Our Thoughts on the Implications of New Data in CLL and MCL From ASCO 2022

The treatment paradigms for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) have undergone rapid evolution in recent years. In this commentary, Anthony Mato, MD, MSCE, and Brad S. Kahl, MD, discuss select studies from the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and their potential impact on the current standard of care in these hematologic malignancies.

MCL: SHINE

Brad S. Kahl, MD:
The phase III SHINE study was designed to evaluate the addition of the BTK inhibitor ibrutinib to frontline therapy for older patients with MCL, and the results were not clear cut. SHINE is an ongoing study of ibrutinib plus bendamustine/rituximab (BR) vs BR for the treatment of newly diagnosed stage II-IV MCL (N = 523), with the primary endpoint of progression-free survival (PFS). Patients with a response after 6 cycles continued with maintenance rituximab plus ibrutinib (or placebo) for a maximum of 12 additional doses of rituximab; ibrutinib (or placebo) was continued until progression or unacceptable toxicity. BR is a commonly used treatment approach for MCL in the United States and globally.

Of note, the median age was 71 years, so this was truly an older MCL population. Results showed that median PFS was 2.3 years longer with the addition of ibrutinib to BR, at 80.6 months vs 52.9 months with BR plus placebo (HR: 0.75; P = .01). That said, looking at the PFS curves and landmark time points, the PFS difference appears less pronounced, with an approximately 10% difference between the 2 arms at 3, 4, and 5 years of follow-up. At 5 years, approximately 50% of the control arm remained in remission vs approximately 60% who received ibrutinib. Response rates were very similar between arms at 89.7% for BR plus ibrutinib vs 88.5% for BR plus placebo. In addition, there was no significant difference in overall survival (OS): Median was not reached in either arm, and at 84 months the OS rate was 57% with placebo vs 55% with ibrutinib. Ibrutinib does add some toxicity, including more bleeding, atrial fibrillation, hypertension, arthralgias, and infections.

So, are the data practice changing? I think this trial is open to interpretation, and healthcare professionals may differ on how they incorporate this into their practice. It is definitely practice influencing. I could see some moving toward incorporating ibrutinib into the front line if this regimen does get an approval, which I think it will based on the data. Although it will be a nice option to have, it’s a situation where there is no OS benefit, and the PFS benefit does carry the risk of added toxicity. In addition, use of BTK inhibition in first-line therapy could preclude its use a second-line therapy; some healthcare professionals, including myself, may prefer to reserve it for relapsed patients. I would compare this with giving rituximab maintenance in follicular lymphoma—whether you choose to give it or not—either way is fine. There are pros and cons to it, which should be discussed with the patient along with their goals and preferences.

One question is how much of the benefit can be ascribed to ibrutinib—my guess is very little, given how well the control arm did at 5 years. I would be curious to see if ibrutinib plus rituximab alone would perform as well at 5 years in the same patient population. The ongoing phase III MANGROVE study (NCT04002297) is comparing zanubrutinib plus rituximab vs BR in previously untreated MCL, so an answer is forthcoming in a few years.

CLL: CAPTIVATE

Brad S. Kahl, MD:
Let’s move on to CLL and discuss updated results presented by Wierda and colleagues from the fixed-duration (FD) cohort of the randomized phase II CAPTIVATE study of first-line ibrutinib followed by ibrutinib plus venetoclax in CLL/small lymphocytic lymphoma (SLL). CAPTIVATE is divided into a minimal residual disease (MRD)–guided randomization therapy cohort and an FD cohort. In the FD cohort primary analysis, the trial met its primary endpoint with a complete response (CR)/CR with incomplete bone marrow recovery rate of 56%. Dr Mato, would you discuss the update presented at ASCO 2022?

Anthony Mato, MD, MSCE:
At ASCO 2022, 3-year follow-up data were reported from the FD cohort of CAPTIVATE. The study design reflects the current trend in CLL therapy to move away from continuous administration and toward a FD schedule due both to patient desire to stop therapy and the cost of treatment. Use of intermittent treatment schedules or treatment holidays with long remission durations also may impact resistance mechanisms.

