COMMENTARY

R-squared Update: Underwhelms in FL, but Impressive in MCL

Bruce D. Cheson, MD; Nathan H. Fowler, MD

Disclosures

December 15, 2014

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Bruce D. Cheson, MD: I'm Bruce Cheson, deputy chief of hematology/oncology and head of hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights from the 2014 annual meeting of the American Society of Hematology (ASH) in San Francisco.

Joining me is Nathan Fowler, associate professor in the Department of Lymphoma and Myeloma at the MD Anderson Cancer Center in Houston, Texas. I thought we would talk about some of the sort of new, and new, drugs—one of which is lenalidomide, which has been around for a while. There has been some interest in it, and the interest is starting to increase. It is a second-generation immunomodulatory drug, and you have a lot of experience with it.

There were some interesting studies at this meeting using lenalidomide in relapsed patients in large cell and mantle cell lymphoma. We know that it has some activity, but we have other drugs with which to treat patients. Here, we saw some studies comparing lenalidomide with standard of care.[1,2]

Single-Agent Lenalidomide vs Single-Agent Investigator's Choice

Nathan H. Fowler, MD: This has been a strategy for a lot of drugs that have been developed recently—to use a single agent against what they call "investigator's choice," or what would commonly be used in the community for patients with relapsed disease. In these two studies, they were looking at lenalidomide's ability to beat what would be considered potentially a standard in the community for relapsed mantle cell lymphoma and relapsed large cell lymphoma.

Both of these were randomized studies. They took patients who most of us would argue don't have a lot of treatment options: patients in whom multiple lines of treatment have failed. The thing in common between these two studies is the way they were designed. They were really trying to see whether single-agent lenalidomide was better than single-agent investigator's choice therapy. They had a laundry list of different types of such drugs as gemcitabine, rituximab, and fludarabine—arguably not the best drugs to use as a control.

Dr Cheson: But that's what's out there.

Dr Fowler: Yes, it's a testament to the lack of good drugs for these patients. Both of the studies were positive. Both showed benefits in overall survival and progression-free survival when single-agent lenalidomide was compared with investigator's choice.

Dr Cheson: In a patient with relapsed large cell lymphoma, in the absence of a clinical trial, would you use lenalidomide as a single agent?

Dr Fowler: If I had a patient in whom multiple lines of treatment had failed, I would definitely consider lenalidomide.

Dr Cheson: It's easy. It's a pill.

Dr Fowler: It's oral. There are data from our center, as well as others, that when using this drug in combination for relapsed large cell lymphoma, the response rate is slightly higher than 50%.

R-squared Regimen for Follicular Lymphoma, Mantle Cell Lymphoma

Dr Cheson: What drugs other than rituximab are being used?

Dr Fowler: Lenalidomide and rituximab are used for mantle cell lymphoma, relapsed mantle cell lymphoma, and relapsed large cell lymphoma. If you add rituximab to lenalidomide as a single agent, not just in low-grade but in some of the more aggressive histologies, you can get a little more mileage.

Dr Cheson: Speaking of lenalidomide and rituximab, about a decade ago, along with the Cancer and Leukemia Group B, we came up with a regimen called "R-squared" (lenalidomide and rituximab). We tested it first in relapsed, not refractory, follicular lymphoma, and got some very impressive response rates. And then we brought it up front and got some very good response rates. But there was a study at this meeting from Eva Kimby and the Nordic group that didn't look the same.

Dr Fowler: We have been thinking about this combination for many years, both when we were together at Georgetown and in Houston. We were able to design up-front regimens with lenalidomide and rituximab, which looked phenomenal. You can argue that single-center experiences won't reflect what you would see in a second study, but as you mentioned, the cooperative groups also showed similar high responses—on the order of 70%-80% in patients with untreated follicular lymphoma.

Dr Cheson: Ours was 90%.

Dr Fowler: The overall response rate was over 90%, and the complete response rate was very good.

Dr Cheson: It was phenomenal.

Dr Fowler: On the backbone of those two studies, several groups have been looking at this combination in untreated follicular lymphoma: the RELEVANCE study, which was the randomized, large phase 3 study that recently completed accrual in this subset of patients.[3]

Dr Cheson: That was R-squared vs R-chemo.It could have been rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP); rituximab, cyclophosphamide, and vincristine sulfate (R-CVP); or rituximab and bendamustine (R-bendamustine), and there were 1000 patients.

Dr Fowler: We recently completed accrual. Of interest, at this meeting we are seeing the results of a Nordic study in which instead of comparing R-squared, or Revlimid®-rituximab, vs chemo, they compared it against rituximab alone..[4] And the schedule of dosing was different with these two drugs. Lenalidomide was used at a lower dose: 15 mg. They also dosed patients continuously. Many R-squared regimens use 21-day-on, 7-day-off schedules. They only used four cycles of treatment.

