MCL Treatments Step Away From Chemotherapy, Closer to a Cure

Ian W. Flinn, MD, PhD

Treatment of relapsed mantle cell lymphoma (MCL) has been challenging because of patents’ rapid development of chemotherapy resistance; however, recent developments in MCL are increasingly moving toward novel approaches that are resulting in improved outcomes. Though a cure has not yet been achieved, it is peeking over the horizon for the first time.

MCL is an aggressive, rare subtype of non-Hodgkin lymphoma with historically poor long-term survival compared with other B-cell malignancies. Frontline treatment depends on multiple factors, including the stage of the disease and the patient’s age and overall health, but in fit patients, it often includes aggressive chemotherapy or chemoimmunotherapy regimens with or without autologous stem cell transplantation followed by maintenance therapy. In some patients, this strategy may lead to long remissions of up to a decade, but relapse is inevitable and associated with a poor prognosis; historically, patients who relapsed have an overall survival (OS) of less than 3 years.¹

During a recent OncLive Peer Exchange^®, a panel of hematologic cancer experts discussed several novel treatments that are changing the relapsed/refractory (R/R) MCL treatment landscape, including Bruton tyrosine kinase (BTK) inhibitors, BTK combinations, and chimeric antigen receptor (CAR) T-cell therapy. “I’m very excited and very hopeful for my patients at this point, because we have a multitude of treatments now that we can use to start extending survival and improving outcomes in our patient groups,” panelist Tycel Jovelle Phillips, MD, said. The hope is that moving these powerful treatments to earlier lines may further improve outcomes and eventually enable patients to be cured.

BTK Inhibitors

The FDA has approved 3 BTK inhibitors to treat R/R MCL: ibrutinib (Imbruvica) in November 2013, acalabrutinib (Calquence) in October 2017, and zanubrutinib (Brukinsa) in November 2019.^2-4 These approvals dramatically changed the treatment landscape of R/R MCL, shifting second- and subsequent-line treatments away from chemotherapeutic regimens, the panelists said.

Table. Efficacy Outcomes in Zanubrutinib Clinical Trials Leading to FDA Approval for R/R MCL³ (Click to Enlarge)

BGB-3111-206 (NCT03206970), a phase 2, open-label, multicenter, single-arm trial conducted in China, included 86 patients with MCL who received at least 1 prior therapy and were treated with oral zanubrutinib 160 mg twice daily. BGB-3111-AU-003 (NCT02343120), a phase 1/2, open-label, dose-escalation, multicenter, single-arm trial conducted globally, including at a few centers in the United States, looked at patients with B-cell malignancies; in that study, 32 patients with R/R MCL received oral zanubrutinib 160 mg twice daily or 320 mg once daily. The primary efficacy outcome measure in both trials was overall response rate (ORR) (Table).⁴

“Both [trials] showed very good remission rates and durable remissions, which were as good as or better than what we had seen in other single-arm phase 2 trials that were conducted with some of the other BTK inhibitors,” Flinn said.

Selecting Between Agents

The panelists proceeded to discuss the 3 FDA-approved BTK inhibitors and the key considerations when choosing between treatment options. These include toxicity profiles; patient comorbidities, adherence, and medication use; and dosing.^5-7 They noted that tolerability seems better with zanubrutinib but that data are still early compared with what is available for ibrutinib and acalabrutinib.

“Ibrutinib was also very good in the beginning, before some of these long-term adverse events [AEs] had come up,” Phillips said. He noted that the trials of all 3 agents had different patient populations, making crosstrial comparisons difficult for both safety and efficacy. “Acalabrutinib and zanubrutinib were [studied] in first relapse for most of the patients, whereas the ibrutinib population was a bit more heavily pretreated, based on the response criteria. It’s kind of hard to gauge it head-to-head, but I think overall, none of us really feel that, at least efficacywise, one is better than another. [The difference] will come to dosing, whether you want to do once daily or twice daily,” he said.

