Rule Reflects on Continued Benefit With Ibrutinib in Relapsed/Refractory MCL

Simon Rule, MD, PhD

The BTK inhibitor ibrutinib (Imbruvica) led to more favorable responses than chemotherapy in patients with relapsed/refractory mantle cell lymphoma (MCL), according to 7.5 years of follow-up of pooled data from 3 clinical trials that were presented during the 2019 ASH Annual Meeting.

Overall, 370 patients from the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) trials received 560 mg of ibrutinib daily until disease progression or unacceptable toxicity. Patients who received benefit from the treatment at the end of the study were able to enroll in the long-term analysis.

"With MCL when you use chemotherapy, each time you use a different kind of chemotherapy, you get less of a response," said Simon Rule, MD, PhD. "This is a common complication with lymphomas."

Because of this knowledge, Rule added, investigators believed ibrutinib would lead to better outcomes compared with the expected outcomes from chemotherapy.

Results showed that the median progression-free survival (PFS) was 12.5 months with ibrutinib versus an estimated median PFS of 10.9 months with each patient’s most recent prior line of therapy. Over half of patients had a longer PFS with ibrutinib compared with their previous line of therapy. Additionally, 27% of patients remained progression free for ≥1 year longer than the prior regimen.

Investigators also noted that patients who were less likely to have high-risk Mantle Cell Lymphoma International Prognostic Index, bulky disease, blastoid variant, and TP53-mutant disease appeared to have longer PFS. The median exposure to the targeted therapy was 11.1 months for all patients. However, almost one-third of patients remained on treatment for at least 2 years, and about half of those remaining continued treatment for ≥4 years.

The objective response rate (ORR) was 69.7%, which included a 27.6% complete response (CR) rate. The ORR in patients who had received 1 prior line of therapy was 77.8%, with CRs in 37.4% of patients. The median PFS in this patient population was 25.4 months, with a median OS of 61.6 months.

Regarding safety, ibrutinib did not induce any unexpected toxicities. The most common grade ≥3 treatment-emergent adverse events were neutropenia (17%), pneumonia (13.5%), atrial fibrillation (5.7%), and dyspnea (4.3%). Additionally, 11.4% of patients developed secondary malignancies, which were primarily nonmelanoma skin cancer.

In an interview with OncLive, Rule, of Plymouth University Medical School in England, discussed the pooled findings, as well as other MCL abstracts that were presented during the 2019 ASH Annual Meeting.

OncLive: What was the rationale for conducting this analysis?

Rule: What we did was we just further followed up on a group of patients [who] we have been looking at for a while now. This is [an analysis of] 3 trials of patients receiving single-agent ibrutinib, and it is just longer-term follow-up to see if longer exposure to the drug will lead to the development of new side effects or if the efficacy remains. [It also provides] an additional safety analysis.

What were the findings from this update?

What we found was a proportion of patients remain on drug with 7.5 years of follow-up. There is no emergence of new toxicity, which is very encouraging. However, the most important part of the analysis was that for the first time, we looked at how response to ibrutinib compared with response to their prior therapies.

With MCL when you use chemotherapy, each time you use a different kind of chemotherapy, you get less of a response. This is a common complication with lymphomas. With MCL when using ibrutinib, we find that ibrutinib responses are generally better compared with the prior therapy.

In 1 group, it was spectacularly better [in this analysis], and that’s the group of patients [who derive] the most benefit from the chemotherapy. Those are the patients who would be more inclined to use chemotherapy again, but this group would receive the most benefit [from ibrutinib]. The average benefit is more than 1 year [longer] than the prior therapy. This is against what we normally find with chemotherapy, but this is further encouraging for the use of these drugs earlier in the treatment paradigm.

What are the next steps for ibrutinib and other BTK inhibitors in the treatment landscape of MCL?

It’s clear that the earlier we use the drug, the better the outcome. The next steps are using the drugs upfront. We [gave] a presentation at ASH on using ibrutinib in asymptomatic patients with high response rates. You can question whether you need to treat those patients at all; nonetheless, you have higher response rates. I have a trial running in the United Kingdom comparing ibrutinib/rituximab (Rituxan) versus chemotherapy in the frontline setting for older patients. This trial will tell us whether it’s better than chemotherapy. I think that is the direction [we’re moving in].

We also have data looking at ibrutinib plus venetoclax (Venclexta). We just saw relapsed data, and there was a poster looking at ibrutinib plus venetoclax and obinutuzumab in the frontline [setting] in patients. This had very impressive results, 14 out of 15 patients had MRD-negative CRs. It is very clear that early use of drug combinations is the way we are going to be going with this disease, and chemotherapy may very well become a thing of the past.

Were you surprised by any of these findings?

BTK inhibitors are very exciting drugs. When you use drugs earlier [in the treatment cycle], you get better responses, and that is what we saw, so it wasn’t a surprise. The surprise was how effective they were in the best patients. The patients who are getting the best responses to chemotherapy get even better responses with ibrutinib. That didn’t necessarily surprise me, but I think it surprised other people because that is a group of patients [who] clinicians would generally be very happy to give chemotherapy to again. Now there is good evidence that you shouldn’t be doing that.

Rule S, Dreyling MH, Goy A, et al. Long-term outcomes with ibrutinib versus the prior regimen: a pooled analysis in relapsed/refractory (R/R) mantle cell lymphoma (MCL) with up to 7.5 years of extended follow-up. Blood. 2019;134(supplement 1):1538. doi: 10.1182/blood-2019-124691.