is that 1 of the things we haven’t mentioned is that it makes it more reproducible for pathologists to come up with the same diagnosis.

: Prior to molecular profiling, it’s subjective. Here you get endometrial cancer, and No. 1, you do a 

 positive, you follow it up with a HER2/neu, regardless if it’s serous or endometrioid, because the pathologist could be wrong. If it’s 

 negative, you do ER-PR. It’s simple and straightforward. Anyone can do it.

 positive—in other words, mutated—then you do 

. If you’re not, you do ER-PR. You do immunohistochemistry on those—basically all patients. It’s basically the nonserous, but they might be wrong.

 We just made a very complicated subject matter very simple.

 All right. That’s rare for you guys. Wow. Hopefully we can keep the momentum going.

I don’t mean to insult my good friend, Dave O’Malley. But there’s a real ability here to be astute and smart, and you’re that, Dave. Thank you. I’m so glad to have you here.

Role of Biomarker Testing in Endometrial Cancer

 I was asked the other day, “Brad, what’s the No. 1 word used to describe endometrial cancer?” One word. I said, “Heterogeneity.” It is a constellation of diseases. Brian, Dr Slomovitz, tell us a little about how we’re classifying these tumors at the molecular level.

 Sure. Thanks for that, Brad. Historically we’ve classified these primarily by traditional factors—histology and endometrioid being the most common—followed by serous and clear cell, which are some of the more aggressive histologic subtypes. We still classify them by stage and grade. But of all the cancers we’re treating, the molecular subtypes have really been well defined in endometrial cancer. Ever since Doug Levine published the first TCGA [The Cancer Genome Atlas] article on endometrial cancer, dividing endometrial into 4 distinct subtypes, we’ve really been able to define clear categories for disease and also come up with better treatment plans based on those categories.

Briefly, there’s MSI [microsatellite instability] high, and there’s the 

 mutations. The MSI high make up about 40% of endometrial cancers. 

 is in the single digits—not that common, with a good outcome. There’s the typical low copy number, we call them, endometrial cancers. Then finally, the most aggressive type, the type that are most likely to be ovarian cancers, the 

 subtype. But they’re really well characterized. Not only can we easily divide the cancers into those groups, but those groups really are prognostic and can determine outcome.

 It’s interesting. As gynecologic oncologists, we use the FIGO [International Federation of Gynecology and Obstetrics]staging system. We don’t use the TNM [tumor, nodes, metastases] system. Stage I is limited to the endometrium, stage II in the cervix, and stage III is in the nodes. But Katie, I’ve heard you talk about the molecular staging—maybe this is what Brian said—that there may be a molecular way to look at prognosis rather than disease spread. Tell us about that.

We still have work to do with that characterization. But certainly, alluding to what Dr Slomovitz just mentioned with the TCGA, there have been other interesting studies done in Europe that are consistent. When you look at endometrial cancers that have loss of 

, which we are very used to seeing in ovarian cancer. But in endometrial cancer, we’ve known about it for a while. It’s mainly those patients with uterine papillary serous or very undifferentiated grade 3 endometrioid cancers can have this 

 signature. They’re serous-like and they have a poor prognosis, even when you are controlling for stage.

A stage I, which is all confined to the uterus, endometrioid vs 1 of the loss of 

 tumors, that latter tumor is going to have a much different prognosis if left untreated. How best to treat it—we’re going to talk about it in this session a little later. But we know that they’re much higher risk for recurrence. They make up a much higher percentage of those patients who present with advanced and recurrent disease, so are high unmet need. On the flip side, Dr Slomovitz also mentioned POLE. That’s an interesting group and we don’t understand it really well yet.

We have a sense that even though they are commonly found in undifferentiated tumors, they still have maybe a better prognosis. There’s been some retrospective looks that they do better than they should histopathologically. But it really hasn’t impacted how we treat them. More to come on that.

Risk Classification of Endometrial Cancer

® titled “Advanced Endometrial Cancer.” This is 

®’s first endometrial cancer discussion. I am so excited to be here. My name is Brad Monk from the University of Arizona and Creighton University, both in Phoenix, Arizona. I’m also part of the US Oncology Network. My hospital is St Joseph’s Hospital and Medical Center in downtown Phoenix. I am joined today by 4 experts in the field from very prestigious academic medical centers. First is Dr Kathleen Moore. I’m going to call her Katie. Dr Moore is at the University of Oklahoma Stephenson Cancer Center. Katie, hello.

 Thank you. Dr Dave O’Malley from The Ohio State University Wexner Medical Center in Columbus, Ohio. Dave, welcome my brother.

 Excited to be here for this inaugural endometrial cancer discussion.

 Thank you. Dr Brian Slomovitz from Florida International University Herbert Wertheim College of Medicine and Broward Health in Fort Lauderdale, Florida. Brian, welcome.

Thank you very much for having me, Brad. It’s really an honor.

 You look very smart with all those plaques behind you, Brian.

 Thank you. Dr Krishnansu Tewari from the University of California, Irvine. I’m going to call you Krish. Thank you. Welcome, my friend.

 This is exciting. As I think all of you are aware, there have been several important advances in understanding endometrial cancer, both from a biologic standpoint but also from a novel therapeutic standpoint. We’re beginning to define frontline treatment, and now we have options in recurrent disease. We’re going to review these options, from a surgical, regional, and systemic opportunity. I’d like to get started on our first topic, and that is to consider the biology and the prevalence and incidence of endometrial cancer or uterine corpus cancer.

Krish, why don’t you go ahead and start about the increasing incidence of endometrial cancer and how that has affected your practice.

 Thank you, Brad. In 7 to 8 years we’ve seen about a 30% increase in the incidence of this disease in the United States. There are about 65,000 new cases anticipated for 2020. Maybe 8 years ago there was 45,000. So it’s an increased incidence. It accounts for probably 30% to 40% of my surgical practice, doing surgery for endometrial cancer. We’re not sure why the incidence is increasing. Certainly, for patients who are overweight, obese, and morbidly obese, not only has that been holding stable, but those conditions have been rising.

