CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: May 10, 2022
Expiration: May 09, 2023
John M. Burke, MD:
This is a single‑arm, pivotal phase II study of the bispecific antibody mosunetuzumab in patients with R/R FL.15 Bispecific antibodies are designed to simultaneously target an antigen on the malignant B‑cell and an antigen on a nonmalignant T‑cell. By doing so, in theory, the bispecific antibodies can redirect the T‑cell to kill the malignant B‑cell. Mosunetuzumab targets CD20 on the malignant B‑cell and CD3 on the nonmalignant T‑cell. There are several CD20 x CD3 bispecific antibodies under investigation in lymphoma, and mosunetuzumab may be the furthest along in clinical development.
In this phase II study, 90 patients with grades 1‑3a FL who had received at least 2 prior systemic therapies, including an anti‑CD20 antibody and at least 1 alkylating agent, were eligible to participate. Mosunetuzumab was initially administered intravenously in 21‑day cycles for 8 cycles. Step-up dosing was used in the first cycle to mitigate CRS. In the second cycle, patients received a single dose of mosunetuzumab (60 mg) on Day 1, but in cycles 3-8, patients received 30 mg of mosunetuzumab on Day 1. Patients who achieved a CR by cycle 8 discontinued treatment, but those with a partial response or stable disease by cycle 8 continued treatment for 17 cycles or until disease progression or unacceptable toxicity. The primary endpoint was CR rate, assessed against a 14% historical control CR rate.
John M. Burke, MD:
The median number of prior lines of therapy was 3, and 68.9% of the patients were refractory to their last therapy; 78.9% were refractory to an anti‑CD20 antibody, but 53.3% were refractory to an anti-CD20 antibody and an alkylating agent. In the study population, approximately 52% of the patients had progressed within 24 months of their initial therapy. With a median follow-up of 18.3 months, approximately 59% of the patients had received 8 cycles of mosunetuzumab therapy, 5.6% had received 9‑16 cycles, and 12.2% had received all 17 cycles. Approximately 23% of the patients discontinued therapy before receiving 8 cycles of mosunetuzumab.
John M. Burke, MD:
The ORR by independent review was 80%, and the CR rate was 60%. The trial met its endpoint of demonstrating a higher CR rate than the historical control CR rate of 14% (P <.0001). The CR rate was 50% in patients with double refractory disease and 71% in those without double refractory disease.
John M. Burke, MD:
The median duration of response in all responders was 22.8 months, and the median PFS in all patients was 17.9 months. The 12-month and 18-month EFS rates in all responders were 62% and 57%, respectively. The median time to first response was 1.4 months.
John M. Burke, MD:
Grade 3 and 4 adverse events were fairly common and were reported in 70% of patients; mosunetuzumab-related grade 3-4 adverse events occurred in 51% of the patients. Only 2% of patients discontinued therapy due to mosunetuzumab-related toxicity, which is a good indicator of the tolerability of the drug. Neurotoxicity was uncommon and reported in only 4.4% of patients, all of which were grade 1-2 events. Grade 3-4 neutropenia was fairly common and reported in 26.7% of patents. All grade infections were reported in 20% of the patients.
John M. Burke, MD:
CRS remains a concern with bispecific antibodies. Any grade CRS occurred in 44.4% of patients, but grade 3-4 CRS occurred only in 2.2%. CRS events occurred mostly during cycle 1, with fewer events in cycles 2 and beyond. The median time to the onset of CRS was shorter in cycle 1 Day 1 compared with cycle 1 Day 15. The median duration of CRS, when it occurred, was 3 days. Among patients who received treatment for CRS, 7.8% received tocilizumab and 11.1% received corticosteroids.
John M. Burke, MD:
Based on these results, it seems likely that mosunetuzumab will receive FDA approval at the investigated dose and schedule for use in patients with grade 1-3a FL who have received at least 2 prior lines of therapies. It demonstrated a high rate of efficacy with an ORR of 80% and a CR rate of 60%.
