Data With Novel Agents Prompt Treatment Sequencing Discussions in MCL and CLL

The role of BTK inhibitors, an established treatment option in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), is evolving with the investigation of noncovalent inhibitors, time-limited regimens, and cellular therapy. 

In an OncLive^® Scientific Interchange and Workshop, Catherine C. Coombs, MD, associate professor in the Department of Medicine at the University of California Irvine School of Medicine, and Alexey Danilov, MD, PhD, professor at City of Hope National Medical Center, and co-director of the Toni Stephenson Lymphoma Center in California, moderated a discussion on the role and sequencing of BTK inhibitors, venetoclax (Venclexta)-based regimens, and CAR T-cell therapy in MCL and CLL.¹ 

Frontline Therapy in MCL: Is There a Standard?

The phase 3 TRIANGLE trial (NCT02858258) established that the addition of ibrutinib (Imbruvica) to chemotherapy with or without autologous stem cell transplant led to improved survival vs chemotherapy and transplant alone.² However, data from the trial have yet to be published, and the regimen remains purely investigational.

“Now we also have emergent data for chemotherapy-free treatment approaches in MCL,” Danilov said, highlighting 2 additional trials that evaluated acalabrutinib (Calquence) and ibrutinib each in combination and rituximab (Rituxan) as frontline treatment in older patients with MCL. Acalabrutinib plus rituximab resulted in 2-year progression-free survival (PFS) and overall survival (OS) rates of 92% and 96%, respectively. The addition of ibrutinib to rituximab led to 3-year PFS³ and OS rates of 87% and 94%,⁴ respectively.

“BTK inhibitors, particularly second-generation BTK inhibitors, are quite well tolerated in patients with MCL,” Danilov said. “There are some cases of atrial fibrillation, maybe some cardiac toxicities, but they are pretty rare.”

Despite these data, the faculty were split regarding whether they would replace chemotherapy and transplant with BTK inhibitors in younger, treatment-naïve patients in the frontline setting.

“When the disease becomes more aggressive, we still have the opportunity to salvage these patients with chemotherapy, with CAR T-cell therapy, [and] hopefully with bispecifics as they come online, so our opportunities for rescuing patients who progress after novel therapy is getting tremendously better. In terms of clinical equipoise, for me, I feel less inclined [to forego a novel agent in the frontline setting in younger patients],” said Bijal Shah, MD, MS, of Moffitt Cancer Center. However, Shah added that chemotherapy still plays a role, particularly for patients with high Ki67, bulky adenopathy, and symptomatic disease.

Brad Kahl, MD, of Washington University, added, “In my own practice I have not started offering chemotherapy-free approaches to younger patients. I’m impressed by the data, but I would like to see some longer follow-up.” Matthew Davids, MD, MMSc, of Dana-Farber Cancer Institute, added that he’s more likely to opt for chemotherapy because there’s no question regarding the efficacy of novel agents post chemoimmunotherapy, whereas there are uncertainties with the activity of chemoimmunotherapy post novel agents.

“Until we have some data in that regard, it makes me hesitant to go in that sequence for a young fit patient where I know that they should tolerate the chemotherapy reasonably well,” Davids said. “Now, when we get into the older patient discussion, I think that calculus changes a bit. [However,] for the young patients, we’ve stuck with the chemotherapy approach and [are] still offering autologous transplant, until we see [data from] TRIANGLE published.”

However, most faculty agreed that if faced with a patient with P53-mutant disease, regardless of age, they would opt for a BTK inhibitor in the frontline setting because of the lack of long-term efficacy with chemotherapy.

In the relapsed setting, with the withdrawn indication for ibrutinib, the panel discussed whether they’d recommend acalabrutinib or zanubrutinib. Comfort and experience seemed to govern most choices, although Shah noted that myalgia is more common with acalabrutinib, whereas hypertension is more likely to result from zanubrutinib, which can be more of a problem for elderly patients, Deborah Stephens, DO, of University of Utah Health, said.

“I’ve been using zanubrutinib preferentially [in the relapsed setting] ever since its approval in MCL, mostly [because] I just wanted to get experience with it because I already had a lot of experience with acalabrutinib, and I’ve been extremely happy with it,” Kahl said.

The faculty also discussed the role of noncovalent BTK inhibitors, including pirtobrutinib (Jaypirca), which received approval from the FDA and nemtabrutinib (MK-1026, formerly ARQ-531), which is still in clinical development. Matthew Lunning, DO, FACP, of University of Nebraska Medical Center, explained that although pirtobrutinib it is associated with median PFS of 7.4 months and an overall response rate (ORR) of 57% (95% CI, 46%-67%) and a complete response rate of 17%,⁵ he views the agent as more of “a setup drug for the closer, which is CAR T-cell therapy.”

Faculty seemed to be more enthused about its use in earlier lines of therapy. Referencing longer-term safety data from the phase 1/2 BRUIN trial (NCT03740529) presented at the 17th International Conference on Malignant Lymphoma, Davids said, “I think [pirtobrutinib] may have a role in earlier lines based on that alone, especially in older populations with comorbidities.” However, until the read out of the phase 3 BRUIN-MCL-321 trial (NCT04662255), which is comparing pirtobrutinib with investigator’s choice of BTK inhibitor in BTK inhibitor–naïve MCL, the panel could not say for certain where the agent will be best used.

