Experts Dissect 3 Practice-Changing Studies for Newly Diagnosed CLL

William G. Wierda, MD, PhD

More and more, the role of chemoimmunotherapy (CIT) continues to diminish in the first-line treatment of patients with chronic lymphocytic leukemia (CLL), as the many new agents and combinations introduced in the past 5 years have shown promise in clinical trials and made their way into clinics.^1,2 Historically, CIT has been the standard first-line treatment for patients with CLL.

These newer treatments include Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), and novel CD20-targeting monoclonal antibodies (mAbs), such as ofatumumab (Arzerra) and obinutuzumab (Gazyva), among others. With such an abundance of new options available or on the horizon, treatment selection has become richer but also more daunting, as factors such as patient age, comorbidities, mutation profile, preferences, and financial picture need to be weighed against, and alongside, safety and efficacy data and dosing schedules.

During an OncLive Peer Exchange^®, a panel of CLL experts reviewed findings from studies presented at the 2018 American Society of Hematology (ASH) meeting in December: iLLUMINATE, Alliance A041202, and ECOG E1912. “There have been [these] 3 large phase III clinical trials presented in the frontline setting that I think are really practice changing,” said moderator William G. Wierda, MD, PhD. “And they are small-molecule inhibitor—based therapies versus chemoimmunotherapy-based regimens.”

The experts also provided practical perspectives on selecting patients for the agents that were assessed in these studies and shared their insights on how these agents are changing the initial management of CLL.

iLLUMINATE Study

Additionally, several panelists noted that they are looking forward to learning the findings of the CLL14 study, which is evaluating the combination of venetoclax (Venclexta) and obinutuzumab versus CIT for patients who have not received prior treatment. The FDA is reviewing a supplemental application for the regimen.The international, randomized, open-label, phase III iLLUMINATE study compared the safety and efficacy of ibrutinib plus obinutuzumab (ibr-G) with chlorambucil plus obinutuzumab (clb-G) as a first-line treatment for CLL or small lymphocytic lymphoma (SLL).^3,4 Patients were aged ≥65 years or <65 years with significant comorbidities or high-risk genomic features (ie, Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del[17p] or TP53 mutation).

After a median follow-up of 31.3 months (interquartile range, 29.4-33.2 ), median progression-free survival (PFS) was significantly longer in the ibr-G group (median not reached) than in the clb-G group (19.0 months; HR, 0.23; P <.0001). The investigator-assessed overall response rate (ORR) was 91% in the ibr-G group and 81% in the clb-G group, with complete response (CR) rates of 41% and 16%, respectively.

“Did we really need this study, given that we have the RESONATE-2 study comparing ibrutinib with chlorambucil?” asked Susan M. O’Brien, MD. RESONATE-2 data led to the FDA approving ibrutinib monotherapy as a first-line treatment for CLL in 2016.^5,6 However, she noted that iLLUMINATE now provides evidence that adding a mAb to ibrutinib can improve its efficacy, a finding that was previously observed with chemotherapy and had led to CIT becoming the standard of care for many years.

“[CRs] are not very common with ibrutinib, but in [iLLUMINATE], it does appear that the obinutuzumab is adding to the ibrutinib, at least in the response rate,” O’Brien said. In RESONATE-2, the independent review committee—assessed ORR was 86% with ibrutinib monotherapy and 35% with chlorambucil monotherapy, with CRs occurring in only 4% and 2% of patients in these groups, respectively.⁵

Following the Peer Exchange program, on January 28, 2019, the FDA approved ibrutinib in combination with obinutuzumab for treatment-naïve CLL or SLL based on the iLLUMINATE data.⁷ Despite iLLUMINATE’s findings, however, O’Brien said her first choice for older patients requiring first-line therapy would still be ibrutinib alone.

