Ian W. Flinn, MD, PhD

Ian W. Flinn, MD, PhD, director of lymphoma research at the Sarah Cannon Research Institute, discusses how he decides when to use the combination of the antibody-drug conjugate polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (Rituxan; pola-BR) in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

The basis of his decision comes from the results of a phase 2 trial (NCT02257567) that looked at 80 patients, randomized 1:1, receiving either 1.8 mg/kg of polatuzumab every 3 weeks plus BR for 6 cycles, or only BR. The primary end point of complete remission (CR) was met with a CR rate of 40% in the pola-BR arm compared with 17.5% in the BR-alone arm.

Moreover, at a median follow-up of 22.3 months, patients on the combination therapy had a median progression-free survival of 9.5 months vs 3.7 months in the B-alone arm (HR, 0.36; 95% CI, 0.21-0.63; 

 < .001). Survival benefit for patients with pola-BR continued to be demonstrated with a median overall survival of 12.4 months with polatuzumab compared with 4.7 months in the patients just on BR (HR, 0.42; 95% CI, 0.24-0.75; 

, Flinn previously discussed these impressive results for patients with a median of 2 prior lines of therapy but does caution that factoring in the patient’s willingness to handle adverse events should be considered. Moreover, he highlights which patients he typically recommends pola-BR for and when to consider other therapies, such as tafasitamab (Monjuvi) in combination with lenalidomide (Revlimid), or loncastuximab (Zynlonta), in this patient population.

I use [pola-BR] in patients who have more aggressive disease, so those patients who need a quicker response, who have bulky disease, as they are the patients that are most likely to use this regimen. [Now,] there are other options. For instance, you can think about [using] other approved agents such as loncastuximab, [which is] a reasonable option. Another reasonable option is lenalidomide and tafasitamab. They are largely immunological based therapies, [and] I tend to use those regimens in patients that perhaps are primary refractory or don't have as aggressive disease. For those patients that you need a quick response in, then I tend to use the antibody-drug conjugate with [BR].

One other thing to think about is, you want to be careful about using an anti-CD19 therapy in patients [for whom] ultimately the goal is to take them to CAR-T cells, because you might downregulate CD19 and make a CAR T-cell ineffective. On the other hand, you want to avoid bendamustine in patients who prior to harvesting of T cells, as bendamustine is a very lympholytic agent and significantly decreases the number of T cells, [because it] might make it difficult for a patient to go on to receive CAR T cells.

Videos

Ian W. Flinn, MD, PhD, discusses what factors go into his decision to use polatuzumab plus bendamustine and rituximab in certain patients with relapsed/refractory diffuse large B-cell lymphoma. 

Deciding When to Use Polatuzumab + BR in R/R DLBCL

Ian W. Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Cancer Institute, discusses his experience using the combination of polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (Rituxan; pola-BR) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

The antibody-drug conjugate pola-BR was approved based on a phase 2 study (NCT02257567) for patients who had at least 2 prior therapies for DLBCL. Flinn says he’s seen good results for this treatment and it serves a valuable role in this setting.

He notes that bendamustine is associated with hematopoietic toxicity that can be difficult for patients to tolerate. Since polatuzumab is believed to be the most active drug in the regimen, he often reduces the dose of bendamustine, which leads to more tolerability with maintained efficacy.

Additionally, Flinn says this therapy can be used with no bendamustine as a bridging therapy to chimeric antigen receptor (CAR) T-cell therapy or between leukapheresis and CAR T-cell infusion. Bendamustine may decrease T-cell counts which would interfere with leukapheresis for CAR T-cell production.

 I think that it has surprisingly great results, and for many patients. I often dose reduce the bendamustine because I think many people think the most active therapy here is the polatuzumab vedotin, and we're not 100% sure how much the bendamustine adds to it. It does—because of the underlying bendamustine rather than the polatuzumab—there is hematopoietic toxicity associated with this. And so, by decreasing the bendamustine, you can make it a little bit more tolerable.

The other thing is that this therapy is supposed to be given on a 21-day basis; we know that that's difficult for any bendamustine-containing regimen. I think by decreasing on bendamustine, it makes it easier for patients to tolerate it. So I've had great results. Sometimes I use this regimen without the bendamustine at all for those patients that I’m trying to bridge to CAR T cells or even for those patients that are between having their leukapheresis and receiving the CAR T cells. It's not a bad therapy to bridge patients to that more definitive treatment.

Ian W. Flinn, MD, PhD, discusses his experience using the combination of polatuzumab vedotin-piiq plus bendamustine and rituximab for patients with relapsed/refractory diffuse large B-cell lymphoma. 