Diabetes is pretty stable, but what’s interesting is that ever since the Women’s Health Initiative was published in 2002, there’s been a decrease in the use of combined hormone replacement therapy. There’s a possible association between lack of progestins and the rise of endometrial cancer. Also, there are fewer hysterectomies being done for benign disease. Those 2 things need to be looked at in more detail. But predominantly, the obesity crisis in the United States is driving the higher incidence.

 It is the most common operation that I do. Virtually all these operations are done minimally invasive. Katie Moore, your partner, Joan Walker, did that pivotal trial called LAP2.

 Do you ever make an incision for an endometrial cancer? There’s been this evolution in cervical cancer that minimally invasive is not good in cervical cancer. But it’s still OK in endometrial, right?

 Right. Yes, occasionally make an incision, certainly if we can’t do it laparoscopically or more accurately robotically, we get the uterus out the old-fashioned way. But it’s pretty uncommon.

 It’s still not outlawed, but maybe someday open hysterectomy for endometrial cancer will be outlawed.

 It’s really interesting that you’re bringing that up, Brad. Dave can probably comment on this. Actually, all of us can as fellowship directors. When I do the numbers for the fellows now, they do not have a lot of open notes.

 That’s right. With sentinel lymph nodes now…

 Even more common lymphadenectomy is rare.

Overview of Endometrial Cancer

Rapid Readouts: Phase III PAOLA-1/ENGOT-ov25 Trial

Bradley J. Monk, MD, FACS, FACOG, US oncology medical director of Gynecologic Oncology Research and a professor at the University of Arizona College of Medicine, discusses emerging therapies in cervical cancer.

Early therapeutic intervention offers the best chance of survival in cervical cancer, explains Monk. Moreover, ​adding immunotherapy to chemoradiation for patients with unresectable locally advanced stage II and III disease could be a potentially promising approach.

Notably, the ​​phase 3 CALLA trial evaluating durvalumab (Imfinzi) plus chemoradiation and ​the phase 3 MK-3475-A18/KEYNOTE-A18/ENGOT-cx11 trial evaluating pembrolizumab (Keytruda) plus chemoradiation are ongoing global studies in this space.

The rationale for this research stems from the fact that chemoradiation can trigger an immune response. As such, the addition of a checkpoint inhibitor may result in a higher response rate compared with chemoradiation alone, Monk concludes.

Bradley J. Monk, MD, FACS, FACOG, discusses emerging therapies in cervical cancer.

Dr. Monk on Emerging Therapies in Cervical Cancer 

Bradley J. Monk, MD, FACS, FACOG, US oncology medical director of Gynecologic Oncology Research and a professor at the University of Arizona College of Medicine, discusses the importance of Pap testing early on in cervical cancer.

When caught early with Pap testing, cervical cancer is almost always curable, says Monk.

By collecting cells from the cervix, this test can also detect other conditions such as human papillomavirus.

Notably, when cervical cancer is caught early, patients can undergo fertility-sparing surgery. In other cases, a hysterectomy may be necessary. In cervical cancer, an open approach is preferred to a minimally invasive procedure which can potentially enhance the spread of disease, Monk concludes.

Bradley J. Monk, MD, FACS, FACOG, discusses the importance of Pap testing early on in cervical cancer.

Dr. Monk on the Importance of Early Pap Testing in Cervical Cancer  

Bradley J. Monk, MD, FACS, FACOG, US oncology medical director of Gynecologic Oncology Research and a professor at the University of Arizona College of Medicine, discusses the limitations of current treatment options in metastatic or recurrent cervical cancer.

Since its approval in 2014, the triplet regimen of bevacizumab (Avastin), paclitaxel, and cisplatin/topotecan has remained the standard frontline therapy for these patients, Monk explains. The combination, which contains the first targeted therapy approved in a gynecologic malignancy, is associated with an overall survival benefit for patients with metastatic disease.

Additionally, in June 2018, pembrolizumab (Keytruda) received regulatory approval for the treatment of women with metastatic cervical cancer who experience disease progression on or after chemotherapy and whose tumors express PD-L1 with a combined positive score of 1 or more. However, the response rate was only 14.3%, says Monk.

Metastatic or recurrent cervical cancer remains a lethal disease. As such, novel regimens are needed to improve responses for patients with this malignancy, concludes Monk.

Bradley J. Monk, MD, FACS, FACOG, discusses the limitations of current treatment options in metastatic or recurrent cervical cancer.



Dr. Monk on the Limitations of Current Treatment in Metastatic/Recurrent Cervical Cancer

 R2-GDP-GOTEL is a phase 2 clinical trial that combined lenalidomide with a very well-known regimen for salvage chemotherapy, R-GDP, which consists of rituximab, cisplatin, dexamethasone, and gemcitabine. The patients were to receive lenalidomide from day 1 to day 14, in addition to the standard dose of R-GDP [rituximab, cisplatin, dexamethasone, and gemcitabine], up to 6 cycles. Patients who completed the regimen and had at least a PR [partial response] or complete remission [CR], they went on to receive lenalidomide as maintenance. They enrolled 79 patients, 78 patients were evaluated for efficacy and toxicity. The overall response rate was 59%, with a CR rate of 32%. The adverse events were mainly related to the chemotherapy, like thrombocytopenia and neutropenia, patients had rashes, also febrile neutropenia of course, reported in about 14% of patients. Further biomarker analysis showed that there was no difference in responses according to the cell of origin, and also the regimen was active in primary refractory lymphoma. Unfortunately, there were 4 toxic deaths in the study. That’s important to know when we add a new agent into our salvage regimen.