In the FD cohort, the median age was relatively young at 60 years, with poor risk features in many patients (eg, 17% with del[17p]/TP53 mutation, 13% with del[17p], 18% with del[11q], and 56% with unmutated IGHV). Of importance, patients with del(17p)/TP53 mutation (n = 27) and patients with unmutated IGHV (n = 89) had an overall response rate (ORR) of 97%, including CRs in more than one half of patients. However, the MRD results were underwhelming compared with combinations such as venetoclax and obinutuzumab; the 3-month posttreatment rate of MRD <10^-4 (undetectable MRD) was only 57%, which dropped to 43% at 12 months post treatment. Most would say that achieving undetectable MRD either in the peripheral blood or bone marrow is the direction toward developing a time-limited therapy. Although this was not as deep a remission as I would have predicted, that said, these were durable remissions, and at 3 years, median PFS had not been reached for any population. Of note, more progression events than expected have been observed in the del(17p) population.

The hope for the FD schedule with an ibrutinib-containing regimen was to improve on efficacy seen with venetoclax and obinutuzumab, but given the progressions in the del(17p) population, the lesson seems to be instead that patients with poor-risk CLL need continuous therapy regardless of which approach is chosen. Of note, OS was similar between groups, with very few deaths.

Also, of 11 evaluable patients who progressed after FD ibrutinib/venetoclax and were retreated with ibrutinib monotherapy, 10 achieved a partial response (PR). The other consideration here is retreatment. After 15 months of therapy, treatment is stopped. What do you do when there is progression? Are the patients sensitive to other therapies? This is an important question, and what we have from this data set is that patients could receive ibrutinib upon progression. In addition, although it is a small number, nearly every patient evaluable for response did respond to ibrutinib.

As a reminder, this is a nonrandomized trial. We are unable to compare ibrutinib plus venetoclax vs ibrutinib or vs ibrutinib plus obinutuzumab. We have this data set to stand alone in a young population. The GLOW trial also uses ibrutinib plus venetoclax, but in an older, less fit population with a chlorambucil-based regimen as the comparator, which is arguably no longer a relevant control arm. When we look at the adverse events in GLOW in older, less fit patients, there appear to be more than we would see with venetoclax plus obinutuzumab, for example. The question now is whether these findings will influence the standard of care in young, fit patients vs older patents? Dr Kahl, what are your thoughts on this study?

Brad S. Kahl, MD:
I am very interested to see further data on time-limited novel combinations in CLL. As you know, venetoclax plus obinutuzumab is approved, but venetoclax plus ibrutinib is not. I think we will see this FDA approval within a year based on results from both GLOW and CAPTIVATE. Now, let’s move on to discuss an early-phase trial of a promising new antibody, zilovertamab.

Phase I/II Trial: Zilovertamab

Anthony Mato, MD, MSCE:
ROR1 is an onco-embryonic tyrosine kinase–like receptor re-expressed at high levels in hematologic malignancies including CLL, MCL, and marginal zone lymphoma, but not in normal adult tissues. Zilovertamab (formerly cirmtuzumab) is an anti-ROR1 antibody that binds to the ROR1 extracellular domain to inhibit tumor growth. At ASCO 2022, Lee and colleagues reported clinical response and safety findings from a small phase I/II study of zilovertamab and ibrutinib in patients with treatment-naive or relapsed/refractory CLL/SLL or relapsed/refractory MCL (prior BTK inhibitor allowed for MCL). In the parts 1 and 2 dose-finding and dose-expansion cohorts, 33 patients with MCL and 34 with CLL received zilovertamab plus ibrutinib; in part 3, 28 patients with CLL were randomized to receive zilovertamab plus ibrutinib vs ibrutinib alone. This study design is primarily to gather safety information but also should help determine if there is a clinical advantage to this novel agent combination over ibrutinib alone.