Improving Tolerability of Polatuzumab + BR for R/R DLBCL

Ian W. Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Cancer Institute, discusses the study design and results of the phase 2 trial (NCT02257567) of the antibody-drug conjugate polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (Rituxan) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

In cohorts C and D of this trial, 80 patients were randomized 1:1 to receive either 1.8 mg/kg of polatuzumab every 3 weeks plus bendamustine and rituximab for 6 cycles, or only bendamustine and rituximab. The primary end point was complete response (CR) rate as assessed by an independent review committee.

The primary end point was met, with a CR rate in the polatuzumab arm of 40%, versus 17.5% in those receiving only bendamustine/rituximab. At a median follow-up of 22.3 months, the polatuzumab arm had a median progression-free survival (PFS) of 9.5 months versus 3.7 months in the other arm (HR, 0.36; 95% CI, 0.21-0.63; 

 < .001). Median overall survival (OS) was 12.4 months with polatuzumab versus 4.7 months with only bendamustine/rituximab (HR, 0.42; 95% CI, 0.24-0.75; 

Flinn says these are impressive results considering that patients had a median of 2 prior lines of therapy. This trial led to the approval of polatuzumab vedotin plus bendamustine/rituximab as third-line therapy for R/R DLBCL.

This was the study of polatuzumab vedotin with bendamustine and rituximab. There are several different arms of this trial, but the pivotal arm was a randomized phase 2 trial that had a 1:1 randomization for patients who had previously treated DLBCL that had relapsed/refractory patients. There were 80 patients on this trial; patients are randomized 1:1 to receive [bendamustine/rituximab] plus or minus polatuzumab. And the primary end point of this study was CR rate.

 The basic results of this study were that 40% of patients achieved a CR rate with a CR with polatuzumab/BR versus 17.5% of patients who are on the [bendamustine/rituximab]-alone arm, and…that met the primary end point of the study which was a higher CR rate as judged by an independent response committee. The other end points of the study were PFS and OS. And there was a substantial improvement in PFS for those patients treated on the experimental arm, it was 9.5 months versus 3.7 months.

 And then the OS was also surprisingly much improved with those patients who received the polatuzumab-containing arm. I say surprisingly, because this was third line, and the magnitude of difference was pretty large; it was 12.4 months versus 4.7 months. And when you think about it, this is not very many patients, just 40 patients per arm. To me, this was very spectacular results.

Ian W. Flinn, MD, PhD, discusses the study design and results of the phase 2 trial of the antibody-drug conjugate polatuzumab vedotin-piiq plus bendamustine and rituximab for patients with relapsed/refractory diffuse large B-cell lymphoma. 

Polatuzumab Shows Improved Survival and Complete Responses in R/R DLBCL

Ian W. Flinn, MD, PhD, director of lymphoma research and a principal investigator at Sarah Cannon Research Institute, and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, discusses the Bruton’s kinase (BTK) inhibitors available for patients with B-cell malignancies and how they compare.

There are many ongoing trials with zanubrutinib (Brukinsa) and other BTK inhibitors in the B-cell lymphoma landscape. Flinn says the biggest issue in these disease settings currently is deciding which BTK inhibitor is better to use for these patients. Head-to-head trials are looking at zanubrutinib with ibrutinib (Imbruvica) versus acalabrutinib (Calquence) with ibrutinib to get a better understanding of how the efficacy and adverse event profiles compare.

Many people think that these drugs are fairly similar in their efficacy, but because some patients have to come off treatment—most prominently with ibrutinib—that cuts into the efficacy because patients are no longer on therapy, according to Flinn. He thinks that may be where the differences are most evident for patients and will help physicians decide which BTK inhibitor is best to use depending on the patient.

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Ian W. Flinn, MD, PhD, discusses the Bruton’s kinase inhibitors available for patients with B-cell malignancies and how they compare.

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Articles

Ian W. Flinn, MD, PhD, director, Blood Cancer Research Program, principal investigator, Sarah Cannon Research Institute, discusses a phase I story which examined cerdulatinib in patients with relapsed/refractory B-cell malignancies.

Cerdulatinib in Relapsed/Refractory B-Cell Malignancies

Ian W. Flinn, MD, PhD, director, Hematologic Malignancies Research Program, Sarah Cannon Research Institute, discusses the mechanism of action and toxicity profile of duvelisib (IPI-145). Duvelisib is being studied for the treatment of hematologic malignancies.

Duvelisib inhibits both delta and gamma isoform.

The hope is that the molecule targets both the tumor cell as well as the microenvironment.

The toxicity profile of duvelisib is still being studied.

To date, the molecule appears to have a similar toxicity profile of other PI3K inhibitors.

Ian W. Flinn, MD, PhD, discusses the mechanism of action and toxicity profile of duvelisib (IPI-145). Duvelisib is being studied for the treatment of hematologic malignancies.