The conclusion is that this is an active regimen, it’s a phase 2. The question is whether this is better than the standard GDP [gemcitabine, dexamethasone, cisplatin]. The reported efficacy of gemcitabine, dexamethasone, cisplatin, the overall response rate is about 45%, with CR rates in the range of 13% to 15%. Keep in mind that the earlier studies didn’t include a PET [positron emission tomography] scan as mandatory to assess for CR rates, so we don’t really know the true CR rates in the earlier studies. That’s just to keep in consideration. Also, I would say that long-term follow-up is needed to see whether that matches the long-term efficacy of this regimen in these patients. Until we know whether we need to add lenalidomide to the gemcitabine, dexamethasone, cisplatin regimen in real life, I think it’s early to say. There were some toxicities and 4 deaths in a relatively small study. I think we should be careful. Whether we need to add it, I think the decision has to be made based on a larger study, or a phase 3 randomized study.

The Smart Start study is a single-center, phase 2 clinical trial that was presented by Jason Westin, MD, and colleagues from The University of Texas MD Anderson Cancer Center. It’s a trial that consisted of 2 phases. There was a lead-in phase of rituximab, lenalidomide, and ibrutinib for 2 cycles, followed by the combination plus chemotherapy. Whether it was R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], it was physician discretion to decide which regimen the patient would go on. The overall response rate was 86%, with a CR rate of 36%, which is expected for lenalidomide and ibrutinib. There is not a high CR rate. But once the patients completed the chemotherapy part, up to 6 cycles, the overall response rate was 100%, with a CR rate of 95%. The 1-year PFS [progression-free survival]—the study has a short follow-up—was 95%.

The adverse events were expected as related to the chemotherapy agents used. There were some toxicities that we typically don’t see in patients who receive chemotherapy, like Aspergillosis. There was a patient who had CNS [central nervous system] Aspergillosis, and 1 patient who died of Aspergillosis, probably systemic Aspergillosis. That underscores the fact that adding another agent into a chemotherapy regimen could be complicated. There are descriptions of fungal infections with ibrutinib, especially in combination with steroids and cytotoxic agents, so that’s something physicians have to keep in mind.

The other interesting thing about this study is the time to initial treatment, that was about 24 days. The reason I’m pointing this out is it’s a little unusual for patients to wait 3 weeks or almost 4 weeks to start therapy, especially with an aggressive lymphoma. That tells us about a possible selection bias. You’re probably selecting the best patients, the more stable patients to do these therapies, whereas the sickest patients, the patient who was in the hospital with aggressive disease, probably is not eligible for this trial.

Overall, I think the combination showed activity in DLBCL [diffuse large B-cell lymphoma], it’s promising activity. Whether that will implicate a change in the standard of care, I think it’s early. We need to sort out this question in a randomized clinical trial, phase 3. Finally, we have to consider the cost, because you’re adding lenalidomide and ibrutinib, and that can easily be a costly therapy over 6 months. I think it’s a study that showed very interesting activity. Tolerability was acceptable. Some of the infections that we typically don’t see with the standard chemotherapy, such as Aspergillosis or fungal infections, were shown in this study, so that’s something we have to keep in mind when we decide whether to do this treatment. I wonder whether patients need to complete 6 cycles of chemotherapy. That’s something that needs to be studied. Probably fewer cycles of chemotherapy would be more convenient and may not impact efficacy. I believe there will be a follow-up study with fewer cycles of therapy to see whether that will be feasible.

Novel Therapies: R2-GDP-GOTEL and Smart Start 

The POLARGO study, as it’s called, is a large, global phase 3 trial that compares a standard chemotherapy regimen, R-GemOx, which is rituximab, gemcitabine, oxaliplatin. And the comparator arm is rituximab, gemcitabine, oxaliplatin with polatuzumab vedotin, which is an antibody-drug conjugate now approved for diffuse large B-cell lymphoma.

The purpose of this study is to demonstrate or test whether the introduction of this antibody-drug conjugate improves the outcome of patients with diffuse large B-cell lymphoma treated with rituximab, gemcitabine, oxaliplatin in the relapsed/refractory setting. This trial is ongoing, but I think there’s a fair amount of optimism that we may see a positive result here, which would improve or expand the number of treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma.

I think you’re referring to the LYSA trial presented at ASCO [the American Society of Clinical Oncology annual meeting], which was atezolizumab, a checkpoint inhibitor, with obinutuzumab and venetoclax in relapsed/refractory large cell lymphoma. This was a small number of patients.

I think 80%-plus of patients had at least 2 lines of therapy, and two-thirds of them were refractory to the last regimen. I don’t remember the exact number of patients, but the trial was reported with an overall metabolic response at the end of treatment of 24%, and an 18% complete metabolic response. It’s early for the follow-up, but this is again one of these combinations, a biological agent plus immunotherapy. That might bring an opportunity to the unmet need of patients who are not eligible for high-dose therapy, transplant, or potentially CAR [chimeric antigen receptor] T-cell therapy. It’s another example of the impact of immunotherapy as well.

I would like to summarize and say that this is a very exciting time in the field of medicine, particularly in lymphoma where we have been, for decades, doing R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], which remained as the standard of care default. But we definitely should be aware that this is not sufficient in a high-risk IPI [International Prognostic Index] patient, double hit, double expresser, and non-GC [germinal center] subtype, and other high-grade lymphoma that I alluded to previously. And I think that these patients should be recommended for clinical trials and probably more intensive therapy and maybe cell therapy consolidation, like the ZUMA-6 trial looking at CAR [chimeric antigen receptor] T-cell therapy as consolidation in patients who have double-hit lymphoma, high-grade lymphomas.