It's unclear what differences contributed to the outcome of the study, but I guess the punch line is that the overall response rate was significantly lower in R-squared in their hands, and the complete response (CR) rate was in the mid-30s.

Dr Cheson: It was actually a negative study.

Dr Fowler: It was statistically negative, yes. The study authors were looking for a difference in the CR rate of around 20%, and at the end of the day, it was around 11%-12%. That is going to require further analysis. Many of us are hopeful that with continued follow-up, the CR rate will improve in the Nordic study, but clearly, the outcomes are different than what we've seen.

Dr Cheson: You saw a very high CR rate with only six cycles.

Dr Fowler: Yes, although I would mention that when we looked at three cycles, our CR rate was around 50%. And there definitely was an improvement in CR when we went from three to six, so it's possible.

Dr Cheson: Some other histologies have been treated with this combination, such as mantle cell lymphoma. Michael Wang from your institution has generated some data with that regimen.

Dr Fowler: That's right. We have seen, both in preclinical models and mouse models and now in human studies, that the combination definitely looks more active than either agent alone. My colleague, Michael Wang, and the group at MD Anderson did that combination in patients with relapsed mantle cell lymphoma. And the responses were quite impressive. That was published in Lancet Oncology[5] not too long ago.

To follow-up on that, there is another R-squared study in untreated mantle cell lymphoma patients that is being presented at this meeting, from the Cornell group,[6] and it looks quite interesting. Many of us in follicular lymphoma have been trying to think of a nonchemo approach to treating patients with new disease. And although I would never have thought that we could do this in mantle cell lymphoma, the data look very impressive.

Dr Cheson: Their response was more than 85%, with more than 80% progression-free survival at 2 years.

Dr Fowler: That is fantastic.

Excited About Small Molecules

Dr Cheson: It is very exciting. That's that drug. But everybody is very excited about small molecules—the kinase inhibitors, and the proapoptotic drugs. You were involved with Ranjana Advani and others in some studies with ibrutinib up front, and you got nice response rates. At this meeting, Nancy Bartlett and coworkers[7] didn't report such good response rates. You had about 56%; she had about 30%. What do you think about that?

Dr Fowler: Just to clarify, in our phase 1 experience, the response rate in low-grade lymphomas was around 50%. Across the board, it was a little bit higher. But in the patients with indolent and follicular lymphoma, in the phase 1 experience, which was about 17 patients, our overall response rate at the active dose level was approximately 55%. That generated a lot of buzz, and now several studies are looking at this drug, ibrutinib, in low-grade lymphomas.

One of the larger studies is coming out at this meeting, by Nancy Bartlett. She saw an overall response rate of around 30%. It's unclear why. This is a perfect example of what we sometimes see in phase 1 trials, which doesn't always reflect what you experience when you expand to phase 2 and 3 trials.

I am hopeful that with continued follow-up, the overall response rate is going to deepen. We saw that in the phase 1 study with ibrutinib in low-grade lymphomas. It's clear that the longer patients remain on study, the deeper the remission. I'm hopeful that that response rate will improve a bit. It's hard to know. The patient populations look very similar to what we saw in the phase 1 study. It may be that this drug, although it has activity in low-grade lymphoma, needs to be combined with other drugs to maximize its activity.

Dr Cheson: Another drug with activity in this setting—idelalisib—has some interesting responses, approximately 60%. And there is another one at this meeting.[8,9] We will call it duvelisib, because no one will know what we are talking about. But it's IPI-145, the delta/gamma inhibitor.

Dr Fowler: That looks very interesting. This drug is similar to idelalisib, which was approved this year for double-refractory, relapsed follicular lymphomas. Like idelalisib, it appears to have significant activity in low-grade lymphomas, with response rates pushing 60%. It is clear that this class of drugs, the phosphoinositide-3 (PI3) kinase inhibitors, will probably have a role in the future treatment of low-grade lymphomas.

Many of us are very excited to see what happens when we start combining these drugs. We have a lot to learn about the biology of how these drugs work in different histologies, and we have learned from some studies that were recently completed that significant toxicity can occur if you combine these drugs without truly understanding the biology. So although we have a lot of great drugs, and they appear active in a lot of histologies, there is still a lot of work.

Dr Cheson: Yes, we need biomarkers that tell us who is going to respond to one vs who is going to respond to the other. They are very exciting, but they are very different.

Thank you, Nathan. There is a lot of good stuff at this meeting, and I appreciate your joining me here to present this to our audience. Thank you for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson, signing off from ASH 2014.

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