Of the 3 available BTK inhibitors, zanubrutinib is the only agent that offers both once- and twice-daily options (160 mg twice daily or 320 mg once daily).⁷ The panelists generally preferred twice-daily dosing. “I think it’s important they designed it as twice a day...so I would, hopefully, try to do twice-a-day dosing. Very rarely would I try once-a-day dosing,” Phillips said. However, he acknowledged that dosing may ultimately hinge on patient adherence. “It’s really about comfort level as far as your patient’s [adherence],” he said. “Some patients will never remember to take that second pill. I’ve heard that argument from people with acalabrutinib [100 mg every 12 hours] versus ibrutinib [560 mg once daily].”^5,6

The panelists also discussed the use of proton pump inhibitors (PPIs). Zanubrutinib appears to be safe for patients also taking PPIs, but data to indicate that efficacy is hampered in patients treated with PPIs who receive acalabrutinib, according to the panelists. “With acalabrutinib, you just don’t absorb it unless you have an acidic stomach,” Flinn said. The data regarding ibrutinib seem more mixed. For example, a 2018 study by de Jong and colleagues concluded that ibrutinib’s bioavailability was not hampered by coadministration with the PPI omeprazole or other pH-altering agents.8 Nevertheless, some panelists observed experiencing less efficacy with it in the setting of PPI coadministration. “I know that there were some data to suggest it’s safe to take ibrutinib even with the proton pump inhibitors, but I was seeing less activity,” panelist Bijal Shah, MD, MS, said.

Overall, the panelists agreed that all 3 agents are likely similarly efficacious, and longer-term follow-up is needed before definitive conclusions can be drawn about the safety of acalabrutinib and especially zanubrutinib compared with ibrutinib. “Even [at] 24 months’ [follow-up], you start to pick up some more hints of some bleeding and other situations that didn’t come up in the initial assessment. As we get more long-term follow-up and we start approaching the 5-year follow-up that we have with ibrutinib, I’d be quite curious to see what the AE profile [for zanubrutinib] looks like at that time,” Shah said.

Regardless of which BTK inhibitor a patient receives, the panelists agreed that the earlier patients start these treatments in the R/R setting, the better their outcomes are likely to be. “Now that we have an acalabrutinib trial in our hands, we want to get them on that trial as soon as we can, so we’re not waiting until third or fourth or fifth line. That also goes for community referrals,” Shah said. “Patients are coming in earlier, they’re not quite as beaten up, and they have a disease that may be a bit more sensitive to BTKs at that point.”

New Frontline and Combo Potential

Studies are being undertaken to see if BTK inhibitors combined with other agents might have a role in the frontline and R/R settings. The panelists discussed possible partner drugs, including anti-CD20 monoclonal antibodies. “The second-generation BTK inhibitors, given that none of them seem to impact T-cell function, seem to be very good partners to the CD20 antibody,” Phillips said. “In my opinion, obinutuzumab [Gazyva] will probably be a better partner long term. Mantle cell lymphoma seems to behave a bit more like CLL [chronic lymphocytic leukemia] than it does large-cell lymphoma, in which it doesn’t appear that a CD20 partner makes a difference.”

The panelists noted that ibrutinib plus rituximab (Rituxan) has shown preliminary promise for indolent MCL in the frontline setting. In the Spanish GELTAMO-IMCL-2015 phase 2 trial (NCT02682641), efficacy data for the first 33 patients, 31 of whom received at least 12 cycles of this treatment, showed an 82% ORR, with 75% being complete responses (CRs).⁹ Among patients who achieved a CR with evaluable minimal residual disease (MRD; n = 23), the rate of undetectable MRD achieved after 12 cycles was 87%. At data cutoff, all responding patients maintained the response with a median follow-up of 25 months, with just 1 patient progressing at 1 year of therapy. The estimated 15-month progression-free survival (PFS) was 96% (95% CI, 89%-100%).⁹

“We try to shy away from chemotherapy, so this would be a novel, nonchemotherapy approach. It has a BTK inhibitor and a monoclonal antibody,” Javier Munoz, MD, MS, said. However, he noted that the GELTAMOIMCL- 2015 trial would have been more informative if it had an ibrutinib-only cohort. “[It is still unclear] whether you need the dancing partner to be a monoclonal antibody,” he said, indicating the same question has surfaced for CLL.