It is really not altered, but probably underestimated. But the future is the biological classification of lymphoma and trying to improve this curve that we see, to identify truly the high grade. And to do this, we need to have a baseline signature that is usable in routine and actionable. I think cell-free DNA, or circulating tumor DNA, is likely to be more usable and used in the future. As I mentioned, immunotherapy is more and more part of the induction or pre-phase consolidation. And again, given all the opportunities that I just mentioned tonight, it reflects on the fact that it is really important to encourage physicians to go to clinical trials, to participate. The reason being is that when you look, the impression is that large cell lymphoma now is a clinical result, the outcome is so great. But when you look at real-world data in high-risk patients, the outcome particularly in a high-risk patient is still very poor. So I would encourage physicians to look at clinical trials in this population as well. Thank you.

Novel Treatment Combinations for R/R DLBCL

We still have unmet needs for patients with diffuse large B-cell lymphoma. As I mentioned, for older patients in their 80s and above, even standard therapy with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is very difficult to receive. And in those cases after failure of less intense regimens, such as mini R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], or bendamustine, or others, there is a significant unmet need for patients to be treated with targeted agents. Tafasitamab with lenalidomide is likely to be an option for those patients in the future, as well as selinexor, and polatuzumab vedotin, which is approved in combination with bendamustine/rituximab.

 I think overall in cancer, immunotherapy will continue to expand dramatically. I think more and more we’re going to try to combine small molecules, biological agents as sort of an induction with or without immunotherapy, and immunotherapy afterward as a consolidation. That’s 1 model. But there’s also lymphoma—more and more we see that we can, as I mentioned for example, the R-squared, ibrutinib window-type trials in the patients who are particularly non-GC [germinal center] subtype and frail patients can respond really well to this and have a shortened version of chemotherapy. And then there are ongoing trials looking at checkpoint inhibitors in combination with chemotherapy. BiTE [bispecific T-cell engager], as I mentioned, combination with trastuzumab, in combination with chemotherapy. More and more we’re going to integrate that.

And the third piece that is important is the role of immunotherapy as an immuno-consolidation post-induction. We know that cell-free DNA might help us with the depth of response in those patients. But we know that the patient’s immune status post-chemotherapy—although we don’t have a great way to quantify it, but based on the ratio data from the Mayo Clinic, for example, the ratio of lymphocytes to monocytes, across the board in a number of diseases and many subtypes of lymphoma—shows that it has a dramatic impact on the outcome. We don’t exactly know yet how to tackle this, but that’s an opportunity as a consolidation eventually. Definitely the question is more novel therapy, more immunotherapy, either in addition or to replace chemotherapy.

 With the new therapies coming to the clinic, how does cost affect your patients’ access to treatment? I’m sure that cost and access impact a patient’s and oncologist’s decision and, hence, care for therapies, especially for an aggressive disease like diffuse large B-cell lymphoma. Not only the cost of the drug itself, but also the cost of the logistics, such as in CAR [chimeric antigen receptor] T-cell therapy. There is a lot of cost implicated in treating the adverse effects, admission to the hospital, admission to the ICU [intensive care unit], the use of a caregiver, the caregiver has to be off work, the patients cannot drive for 2 months. There is cost in relation to that.

When you talk about the combination of tafasitamab and lenalidomide, I would think that it will be a top price for tafasitamab. But then you have to add the cost of lenalidomide, and whether insurance can cover part of the cost of lenalidomide, there may be a copay for patients. That should be considered in terms of the cost. Tafasitamab is a treatment that is given indefinitely. Patients get treatment for as long as they respond or for as long as they tolerate the medication. So that’s a cost because patients have to keep coming to an infusion center, they have to maintain a line. If they have complications related to the line, like infections or thrombosis, that adds to the cost because we have to treat those conditions. It’s important to consider those.

In the case of selinexor, which is a single oral agent, it will have definitely a top price. It doesn’t have the cost of hospitalization, it doesn’t have the cost of having an IV [intravenous] line. It’s an indefinite treatment, so if there is a patient who had a response, those patients have to remain on the drug for a long time. As far as I remember, in the trial some patients went on treatment for up to 3 years. That should be a consideration in regard to the cost. However, there are other costs that should be considered for selinexor. It’s a novel agent, has specific adverse effects that need to be taken care of, such as diarrhea, nausea, adding the medications to treat the nausea, adding the medications to treat the diarrhea. There are issues with cytopenias as well as thrombocytopenia. There are recommendations in the trial about using growth factors, they also have costs. So it is important to keep in mind when we use the novel therapies available, the other costs that are outside of the specific medications.

Relapsed/Refractory DLBCL: Unmet Needs

There is a potential for tafasitamab in combination with lenalidomide to significantly impact the treatment landscape for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting.

As I mentioned, the standard approach really should still be CAR [chimeric antigen receptor] T-cell therapy for patients who are young and fit enough to receive this therapy. But for patients who relapse after CAR T cell, or who are unable to make it to an authorized treatment center for CAR T, or are of significantly advanced age or with poor performance status, in those cases more traditional pharmacologic therapies are likely to be needed. And they will probably cycle through on an ongoing basis as the patients will likely eventually lose their response to these agents.

In the case of tafasitamab, this is an anti-CD19 monoclonal antibody, which was studied in a phase 2 trial in combination with lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. And what was reported and recently published was that a high proportion of patients, somewhere in the 40% to 50% range, achieved reasonably long-term remission with an impressive overall response rate of this combination.

With the anticipated approval of tafasitamab, in combination with lenalidomide for diffuse large B-cell lymphoma, I think we’re going to have more in our armamentarium and more options for patients with this disease.

The Re-MIND study was presented at the ASCO [American Society of Clinical Oncology] annual meeting. It’s an interesting study looking at lenalidomide as a single agent in the relapsed large cell lymphoma and to use it as real-world evidence to compare with the L-MIND trial, which was tafasitamab plus lenalidomide, where I mentioned the results were very impressive. This was to try to compare the outcome of this population with a combination versus a single agent. I think this was an important work because the awareness of the importance of real-world data is increasing rapidly. And these real-world data can confirm the clinical benefits of a new trial but also give you, if we can see a control group, although this was not completely matched as a control group, to suggest that the combination was really beneficial, with the anti-CD19 in addition to lenalidomide.