Compared with CAR T‑cell therapy, mosunetuzumab offers easier administration and potentially fewer insurance coverage issues, although patients will need to continue therapy for up to 6‑12 months vs only 1 dose of CAR T‑cell therapy infusion. The rates of CRS and neurotoxicity also appear favorable with mosunetuzumab compared with CAR T-cells, but CRS is still an issue, and some patients may need tocilizumab and/or corticosteroid therapy. Since most community oncologists may lack experience in the management of CRS, it will be important to provide education and training to prepare physicians for the management of CRS, which will likely occur in some patients who are treated with mosunetuzumab.
Overall, I think mosunetuzumab will likely be a very useful tool in the management of patients with R/R FL. In ongoing and future trials, I expect to see the use of mosunetuzumab in different combinations and in earlier treatment settings.
Peter Martin, MD:
Bispecific anti‑CD20/anti‑CD3 antibodies are clearly among the most active agents in R/R FL compared with already approved drugs. It is also clear that these bispecific antibodies are not just acting as anti‑CD20 antibodies. They have distinct adverse events, including inflammatory adverse events and infections, and they differ from CAR T‑cells in that the rates of CRS are significantly lower. There are some challenges related to the delivery of bispecific antibodies, including step‑up dosing and the potential need for hospitalization. These are drugs that will need some experience to be used effectively.
A major question that remains regarding the use of bispecific antibodies is where they fit relative to CAR T‑cell therapy, and there is no clear answer to that question yet. However, we can conclude that combination studies will likely be easier to perform with bispecific antibodies than with CAR T‑cells, and this is probably 1 of the biggest advantages of bispecific antibodies. Like Dr. Burke stated, I also expect that over the next several years, we will see combination studies that may make these already effective agents even more effective.
Peter Martin, MD:
The single‑arm, phase II ELARA trial evaluated tisa-cel in 97 patients with high‑risk R/R FL. The study enrolled patients with grade 1-3a R/R FL who had not previously received an anti-CD19 therapy or allogeneic hematopoietic stem cell transplant. Patients with histologic transformation were excluded from this trial.
The study design was fairly straightforward, with an apheresis phase followed by optional bridging chemotherapy and restaging with lymphodepletion. Of note, the lymphodepletion in this study included bendamustine or the standard fludarabine/cyclophosphamide conditioning regimen used in many CAR T‑cell studies. This was followed by tisa-cel infusion with posttreatment follow-up every 3 months for the first year and then every 6 months until the end of the study. The primary endpoint was CR rate by independent review.
The primary analysis of the results from the ELARA trial at a median follow-up of 11 months was previously reported.16 At ASH 2021, the results of the ELARA trial with extended median follow-up of 17 months were presented.17
Peter Martin, MD:
The safety analysis with extended follow-up showed that 96.9% of the patients experienced an adverse event, and nearly one half of all patients (48.5%) experienced some degree of CRS. Of note, all the CRS events were grades 1 and 2, and the use of tisa-cel resulted in a very low rate of grades 3/4 neurologic events. These results potentially reflect the tolerability of tisa-cel relative to the other CAR T‑cell therapies.
Peter Martin, MD:
At the primary analysis of the ELARA trial, an overall response rate of 86% and CR rate of 66% were reported. With extended median follow-up of 17 months, the overall response rate was maintained at 86.2% with a CR rate of 69.1%. The responses appear durable, with a 12‑month PFS of 67% in all patients and a 12-month PFS of 85.5% in patients who achieved a CR. The median PFS was 29.5 months. Overall, the efficacy results are impressive.