Before turning to CLL, the panel briefly highlighted the use of cellular therapy in MCL, spotlighting the data with brexucabtagene autoleucel (brexu-cel; Tecartus) and lisocabtagene maraleucel (liso-cel; Breyanzi), which have shown ORRs of 91.0% (95% CI, 81.8%-96.7%)⁶ and 86.5% (95% CI, 76.5%-93.3%),⁷ respectively.

Notably, findings from the phase 1 TRANSCEND-NHL-001 trial (NCT02631044) showed lower rates of cytokine release syndrome and neurotoxicity compared with those seen in the phase 2 ZUMA-2 trial (NCT02601313), at 61% and 31% vs 91% and 63%, respectively.

“The problem with MCL is you can see real immune effector cell–associated neurotoxicity syndrome [ICANS]. These patients can get sick and it’s hard. Certainly, high tumor burden predicts for some of that, so if I’m seeing one of those higher tumor burden patients, that’s where I’m thinking this may be a place where [I go for] liso-cel.” Shah said. “However, for the others, I really like the data that’s been generated with brexu-cel, and I’ll probably still continue to use brexu-cel in this space. Bispecifics [may be] an opportunity to be able to really use immunotherapy to rescue these CAR T-cell therapy failures without making patients too sick along the way.”

CLL: Fixed-Duration or Continuous Therapy in the Frontline?

Offering perspective, John Allan, MD, of Weill Cornell Medicine, said “I do look at [age because] the ramp up, the anti–CD20 antibody, there are some issues there for older patients. I do seem to favor BTK inhibitors for them, honestly. For younger patients, I’m favoring fixed-duration venetoclax and obinutuzumab [Gazyva] typically.”

In updated data from the phase 3 CLL14 trial (NCT02242942), the 6-year PFS rate was 53.1% with venetoclax and obinutuzumab vs 21.7% with chlorambucil and obinutuzumab (HR, 0.40; 95% CI, 0.31-0.52; P <.0001).⁸ Moreover, the time to next treatment rate was 65.2% with venetoclax and obinutuzumab vs 37.1% with chlorambucil and obinutuzumab.

“I also use venetoclax and obinutuzumab in the frontline [setting] in P53 aberrant and P53 non-mutated [disease]. A median treatment-free period of 4 years also means that some patients will enjoy a treatment-free period [of] longer than 4 years, which will allow them to go to Santa Monica Beach and not develop atrial fibrillation during those 4 years, so there is a big advantage in the treatment-free period,” Danilov explained.

“For me, still, the only variable that kind of changes my practice in terms of using BTK inhibitors is TP53 status,” Mazyar Shadman, MD, MPH, of Fred Hutch Cancer Center, said.

Both Jakub Svoboda, MD, of Penn Medicine, and Catherine Coombs, added that although they tend to favor fixed-duration therapy, patients will sometimes vocalize otherwise. “For a young person, I do favor the defined duration of therapy, but there are some people who really hate the idea of coming for the obinutuzumab and being monitored closely the first several weeks for the ramp up,” Svoboda said.

Notably, the phase 2 ReVenG trial (NCT04895436) is evaluating retreatment with venetoclax plus obinutuzumab and will be led by Matthew Davids. However, Davids cautioned that despite the data, convincing community oncologists to adopt BCL-2 inhibitors may be a challenge, and it is one worthy of consideration if the data are not translated into the clinical setting.

Offering community perspective, Tara Graff, DO, of Mission Blood and Cancer, said, “For your average community oncologist who is just trying to figure out how to stop doing chemoimmunotherapy, using venetoclax and tumor lysis syndrome and all that is still a thing. I don’t think about it in my day-to-day, but there are still some community groups that don’t want to use venetoclax.”

In the relapsed/refractory setting, the phase 3 ELEVATE-RR (NCT02477696) and ALPINE (NCT03734016) trials demonstrated noninferior OS and superior PFS with acalabrutinib (HR, 0.82; 95% CI, 0.59-1.15)⁹ and zanubrutinib (HR, 0.65; 95% CI, 0.49-0.86; P =.0024),¹⁰ respectively, compared with ibrutinib.

“The difference between ALPINE and ELEVATE-RR is the ALPINE study took all-comers with respect to cytogenetics. It also did require measurable lymphadenopathy [per] the inclusion criteria and accrued a slightly less refractory population,” Coombs said. “However, both are very good drugs, and I’m glad to have them both as options.”

Pirtobrutinib, although not yet approved for use in CLL, is now listed as second- or third-line therapy in the National Comprehensive Cancer Network guidelines.¹¹ “I haven’t used pirtobrutinib off a clinical trial to date. I don’t think I would use it before a covalent inhibitor, and I don’t think that I would use it for before venetoclax, so I think it’s kind of that third-line savior,” Lunning said. “I just don’t know how long it’ll work. But it will buy us some time for probably a different clinical trial to come along.”

The question of sequencing for CAR T-cell therapy, if it were to be made available in CLL, was also raised. However, the faculty agreed that the data have been underwhelming, and if anything, they would use the therapy as a bridge to allogeneic transplant. “I think it’s going to be a long road to getting a consistently more effective CAR T-cell therapy product in CLL,” Davids concluded.

References

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9. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
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