Emerging Treatments for Relapsed/Refractory DLBCL

The FDA approval for selinexor is anticipated this summer, and it is likely to be approved for relapsed or refractory diffuse large B-cell lymphoma [DLBCL].

The treatment landscape for diffuse large B-cell lymphoma is changing now that we have CAR [chimeric antigen receptor] T-cell therapy. It’s important to know that although a proportion of patients with CAR T cells may be cured, as I mentioned previously, with this therapy, 60% or more of the patients will not enter durable remission and will relapse.

For those patients, there are limited treatment options. Polatuzumab vedotin is a treatment option for those patients in combination with bendamustine and rituximab, which is approved in this setting. It’s anticipated that selinexor will also be approved in this setting.

This is an oral agent that can be used as a single agent in third-line therapy, as I mentioned, it was just approved. But I think the real benefit will be when we start to combine this with other agents, and hopefully have better disease control.

In my opinion, what I look at more is efficacy, how efficacious is a drug or a regimen. For patients with DLBCL, what I typically do is ask them what are their goals, if their goals are to cure the disease, or to maintain the disease in some type of remission, but no cure. If they want to achieve a cure and they’re healthy enough to do it and they don’t have a lot of significant comorbidities, I offer what is the standard of care, which is CAR T-cell therapy. That’s the main thing. I would say with all the CAR T-cell drugs available, essentially, the majority of patients could get CAR T-cell therapy. Age is not a limitation. Our oldest patient was 84 years old, he was in good shape, he was able to get treatment and he’s in remission. I think that’s a reason we have to offer what is the best care and best option, which is a curative option.

If the patient prefers not to undergo CAR T-cell therapy, not only because of the adverse effects, but also because of the logistics—traveling, leaving home, staying in a different place—that’s definitely a factor in deciding whether to pursue CAR T-cell therapy. In those cases in which CAR T cell is not possible for all those reasons, the patient is too weak, too sick, or logistic reasons, then oral agents such as selinexor play a role. Also other agents can be given closer to home, like monoclonal antibodies such as tafasitamab or polatuzumab. Those are viable options in the community.

When you have all these options, you have to choose the option that is more efficacious, but at the same time, less toxic. As I mentioned before, the monoclonal antibodies are used commonly by community oncologists, so they’re familiar with it. I wouldn’t see a problem in using tafasitamab orpolatuzumab. So there are options for those patients and they know how to use them. Selinexor is a novel agent, so you have to try to learn how to manage the adverse effects. Also the activity is modest. I don’t deny there is activity, but it’s not probably the greatest clinical activity, if you compare it to tafasitamab with lenalidomide, or polatuzumab/bendamustine/rituximab.

Finally, the other aspect is the maintenance of an IV [intravenous] line. So far, selinexor is the only oral agent approved for diffuse large B-cell lymphoma in the relapsed/refractory setting as a single agent. That’s definitely convenient because patients just take 1 pill. But again, it’s probably the less important factor in my opinion.

One of the things that has come up recently, one of the concerns, is that we’re experiencing the global pandemic of COVID-19 [coronavirus disease 2019]. This has led to some concern about intensive treatment regimens that are highly immunosuppressive, including autologous stem-cell transplantation, and potentially CAR T-cell therapy.

In my mind, the risks and benefits of using immunosuppressive therapy have to be weighed against the risk of infections, including COVID-19. But for a treatment for a disease such as relapsed diffuse large B-cell lymphoma, I think the benefits of the therapies that we discussed, including transplant and CAR T, still outweigh those risks.

There may be patients who are presented with the option of continuing to receive IV therapy as opposed to an oral agent like selinexor that can be taken at home. And it’s possible that an oral agent may be safer because of less exposure to the patient, but it also has to be taken into account that some of these agents can cause neutropenia and even if they’re oral, and that can predispose patients to infection.

SADAL Trial Regimen FDA Approval

The mechanism of action for selinexor, which is a novel targeted agent, is that the medication works as a selective inhibitor of nuclear export. Nuclear exporters are proteins that cycle transcription factors and other regulatory proteins between the nucleus and the cytoplasm of the cell.

By inhibiting this nuclear export protein, selinexor leads to accumulation of various protein regulators that leads to reduction, cell proliferation, and apoptosis of the target cell. We know that certain malignant cells, including diffuse large B-cell lymphoma [DLBCL], are sensitive to this agent, and recent data have shown that it’s clinically active in this disease.

Selinexor is an exportin XPO1 that is an inhibitor. XPO1 is overexpressed in lymphoma and correlates with a poor outcome. This oral selective nuclear transport inhibitor has shown activity in a preclinical setting and was tested in aggressive lymphoma, in large cell lymphoma, in the third-line setting. It was testing a number of lymphomas in the SADAL study, including large B-cell lymphoma. These patients have really no options. This was a heavily pretreated population of 120-plus patients. And the response rate was 36% and 15% CR [complete response]. This was something that was very interesting because we had some patients who were not very high-risk large cell lymphoma but multiple failures and who had very durable response.

It was a single agent. This is really interesting, and it was approved last month in June. Based on that, the next step is to try to build up this activity and the mechanism that would make a lot of sense combined with other agents. It is being looked at in a very interesting trial that is looking at the number of different arms, combining selinexor with chemotherapy, biological agents, and checkpoint inhibitors to see how we can build a new regimen for patients who are not eligible for CAR T [chimeric antigen receptor T-cell therapy] or transplant or fail after CAR T cells.