Peter Martin, MD:
Efficacy analysis was performed in 9 high-risk subgroups, including patients with a high Follicular Lymphoma International Prognostic Index score at study entry, patients with early disease progression, those with bulky disease at baseline, patients with double refractory disease, and patients with a high C-reactive protein prior to tisa-cel infusion. Of interest, a high total metabolic tumor volume (>510 mL) was associated with a higher incidence of bulky disease, high Follicular Lymphoma International Prognostic Index score and a high C-reactive protein; however, these numbers are all still quite small.
Peter Martin, MD:
Consistent with other CAR T‑cell trials in R/R lymphomas, the ELARA study demonstrated the efficacy of tisa-cel in R/R FL, which is clearly encouraging. The follow-up period for these CAR T-cell therapy studies is still too short to confidently comment on durability or curability, especially in DLBCL. With an 11-month follow-up, the 6-month PFS rate in the ELARA trial was 76%. With extended follow-up however, it is worth noting that relapses continue to occur with tisa-cel, with a 12-month PFS rate of 67%. With time, we may ultimately learn that CAR T‑cells are not as effective in FL as they seem to be in DLBCL, or at least they may not be effective in all patients.
The other notable feature of this trial was the tolerability of tisa-cel, with no grade 3/4 CRS events and rare occurrence of grade 3/4 immune effector cell–associated neurotoxicity syndrome. It is hard to know whether this outcome is a product of the disease or the specific CAR T‑cell therapy used in the study. Nonetheless, the results are encouraging. This raises the question of whether there is a scenario in which you can select a specific CAR T‑cell product based on the situation, considering the patient population and the disease at hand. These are interesting questions that will need to be answered as multiple different CAR T-cell products become available in the future.
John M. Burke, MD:
It is likely that the ELARA trial results will lead to approval by the FDA of tisa-cel for R/R FL, which would make tisa-cel the second CAR T‑cell product to get approval for this disease. CAR T‑cell therapy definitely has a role in R/R FL, but it is still debatable exactly where it should be used, whether it will be used for the majority of patients, or if it will be reserved only for younger, healthier patients with particularly aggressive disease. In summary, tisa-cel still needs to find its place in R/R FL, but it is likely to become a new option for patients with this disease.
John M. Burke, MD:
The use of a PI3K inhibitor is another treatment strategy in the management of R/R FL. Copanlisib is a PI3K inhibitor that targets the alpha and delta isoforms and is currently approved for R/R FL after 2 or more prior therapies. Three other PI3K inhibitors—idelalisib, duvelisib, and umbralisib—had been approved for patients with R/R FL, but recently all have had their indications in the United States withdrawn for relapsed FL. Parsaclisib is a novel investigational PI3K inhibitor that selectively inhibits the delta isoform. Based on its unique molecular structure, it is expected to improve selectivity and potency while at the same time causing less toxicity, particularly hepatotoxicity, compared with the other PI3K inhibitors.
The phase II CITADEL‑203 trial evaluated the efficacy of parsaclisib in 126 patients with R/R FL (grades 1‑3a).18 Eligible patients had received at least 2 prior systemic therapies but without any prior exposure to a PI3K or BTK inhibitor. All patients were ineligible for hematopoietic stem cell transplant. One of the goals of the trial was dose finding, so patients initially were assigned sequentially to receive 1 of 2 doses, either 20 mg daily for 8 weeks followed by 20 mg weekly or 20 mg daily for 8 weeks followed by 2.5 mg daily. An analysis performed after roughly 23 patients had been enrolled onto each arm led the investigators to believe that the daily dosing strategy would be more effective, so the weekly dosing schedule was discontinued although enrollment to the daily dosing group continued. Of the 126 patients enrolled on the study, 103 were in the daily dosing group. The primary endpoint of the study was ORR by independent review.
John M. Burke, MD:
The baseline characteristics show that patients had received a median of 2 prior lines of therapy and that approximately 49% of patients were refractory to their most recent line of therapy.
John M. Burke, MD:
The ORR in the daily dosing group was 77.7%, and the CR rate was 19%. The median duration of response was 14.7 months, and the median PFS was 15.8 months.