In this early analysis, the combination appears well tolerated, with toxicities as expected from other studies of BTK inhibitors and antibodies. Few grade 3/4 adverse events were reported in either MCL or CLL in parts 1 and 2 but did include 4 cases of grade ≥3 fatigue in the MCL group and 7 cases of grade ≥3 hypertension in the CLL group. Of note, in the dose-finding and dose-expansion phases, >65% of patients in the MCL group and nearly 75% in the CLL group experienced decreased platelets and hemoglobin, but very few reached grade ≥3. With the caveat of very small patient numbers, similar rates of treatment-emergent adverse events were seen in the randomized phase II portion, as well.

In the randomized portion of the study, 15 of 16 CLL patients in the zilovertamab plus ibrutinib arm achieved a PR, for an ORR of 93.8%, compared with 7 of 7 in the ibrutinib-only arm, for an ORR of 100%. By contrast, in the earlier parts 1 and 2, the MCL group achieved an ORR of 85.2% (23/27), with 40.7% with CR and 44.4% with PR. The median duration of response was 34.1 months in MCL and was not yet reached at data cutoff in both the zilovertamab plus ibrutinib and ibrutinib arms in CLL in part 3. Median PFS in the MCL group was 35.9 months, which compares favorably with historical data for ibrutinib monotherapy, and was not reached in the CLL group. Favorable PFS was seen in heavily pretreated patients, including those in higher-risk Mantle Cell Lymphoma International Prognostic Index subgroups and those with TP53 mutations. Median OS was not reached in either MCL or CLL or with the combination vs ibrutinib alone. Overall, the response rates are not overwhelmingly different from what I would anticipate with ibrutinib alone in CLL and not much different from what I would expect with ibrutinib plus an anti-CD20–directed therapy in earlier lines of therapy. To me, at this point, this drug may have more of a role in MCL than CLL, but it is still very early in clinical development. The toxicities do not seem to be limiting.

Brad S. Kahl, MD:
I agree that zilovertamab has great potential in these early data, and I look forward to a larger randomized trial to clarify the benefit.

Looking Forward

Brad S. Kahl, MD:
Dr Mato, you’ve been heavily involved in the development of the third-generation BTK inhibitor pirtobrutinib. I’ve started to use it myself in MCL trials. What is your perspective on the potential of pirtobrutinib in CLL and MCL?

Anthony Mato, MD, MSCE:
I think this drug has great potential in relapsed/refractory CLL. The phase I/II BRUIN study of pirtobrutinib enrolled more than 250 patients with CLL who had previously been treated with a covalent BTK inhibitor. There is a lack of effective standard-of-care treatments for previously treated CLL; in this study, responses were seen in nearly 70% of these patients. Moreover, median PFS has not yet been reached, and only 1% of patients discontinued due to adverse events. In MCL, the remissions seem less durable but are still impressive in a population with prior BTK inhibitor exposure and without many good options. With minimal adverse events, this drug seems like a great building block for combination therapy, and the trajectory to earlier lines of CLL treatment will be determined pending ongoing randomized trials.

Brad S. Kahl, MD:
What other approaches are underway that you feel may become important in the management of CLL?

Anthony Mato, MD, MSCE:
Exciting frontline studies are currently underway and enrolling, including the phase III CLL17 study of ibrutinib monotherapy vs FD venetoclax plus obinutuzumab vs FD ibrutinib plus venetoclax in patients with previously untreated CLL (NCT04608318). This large study will enroll nearly 900 patients and will not be complete until 2027. Another important ongoing trial is the phase III MAJIC study of acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in previously untreated patients with CLL/SLL (estimated N = 600); the primary completion date is in 2029 (NCT05057494). These trials are notable to me because they are using relevant, modern comparators. These 2 studies should substantially help guide treatment choices for patients with poor-risk CLL.

Expert Guidance on Treatment Selection: Interactive Decision Support Tools
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