AbbVie Withdraws Ibrutinib MCL and MZL Indications in the United States

AbbVie has announced the intention to voluntarily withdraw indications for ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL) who have previously received at least 1 therapy and in those with marginal zone lymphoma (MZL) who require systemic treatment and have received at least 1 prior anti–CD20-based therapy.¹ Notably, other approved indications for this agent are not affected by this decision.

In November 2013, the FDA granted an accelerated approval to ibrutinib in the MCL population based on an investigator-assessed overall response rate (ORR) of 65.8% (95% CI, 56.2%-74.5%) reported among 111 treated patients enrolled to an open-label, multicenter, single-arm phase 2 study (NCT01236391).² The median duration of response (DOR) in these patients was 17.5 months (95% CI, 15.8-not reached [NR]).

A few years later, in January 2017, the regulatory agency awarded the BTK inhibitor accelerated approval for use in the MZL population, again based on ORR data. In 63 efficacy-evaluable patients enrolled to the open-label, multicenter, single-arm, phase 2 PCYC-1121 study (NCT01980628), ibrutinib induced an ORR of 46% (95% CI, 33.4%-59.1%) by independent review committee assessment; this included a complete response (CR) rate of 3.2% and a partial response (PR) rate of 42.9%. The median DOR as NR (range, 16.7-NR).³

The voluntary action is because of requirements associated with the accelerated approval status granted by the agency for these diseases.1

Because the decisions were based on ORR data from phase to studies, the clinical benefit of ibrutinib needed to be confirmed in additional studies. To this end, the confirmatory phase 3 SHINE (NCT01776840) and SELENE (NCT01974440) studies were conducted in those with previously untreated MCL and relapsed or refractory MZL, respectively.

Although SHINE met the primary end point of progression-free survival (PFS) the combination of ibrutinib and chemoimmunotherapy was linked with more toxicity vs the control regimen. SELENE did not meet its primary end point of PFS.

“We pursued accelerated approvals for MCL and MZL indications for [ibrutinib] in the United States to offer a treatment to patients who at the time had limited therapeutic options,” Roopal Thakkar, senior vice president and chief medical officer of AbbVie stated in a press release. “While we are disappointed in the outcome of the confirmatory trials for these indications, we remain confident in the benefit/risk profile of [ibrutinib] for patients living with multiple forms of blood cancer around the world.”

Taking a Deeper Look at the Confirmatory Studies

SHINE

The phase 3 SHINE trial enrolled patients with a centrally confirmed diagnosis of MCL with cyclin C1 overexpression or translocation breakpoints at t(11;14) who had previously untreated stage II to IV disease, and at least 1 measurable disease site.⁴ Patients were required to be at least 65 years of age, have an ECOG performance status of 0 or 1, and acceptable organ function.

Study participants were randomly assigned 1:1 to receive ibrutinib at 560 mg once daily (n = 261) or matching placebo (n = 262) plus bendamustine at 90 mg/m2 on days 1 and 2 of each 28-day cycle, rituximab (Rituxan) at 375 mg/m2 on day 1 of each cycle given every 4 weeks for 6 cycles. After induction treatment, those who achieved an objective response went on to receive daily ibrutinib or placebo plus maintenance rituximab at 375 mg/m2 given every 8 weeks for up to 12 additional doses.

Investigator-assessed PFS served as the primary end point of the trial, and secondary end points comprised CR, minimal residual disease (MRD) undetectability, and time to worsening of disease-related symptoms and concerns. Safety of the BTK inhibitor was also assessed.

At a median follow-up of 84.7 months (range, 0.1-97.5), the median PFS with ibrutinib was 80.6 months (95% CI, 61.9-not evaluable) vs 52.9 months (95% CI, 43.7-71.0) with placebo (stratified HR, 0.75; 95% CI, 0.59-0.96; P = .01). Notably, the PFS benefit provided with ibrutinib over placebo was noted across the majority of prespecified subgroups. However, those with a simplified MIPI score of high risk and those whose tumors harbored TP53 mutations did not derive a clear benefit with the BTK inhibitor.

Objective responses were achieved by 89.7% of those in the ibrutinib arm and 88.5% of those in the placebo arm; investigator-assessed CRs were achieved in 65.5% and 57.6% of patients, respectively. Moreover, 62.1% of those in the ibrutinib arm achieved undetectable MRD in the peripheral blood or bone marrow vs 56.5% of those in the placebo arm.

Overall survival (OS) was comparable between the treatment arms (HR, 1.07; 95% CI, 0.81-1.40).

The incidence of grade 3 or 4 toxicities during treatment was 81.5% in the investigative arm vs 77.3% of those in the control arm. The most frequent grade 3 or higher adverse effects (AEs) reported in 10% or more of patients included neutropenia (47.1% vs 48.1%, respectively), pneumonia (20.1% vs 14.2%), lymphopenia (16.2% vs 11.9%), anemia (15.4% vs 8.8%), thrombocytopenia (12.7% vs 13.1%), rash (12.0% vs 1.9%), and leukopenia (10.0% vs 11.2%).

SELENE

Patients with histologically confirmed indolent B-cell non-Hodgkin lymphoma with a histological subtype limited to follicular lymphoma or MZL at initial diagnosis were enrolled to the phase 3 SELENE trial.5 To be eligible, patients were required to have received at least 1 previous treatment with a CD20 antibody plus a chemoimmunotherapy regimen, have relapsed or refractory disease, at least 1 measurable disease site, and an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to receive ibrutinib at 560 mg or placebo plus chemoimmunotherapy which comprised 6 cycles of bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Treatment continued until progressive disease, intolerable toxicity, or study end.

In addition to PFS serving as the primary end point, secondary end points included OS, CR rate, ORR, DOR, patient-reported lymphoma symptoms and concerns, as well as safety.

Data from the study will be shared at a future medical meeting.

References

1. Update on Imbruvica (ibrutinib) US accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. AbbVie. April 6, 2023. Accessed April 7, 2023. https://news.abbvie.com/news/press-releases/
2. Imbruvica (ibrutinib) capsules now approved in the US for mantle cell lymphoma patients who have received at least one prior therapy. News release. Janssen Biotech, Inc. November 13, 2013. Accessed April 7, 2023. https://www.jnj.com/media-center/press-releases/
3. US FDA approves Imbruvica (ibrutinib) as first treatment specifically indicated for relapsed/refractory marginal zone lymphoma (MZL) – a rare type of non-Hodgkin’s lymphoma. News release. AbbVie. January 19, 2017. Accessed April 7, 2023. https://news.abbvie.com/news/
4. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817
5. A study of PCI-32765 (ibrutinib) in combination with either bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in participants with previously treated indolent non-Hodgkin lymphoma (SELENE). Clinicaltrials.gov. Updated March 24, 2023. Accessed April 7, 2023. https://www.clinicaltrials.gov/ct2/show/NCT01974440