Another potentially exciting partner drug, according to the panelists: venetoclax (Venclexta), an orally bioavailable small molecule BCL-2 inhibitor. The combination of venetoclax and ibrutinib showed sustained good results in the 3-year update (median follow-up, 37.5 months; range, 1.4-45.3 months) of the phase 2 Australian AIM (NCT02471391) study, which included patients who had R/R MCL (n = 23) or were treatment naïve but not candidates for chemotherapy (n = 1).¹⁰ The median duration of response and time to progression had not been reached and were estimated to be 74% and 60%, respectively, at 30 months. The median PFS was 29 months; the median OS, 32 months.

Twelve patients had aberrations of TP53, a marker associated with a particularly dismal prognosis. In this group, the ORR was 58% without positron emission tomography (PET) and 50% with PET, with a CR rate of 50% with or without PET. Five patients with MRD-negative, PET-confirmed CR electively stopped treatment after a median of 18.5 months. Of these patients, 1 experienced radiological progression after 7 months, but the other 4 remained free of clinical or MRD progression 18 months after treatment discontinuation.¹⁰

“The remissions we’re getting are durable, and that’s powerful. There were even MRD-negative patients who came off the study who continue to remain in remission, getting to the ability to begin a biological doublet or maybe even a triplet with rituximab. Being able to pull off therapy and continue to see a durable remission is something our patients want to see. It’s something all of us want to see,” Shah said. He noted that because it is so expensive, venetoclax is generally difficult to obtain for patients in the United States. “It is still hard for us to get from an insurance-approval standpoint and a co-pay standpoint. That’s what has really challenged our ability to get more experience [with it],” Shah said.

CAR T-Cell Therapy

Cellular therapies are showing considerable promise in patients with MCL who have multiple relapses, including after BTK inhibitor therapy, the panelists said. They were particularly excited by the results of the ZUMA-2 trial (NCT02601313), in which 74 adults (median age, 65 years) with R/R MCL who had received up to 5 prior lines of therapy, including a BTK inhibitor, were treated with the anti-CD19 CAR T-cell therapy KTE-X19.¹¹ The primary efficacy analysis, which included 60 patients, showed an ORR of 93% and a CR rate of 67%. The intention-to-treat analysis that involved all 74 patients showed an ORR of 85%, with a CR rate of 59%. The median follow-up of the primary efficacy analysis was 12.3 months (range, 7.0-32.3 months), with 57% of the 60 patients in remission. At 12 months, the estimated PFS and OS were 61% and 83%, respectively.¹¹

“This is a home run from where I’m sitting. I’m just trying to figure out how soon it’s going to be something that I can use in practice,” Shah said. “That’s to give you a sense of how excited I am.”

Munoz, one of the ZUMA-2 investigators, emphasized that the trial is particularly remarkable because the population studied historically would survive less than 6 months. “Twenty-one percent of patients had blastoid mantle cell lymphoma, so we were not cherrypicking when it came to patients,” he said.

On February 2, 2020, based on the ZUMA-2 data, the FDA accepted the manufacturer’s biologics license application and granted KTE-X19 priority review designation.¹² The Prescription Drug User Fee Act target action date is August 10, 2020.