John M. Burke, MD:
This waterfall plot is very impressive, indicating that 95% of the evaluable patients had at least some reduction in their disease burden with parsaclisib therapy. Also, only a few of the patients experienced disease progression as their best response. Of the 113 evaluable patients with a regression in target lesions, 86% experienced greater than 50% reduction in the size of the target lesions compared with the baseline.
John M. Burke, MD:
As is fairly typical with PI3K inhibitors, diarrhea was relatively common with events of any grade occurring in 44% and grade ≥3 events in 14% of patients in the daily dosing group. Neutropenia occurred in 16% of the daily dosing group with 11% of this being grade ≥3. Elevations in the transaminase levels occurred in 59% of the patients, but only 2 patients had grade ≥3 events.
John M. Burke, MD:
There were 2 deaths from parsaclisib-related adverse events on the trial, 1 from Stevens‑Johnson syndrome and the other from pneumonia. Serious adverse events occurred in 46% of patients, including mostly typical PI3K inhibitor toxicities like diarrhea, colitis, pneumonitis, and febrile neutropenia.
John M. Burke, MD:
The treatment interruptions, reductions, and discontinuations due to adverse events provide a sense of the tolerability of parsaclisib. Treatment interruptions occurred in 48% of patients in the daily dosing group, with dose reductions in 20% and treatment discontinuations in a relatively high number of patients (25%). The reasons for these modifications included diarrhea, colitis, neutropenia, and rash. In the daily dosing group, the median time to the onset of grade ≥3 diarrhea was 6 months. The median time to improvement to grade ≤2 was 18 days, meaning that if a patient developed grade ≥3 diarrhea, it tended to last for a couple of weeks. The results regarding the median time to the onset of grade ≥3 colitis were similar to that reported for diarrhea. In the 7 patients who had grade ≥3 colitis, the median time to improvement to grade ≤2 was 14 days.
John M. Burke, MD:
Parsaclisib appears to have impressive clinical activity in R/R FL. However, it is a little disappointing that its toxicities persisted despite the attempt to modify the dose of parsaclisib to reduce toxicities. When the CITADEL-203 trial was designed, the hope was that the investigators would be able tweak the dose or shorten the duration of treatment to reduce some of the toxicities, but the toxicity issues remained problematic, as 25% of the patients had to discontinue therapy due to treatment-related adverse events, most commonly diarrhea. Physicians and patients should be aware that although it has high activity in R/R FL, dose reduction strategies do not eliminate the risk of the typical PI3K inhibitor–related toxicities with this agent.
Parsaclisib is also being investigated in the phase II CITADEL-205 trial for patients with R/R mantle cell lymphoma (MCL) who have had no prior exposure to a PI3K or BTK inhibitor.19 In the CITADEL-205 trial, parsaclisib showed clinical activity in R/R MCL. The efficacy results with parsaclisib in the CITADEL-205 trial in R/R MCL are similar to those obtained in the CITADEL-203 trial in R/R FL. Also, the toxicity profile in patients with R/R MCL was similar to that reported in R/R FL. Since all patients will not be able to receive BTK inhibitors due to preexisting issues like atrial fibrillation or because the patient is already receiving a strong CYP3A inducer, a PI3K inhibitor treatment option may have a role in some patients.
Peter Martin, MD:
A question that may be asked is whether there is a need for another PI3K inhibitor in the management of FL. The answer to this question can be found, in part, in the multiple changes that are occurring in the treatment landscape for FL. Very recently, the indications in R/R FL for 3 PI3K inhibitors—idelalisib, duvelisib, and umbralisib—were voluntarily withdrawn from the US market. Also, the new drug application for parsaclisib in R/R FL and MCL was also recently withdrawn. Although copanlisib is still approved for the treatment of R/R FL, these changes in the treatment landscape may be reflective of some of the challenges of acquiring full approval status in a fairly small number of patients who have other treatment options available to them.
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