Selinexor is a novel agent that has been recently approved for relapsed/refractory diffuse large B-cell lymphoma, after at least 2 lines of therapy. In the trial, about 17% of patients discontinued the drug because of side effects, mainly related to GI [gastrointestinal] toxicity, nausea and diarrhea, and also hematology toxicity, specifically neutropenia and thrombocytopenia. This trial, when it was studied in non-Hodgkin lymphoma, actually utilized a higher dose of selinexor. In the SADAL study, they actually used a lower dose of selinexor but also showed the adverse effects I just mentioned. Part of it included the use of olanzapine during the treatment, especially given the day before, following 5 days after the treatment. Also, they include the use of appetite stimulants and growth factor support to prevent the hematology toxicity. They reported that the adverse effects were manageable in those patients, but they still show a significant rate of GI toxicity specifically.

As I mentioned, in the SADAL study, selinexor in relapsed/refractory DLBCL, they administered the drug at 60 mg on days 1 and 3 every week until disease progression or development of intolerance. All patients were required to receive ondansetron, which is a common antiemetic medication for cancer patients. After patient discussion, they also received olanzapine to prevent nausea. In the non-Hodgkin lymphoma study, which was probably 3 years ago, they included all histologies, including DLBCL. They tested the selinexor at 3 mg/m2, all the way to 80 mg/m2, which was the highest dose. They actually break down in those levels, and essentially there was no significant difference in response rates, even with the lowest dose. They showed an overall response rate of 31%, but that was across all histologies. Based on that data, I don’t think those modifications could have affected the efficacy of the drug. I believe that actually was a good move from the investigators—to use a lower dose, a less toxic drug—because it seems that the toxicity was dose related.

Selinexor has an advantage. The main advantage is it’s a single agent and an oral agent. These 2 factors actually help physicians treat patients. Because they don’t need an IV [intravenous] line, the patients don’t have to come every time to get the therapy. So it’s convenient. The schedule could be a challenge. Patients get selinexor on days 1 and 3 every week, so I’m not sure whether patients will be able to remember. It’s easy when you take a drug every day or once a week, but if it’s twice a week, you may forget. It’s important for the clinicians or the nurses to follow up with the patients when they receive this therapy.

Also, it’s important to know that this is a novel agent with a novel mechanism of action, so the toxicity profile is also novel. Physicians are familiar to use monoclonal antibodies like tafasitamab, so there may be more appeal to use that drug as opposed to selinexor because it’s still unknown, it’s new, and no one has used it, unless they did it for myeloma patients with selinexor.

There are other drugs that are not approved for DLBCL but that doctors are familiar with, like lenalidomide. Lenalidomide has activity in relapsed/refractory DLBCL. Physicians know how to use it because it has been in the market for a while for other conditions such as MDS, myelodysplastic syndrome; mantle cell lymphoma; or even multiple myeloma. Physicians are very familiar with it, and even if it’s not approved, I don’t see any issues with insurance approval or around the co-pays that we sometimes see with this drug.

When using selinexor, physicians have to make sure they know the efficacy and toxicity, so that patients are not surprised and they’re managed appropriately.

SADAL Trial Overview 

 The long-term treatment outcomes for patients treated with CAR T [chimeric antigen-receptor T-cell] therapy are very impressive in the sense that historically we knew that these patients really had very limited overall survival. What we can see in some of the long-term studies is that there are about 30% or 40% of patients who achieve durable remission after treatment with CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma.

This really represents a paradigm shift where previously most of the treatments would have been palliative or clinical trials of new drugs. This really has become the standard of care, and it suggests that patients can be cured with this approach.

Given the known adverse effects of CAR T-cell therapy, especially CRS [cytokine response syndrome] and neurotoxicity, there is always a concern of how our older-patient population will tolerate these therapies. The way I see it, it’s more than age. It’s a functional age that is driven by other factors, like physical health or impact of comorbidities.

This interesting study is based on the retrospective study of 77 patients. They include patients over the age of 70 years old, and what they did is they divided patients from 70 to 74 and 75 years and older. Patients received a standard of care CAR T-cell therapy, either tisagenlecleucel or axi-cel. One, the PFS [progression-free survival] was no different, the overall survival was worse in patients older than 75 years old, and more interestingly, it was what they analyzed actually. They did a multivariate analysis that showed the use of axi-cel and risk score, hematopoietic cell therapy comorbidity score that is used commonly in transplant patients. When the score was more than 2, it was associated with a worse PFS. In terms of toxicity, they found out that patients who developed grade 3/4 cytokine release syndrome was associated with higher CIRS [cumulative illness rating scale] score, which is a comorbidity-illness score that measures the comorbidity and the impact on the patients, and also the use of axi-cel was associated with CRS. In addition, the CRES, which is CAR T-cell-related encephalopathy syndrome, was also associated with older age and CRES score of more than 6.

What this tells us is this is a valuable study that is evaluating patients older than 75 years old and the toxicity associated with CAR T-cell therapy. In real life, we do see those adverse effects. We prefer to use the less toxic product that’s proven by this study. We feel the axi-cel, while it’s very effective treating lymphomas, is essentially more toxic than tisagenlecleucel or other similar CAR T cells. However, age by itself is not the only factor that we keep in account. We also take into account other factors, specifically comorbidities, that we call functional age.

CAR T-Cell Therapy Clinical Trials 

 I alluded to the limits and practical issues to get access to the CAR [chimeric antigen-receptor T] T-cell therapy. But what do we do to try to make it better? With this ASCO [American Society of Clinical Oncology] 2020 Annual Meeting data, there was a small experience on re-treatment. Can you re-treat those patients with CAR T? And the reasoning behind this is that there is some evidence that these T cells will not stick around long enough. There was some discussion that on the need or not to have precise CAR T-cells. We had about one-third of the long responders in the ZUMA-1 trial who did not have resistant, long-term precision CAR T cell.