The panelists proceeded to discuss whether KTE-X19 could be used in earlier lines of therapy. In the ZUMA-2 trial, patients had to come off their BTK inhibitor, posing a challenge. “You stop [treatment with a BTK inhibitor], and [patients] progress so rapidly, and they’re too sick to go on to the trial,” Flinn said. He suggested that one strategy might be to continue the BTK inhibitor while the patient awaits cellular therapy. Phillips noted that the strategy of using ibrutinib in combination with or as a bridge to CAR T-cell therapy has been shown to minimize the bulk of disease in patients with CLL and is worth exploring in MCL. He added that moving KTE-X19 to earlier treatment lines would be the natural next step, especially as more data mature and the durability of responses becomes clearer. “If you move [KTE-X19] to the second-line setting, how long are these patients going to be able to stay in remission? Could we potentially use the C-word in patients with mantle cell lymphoma? A lot of us have been very reluctant to ever utter the word cure when we talk to patients,” he said.

Another challenge with CAR T-cell therapy is its AE profile. In the ZUMA-2 trial, common AEs of grade 3 or higher included cytopenias (94%) and infections (32%). Grade 3 or higher cytokine release syndrome [CRS] and neurologic events occurred in 15% and 31% of patients, respectively. None of these events were fatal, but 2 grade 5 infectious AEs occurred.¹¹

“We all talk about the neurotoxicity and the CRS being reversible, and that’s true. But when you’re going through it, it doesn’t feel reversible. There have certainly been times where even I have been anxious. We’re going to watch them more closely, we’re going to start the rescue medicines, and we’re going to do what we need to do to get people better,” Shah said. He suggested that toxicity may be reduced if CAR T-cell therapy moves into earlier treatment lines because these patients have lower tumor burdens. “We’ve got to get it in early—simple induction, CAR T-cell treatment, maybe the C-word,” he said.

Future Directions

In their concluding remarks, the panelists concurred that this is a very hopeful time in MCL, with treatment shifting away from chemotherapy and toward novel approaches that may eventually lead to a cure. “Try to shy away from chemotherapy in the R/R setting and at least think about novel therapies. Think about clinical trials. Consider referring the patient to a specialized cancer center,” Munoz advised. “The future is bright when it comes to mantle cell lymphoma.”

“We don’t have as much experience in the United States [with it] because a lot of the development was done ex-US. There were 2 different pivotal trials that led to the approval. One was done within China, and the other was done outside of China,” moderator Ian Flinn, MD, PhD, said.

References

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2. FDA approves Imbruvica (ibrutinib) for mantle cell lymphoma (MCL). News release. Royalty Pharma. November 13, 2013. Accessed March 4, 2020. bit.ly/2yBvFmu
3. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. FDA. October 31, 2017. Accessed March 4, 2020. bit.ly/2wSXxlD
4. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. FDA. November 15, 2019. Accessed March 4, 2020. bit.ly/2wSXxlD
5. Imbruvica. Package insert. Pharmacyclics LLC; 2019. Accessed March 4, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/205552s029,210563s004lbl.pdf
6. Calquence. Package insert. AstraZeneca Pharmaceuticals LP; 2019. Accessed March 4, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210259s006s007lbl.pdf
7. Brukinsa. Package insert. BeiGene USA Inc; 2019. Accessed March 4, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf
8. de Jong J, Haddish-Berhane N, Jiao J, Sukbuntherng J, Ouellet D. The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure. Cancer Chemother Pharmacol. 2018;82(2):299-308. doi:10.1007/s00280-018-3613-9
9. Gine E, de Fatima De La Cruz M, Grande C, et al. Efficacy and safety of ibrutinib in combination with rituximab as frontline treatment for indolent clinical forms of mantle cell lymphoma (MCL): preliminary results of Geltamo IMCL-2015 phase II trial. Blood. 2019;134(suppl 1):752. doi:10.1182/blood-2019-122191
10. Handunnetti SM, Anderson MA, Burbury K, et al. Three year update of the phase II ABT-199 (venetoclax) and ibrutinib in mantle cell lymphoma (AIM) study. Blood. 2019;134(suppl 1):756. doi:10.1182/blood-2019-126619
11. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
12. U.S. FDA grants priority review for Kite’s KTE-X19 biologics license application (BLA) in relapsed or refractory mantle cell lymphoma. News release. Kite. February 10, 2020. Accessed April 5, 2020. bit.ly/34aLtbB