Currently, ibrutinib is the National Comprehensive Cancer Network (NCCN)-preferred first-line regimen for CLL across patient cohorts, including older (≥65 years) and younger (<65 years) patients, those with and without significant comorbidities or frailty, and those with or without del(17p) and/or TP53 mutations.⁸ Ibr-G and chlorambucil alone or with an anti-CD20 mAb can be considered in the absence of del(17p) or TP53 mutations for frail patients unable to tolerate purine analogues, for older patients, and for younger patients with significant comorbidities.⁸

Currently, ibrutinib is the only BTK inhibitor approved for the treatment of CLL, but acalabrutinib is showing promise as a potent second-generation BTK inhibitor with minimal off-target activity in several phase I/II trials in the treatment-naïve and relapsed/refractory settings.⁹ Several of the Peer Exchange panelists were involved with the phase I/II ACE-CL-001 study, which included 99 patients with previously untreated CLL; the results showed an ORR of 97% with acalabrutinib, with 5 patients (5%) achieving a CR and 91 (92%) achieving a partial response (PR).¹⁰

The panel noted that data from several other trials are anticipated, including the phase III ELEVATE-CLL-TN study (NCT02475681), which is similar in design to iLLUMINATE. The study is comparing acalabrutinib with or without obinutuzumab versus CIT (ie, clb-G) in treatment-naïve patients ≥65 years or <65 years with a Cumulative Illness Rating Scale score >6 or a creatinine clearance of <70 mL/min.¹¹

Alliance A041202 Trial

“It’ll be interesting when those data become available in terms of helping us to decide what [acalabrutinib] looks like with the CD20 in the frontline setting and what that adverse effect [AE] profile looks like relative to what we saw with ibrutinib,” Anthony R. Mato, MD, said. Ibrutinib has been associated with significant toxicity, including several life-impacting AEs, such as atrial fibrillation.The multicenter, phase III Alliance North American Intergroup Study A041202 compared CIT with bendamustine plus rituximab (Rituxan) versus ibrutinib with or without rituximab in untreated older patients with CLL.¹² After a median follow-up of 32 months, the median PFS was 43 months with CIT and was not yet reached in either ibrutinib arm.

The hazard ratio comparing ibrutinib monotherapy with CIT was 0.39 (1-sided P <.001) and the HR comparing ibrutinib plus rituximab (IR) with CIT was 0.38 (1-sided P <.001). The addition of rituximab did not prolong PFS compared with ibrutinib alone, indicating that not all mAbs may improve the efficacy of ibrutinib.

“That sort of seconds what Jan Burger, MD, PhD, presented at the 2017 ASH [annual meeting], where he also didn’t show any difference in PFS between those 2 arms, questioning whether adding a CD4 antibody like rituximab is helpful to patients who are already taking ibrutinib,” Alexey V. Danilov, MD, PhD, said. The study by Burger et al included treatment-naïve patients with high-risk CLL (ie, del[17p] or TP53 mutations) or relapsed CLL.¹³

Danilov also noted that there was no overall survival (OS) benefit in either of the ibrutinib arms. “The curves completely overlapped over [the] 32-month follow-up on the study,” he said.

O’Brien suggested that the lack of an observable OS might be the result of patients being able to cross over to ibrutinib later in the study if they were not randomized to receive it up front. She also suggested that with all the available effective salvage options, OS rates might not be as critical to up-front therapy selection.

“Obviously, ibrutinib is very effective in people who relapse after bendamustine plus rituximab, and now we also have venetoclax [Venclexta], which is very effective even in patients failing chemotherapy and failing ibrutinib. So, I kind of think that, with time, it’s going to be much harder to see any real difference in survival in any frontline studies,” she said.

Ibrutinib toxicities in A041202 were similar to those seen in other studies. Grade ≥3 treatment- emergent AEs were seen in 428 of 537 evaluable patients, with 61%, 41%, and 39% of patients experiencing hematological AEs (P <.0001) and 63%, 74%, and 74% experiencing nonhematological AEs (P = .03) in the CIT, ibrutinib monotherapy, and IR arms, respectively.¹³

“There were grade 5 toxicities in both experimental arms, at 7.8% [ibrutinib] and 7.7% [IR], compared with <3% in the bendamustine plus rituximab arm,” Danilov said.