With the recovery of the B cells and even immunoglobulin, after a year we can see the CAR T cells disappear. But there’s also the idea that we can re-treat those patients who relapse. This was a small number of patients who were from the axi-cel setting, and over half the patients achieved a response: 4 CR [complete response], 3 PR [partial response]. What was interesting is that some of these responses can be durable: close to 3 months, up to 225 days for the longest. There was a rate of CRS [cytokine release syndrome] at re-treatment, but it seems there was less neurotoxicity and maybe also less CAR T expansion. We don’t know exactly how to read this, but it’s feasible.

There is an interesting question being explored at some other trials: Can we do repeat infusion of CAR T? That’s 1 strategy. The other 1 is that can we improve by bringing the CAR T earlier. That’s the question about the timing of the CAR T if we do it earlier in the second line. There’s the ZUMA-7 trial that has completed, but the results are pending. This other study is with liso-cel and tisa-cel also at a second line with a crossover, so in second-line therapy, randomizing against salvation transplant.

There was an interesting study looking at liso-cel in patients who are not transplant eligible. It is an interesting study because liso-cel potentially has an initial toxicity profile, so it might be easier to do. It’s a slightly different product when the CD4 and CD8 subtype of T cells are prepared separately and infused separately. They get the same for the patient. What was impressive in that study was not a huge number of patients but that the overall response rate was 89% and the CR rate was 56% with very low toxicity, and 12 of 29 patients we have done as an outpatient. This is really important because that offer is potentially an option for these nontransplant-eligible patients. It’s for durability, but this is something to take into account.

As for the results and data on the dual CAR T anti-CD19 and -CD22 in combination with pembrolizumab, there’s a very interesting study called the ALEXANDER study. The rationale for this is there is a subset of patients in large cell lymphoma that become resistant to CAR T because they lose CD19 expression. It’s something we see more frequently in ALL [acute lymphoblastic leukemia] as a mechanism of resistance than in large cell lymphoma, but it still happens. And so we try the dual CAR T CD19,-CD22 with PEMBRO [pembrolizumab] to try to see if we can improve. Knowing that a checkpoint blockade is also 1 of the mechanisms of resistance, can we improve the responses seen? This is dose escalation, not a large number of patients. But the response rate was very high: 10 of the 11 CRs. A small number are ongoing. There was no grade 3 CRS and 1 grade 3 neurotoxicity. The recommended phase 2 is 150 to 450 million, and we did want PEMBRO [pembrolizumab] selected.

The last study at ASCO that is worth mentioning was the ALLO CAR T-cell off the shelf. That is a product called ALLO-501, a gene-editing-based technology to remove the T-cell receptor and CD52. This is also used as a dose escalation, presented by Dr Sattva Neelapu. It shows a response rate of 63% with half these patients in complete remission, and 75% of the patients who responded were still in response at the time of cutoff.

That’s also interesting because there was no GvHD [graft-vs-host disease], and there was allogeneic healthy T cell. There was no dose-limiting toxicity, 1 grade 3 CRS, and no neurotoxicity. That’s very appealing because it would be off-the-shelf, ready-to-go T-cells. Potentially that’s very important because 1 of the factors of failure of CAR T is the T-cell fitness. Patients who are heavily pretreated have a lot of immunosuppressive adverse effects with the active disease of ongoing lymphoma. These patients don’t have the best activity. If we have normal allogeneic normal T cells, that might address the problem.

The last aspect that is also important was from ASH [American Society of Hematology Annual Meeting], and this is the BiTE [bispecific T-cell engager] antibody because we know that patients still can fail quite a bit of CAR T cells, and it was an anti-CD20 bispecific antibody, a BiTE antibody, presented in a plenary session at ASH. It was very impressive because this was a response rate of 39%, 22% CR. But there were some responses, durable and a CR durable in continued remission, even in patients who had stopped therapy after 16 months of treatment. This is also being explored in the frontline setting in combination with chemotherapy, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–POLA [polatuzumab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. A number of initiatives are trying to address the new unmet need that we have in CAR T cells. Now we know how to manage more toxicity. Can we improve on efficacy and look at easier ways to use those CAR T cells?

CAR T-Cell Therapy Response Rates

 Chimeric androgen receptor T cells, or CAR T cells, are autologous T cells, T lymphocytes, that are derived from the patient. They have to be collected through a standard leukapheresis procedure at an authorized treatment center. Then the cell product in a self-contained isolated sterile container is shipped to a manufacturing center. Right now, in 2020, there are 2 FDA-approved therapies, axi-cel and tisa-cel. The 2 FDA-approved therapies are both directed against anti-CD19 on the target of B cells. And the chimeric antigen receptor is introduced into the patient’s own T cells through a viral transduction method, which is done, again, in an authorized treatment center in a manufacturing facility that works with an authorized treatment center. That viral transduction process takes a couple of weeks to take place, then those cells expand to sufficient numbers that can then be used to be delivered to the patient for therapeutic benefit.

In our center we have been involved quite a bit in CAR T cells with the NCI [National Cancer Institute] for 7, 8, 9 years ago now. When the patients who are candidates for this with the approved CAR T cells are in third-line setting, there are a number of ongoing trials that they are trying to look at if we can take advantage of this approach early on in the disease.

But what’s really important to summarize is that there are 3 different products among the most advanced axi-cel therapies from the ZUMA-1 data. Now that we have follow-up with this, the tisa-cel from JULIET and liso-cel from the JCAR017 trial TRANSCENDWORLD, they’re slightly different in terms of the signal CD28 for axi-cel and 4-1BB for tisa-cel and liso-cel. There’s a slight difference in the population of relapsed/refractory, the dosing process, the bridging therapy allowed on that. What is interesting is that the response rates went from 52% to 83% and the CR [complete response] rate from 40% to 58%. In a population that really has no option, this is quite considerable. And what is interesting in that setting is that there is some late delayed response. Up to 20%, 30% of patients can have a late response. Sometimes it can take up to a year, and that’s really important. Typically patients respond very rapidly, but it can take a while because it’s a live therapy. This is very important.

With our long-term follow-up, what is interesting also is that particularly in the ZUMA-1, where we have the longest follow-up, we’re at 27 months and close to 40% of the patients are doing really well and half the patients are alive. This is very impressive, and potentially a good fraction of these patients can be cured. One issue is the durability of the remission in this population, because the relapse is still definitely an issue, and the salvage after CAR T is very difficult. The patient who has CNS [central nervous system] involvement, for example, is also a significant issue.

There are some data—not a lot of data, particularly on tisa-cel—looking at patients who had known CNS disease, including disease with some durable responses. But overall, there’s not a lot of experience, and it could be a challenge, particularly toxicity from T cells. Toxicity from the CRS [cytokine release syndrome] and the neurotoxicity are very well known now. But we can manage this toxicity much better preemptively with tocilizumab and then with steroids. One of the questions that comes up is, what’s the best timing and the best combination that you can build on CAR T cell and how we overcome the resistance to CAR T? Those are the issues that I can see in CAR T.

How does CAR T-cell therapy affect patient outcomes and costs? We currently have 2 CAR T-cell products approved for relapsed/refractory diffuse large B-cell lymphoma, tisagenlecleucel and axicabtagene ciloleucel, but there has not been a comparison head-to-head. In clinical practice, there are some differences in terms of toxicity and efficacy. They both have the inherent risk of CRS and neurological events. There is probably more toxicity with axi-cel than tisagenlecleucel. But in general, both carry the same risk, so the patient has to be monitored closely in CAR T-cell therapy centers.

One of the challenges is some patients live far away from the centers, so they have to relocate into the cancer center, and that adds cost. They need a caregiver to stay off work for 1 or 2 months, and that’s another type of cost that families endure with the CAR T-cell therapy. I’m not talking about the cost of the treatment. CAR T-cell therapy is a very expensive treatment. There are also the management of the adverse effects, the use of tocilizumab on admission to the hospital, the use of an intensive care unit bed. Those factors increase the cost. For these reasons, cost and logistics, some patients may decide not to do CAR T-cell therapy, even though it’s a curative option.

CAR T Cell Therapy in Relapsed/Refractory DLBCL

 For patients who have relapsed or refractory diffuse large B-cell lymphoma [DLBCL], the standard of care remains second line, sometimes called salvage chemotherapy, usually with a platinum-based regimen such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin].

About half of patients who have relapsed or refractory DLBCL, who receive salvage or second-line platinum-based chemotherapy, will achieve a remission. Those patients are most appropriate to be referred on to consolidation, high-dose chemotherapy with autologous stem-cell transplant.

Of the patients who then go on to transplant, probably about 40% or in some series about half, will have a durable remission. But remember, only about half of the relapsed patients make it to transplant. So we’re talking about less than 1 of 4 patients with relapsed disease actually being cured with a standard salvage approach.

Second, for patients who receive second-line chemotherapy and fail to have an adequate response to let’s say a platinum-based regimen—such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], or maybe rituximab with gemcitabine and oxaliplatin—it’s another regimen.

For those patients, the outcome has historically been extremely poor with very short overall survival measured in months. Over the past couple of years, since 2018, we’ve had FDA approval of anti-CD19 CAR [chimeric antigen receptor] T-cell therapy, which is the most appropriate treatment for patients who do not respond to second-line chemotherapy.

 Yes. Polatuzumab vedotin is an antibody-drug conjugate, humanized anti-CD79B monoclonal antibody, conjugated into MMAE(?). CD79B is a B-cell specific marker expressed on the surface of a number of lymphomas but particularly diffuse large cell lymphoma. As I mentioned, this was a treatment that was done in patients with relapsed/refractory, not candidates for transplant. In 40 patients per arm, the CR [complete response] rate was 40% versus 50%. It was a clear advantage in the duration of response, PFS [progression-free survival], and overall survival. This was relatively easy to tolerate. This is a population that is sometimes difficult because they have received several lines of therapy. But there is an ongoing phase 3 POLARIX trial that is trying to integrate this in a complex frontline setting to compare with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. This is really going to be an important aspect, particularly because these patients might not be candidates for doxorubicin. Who knows, in the future that might be an option for these patients.

As we mentioned before, there will be a significant percentage of patients who will not respond to standard chemotherapy such as R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and the standard of care for those patients is to receive chemotherapy followed by autologous transplant. However, this standard of care may not be applicable for all patients for many reasons, such as comorbidities, old age, access, or patients cannot get into a transplant center, for instance. The same applies for other regimens that are currently approved, like the CAR T-cell therapy, in which again the logistics, the cost, and the access will be a challenge for them.

In that regard, treatment options for ineligible patients for CAR T-cell therapy or transplant are needed. One of the agents that are approved, polatuzumab in combination with bendamustine and rituximab, is an interesting option for patients because it can be done in the community. Community doctors are familiar with the administration of BR [bendamustine, rituximab], and polatuzumab is a monoclonal antibody that has been approved for over 6 months already, and oncologists are familiar. It’s a time-limited therapy option, so patients don’t have to be on indefinite therapy, which is a convenience. But it’s not a curative option. That should be considered.

Other agents that are in the pipeline, like tafasitamab, is also an outpatient option. One of the disadvantages is that while it has good overall response rates, patients have to remain on treatment. So in theory, we cannot talk about cures with this regimen. Finally, selinexor, which is a recently approved regimen, is oral. The advantage is it’s not an IV [intravenous], you don’t need a line; however, some of the toxicity profile remains challenging because it’s a new agent and the doctor has to be familiarized with the agent. Also, its efficacy—in my opinion, it’s a modest efficacy, about 31% response rate, a little over 10% to 15% CR rates. That is the information that physicians need to know, that they can transmit to their patients in order to make a decision.

Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology

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