Although both ibrutinib arms showed improvement over bendamustine-and-rituximab—based CIT, the panelists did not uniformly agree that ibrutinib would be a suitable replacement for CIT in all cases.

ECOG E1912 Trial

“Certain patients, because of their comorbidities, may not be the best candidates for ibrutinib,” Danilov said, noting there is a 20% to 30% discontinuation rate with this drug due to its AE profile. Therefore, he said he would have discussions with his older patients reviewing the risks and benefits of both treatment strategies before making a decision. Currently, IR has an NCCN category 2B recommendation for patients <65 years who do not have any significant comorbidities or highrisk genomic features.⁸The multicenter ECOG-ACRIN Cancer Research Group E1912 trial compared the efficacy of ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide, and rituximab (FCR) as a first-line treatment in younger patients (≤70 years); FCR is considered to be the most efficacious CIT.¹⁴

After a median follow-up of 33.4 months, there were 77 PFS events and 14 deaths, with 10 occurring in the FCR arm and 4 in the IR arm, despite there being twice as many patients in the IR arm. The hazard ratios for PFS favored IR (HR, 0.35; P <.00001), and the hazard ratio for OS favored IR (HR, 0.17; P = .0003). Subgroup analysis for PFS showed IR to be superior to FCR independent of age, sex, performance status, disease stage, del(q23) status, and IGHV-unmutated status, but not independent of IGHV-mutated status.

“I think what was surprising to most of us was the OS benefit…[but] we know that FCR is going to have this long-term plateau. And so even though there’s an early OS difference in favor of IR, it’s hard to know in the long term if that’s going to translate into an OS benefit,” Matthew S. Davids, MD, MMSc, said.

Putting the Trials in Perspective

Another surprising finding was the favorable toxicity profile with IR versus FCR. “It actually looked a lot more favorable than what we’re used to seeing in the older population,” Davids said. In the study, grade ≥3 treatment-related AEs were more common in the FCR arm than in the IR arm (72.1% vs 58.5%, respectively; P = .004), with FCR more frequently associated with grade 3 and 4 neutropenia and infectious complications. “Until now we really haven’t had a robust data set for IR in the younger fit patients, and I think this really adds to our knowledge of that population,” he said.The panel had differing opinions on the role of CIT in the frontline setting based on the data from the 3 trials discussed. Mato said that the ALLIANCE data confirmed what he was already doing. “For me, the conversation regarding older patients has already moved beyond bendamustine-based therapy…[and] the younger-patient population, I think, will probably move again toward ibrutinib,” he said. He added that the only patients he will discuss CIT with are the young, fit, non-del(17p), non-TP53—mutated patients who are Coombs test–negative, who make up about 5% of the patients with CLL he sees.

O’Brien said she would be cautious about offering ibrutinib even to young, fit patients with mutations, who make up a group who may be cured with FCR. “What I want to know is their plateau on that curve with ibrutinib.…It’s difficult to give up what might be a cure fraction, or let’s even say they’re not cured, but they get 17 years’ remission after 6 months of chemo; it’s hard to dispute that as a fantastic endpoint. So even if the curves were a little bit more separate now, it still wouldn’t, in my mind, address the plateau issue, which we’re going to have to have longer follow-up to know,” she said.

Davids said he would use FCR for patients with an IGHV mutation and would favor ibrutinib alone for unmutated patients. Danilov agreed but said he would perform next-generation sequencing on young, mutated-IGHV patients to ensure FCR is appropriate. He said if he finds a TP53 mutation or NOTCH1 mutation, he would likely steer away from FCR.

Wierda stressed the importance of knowing patients’ mutation profile. “While it’s more routine for people to get FISH [fluorescence in situ hybridization] and to know del(17p) status, I think fewer people in the community are getting TP53-mutation status, and that is a very important characteristic to know about when selecting frontline [treatment] and treatment for relapsed disease,” he said.

References

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