Bruton Tyrosine Kinase Inhibitors Signal Promise in the Treatment of Chronic Lymphocytic Leukemia
February 18, 2020 12:00am
By Thao K . Huynh, PharmD , BCOP
Presentations at the 60th American Society of Hematology Annual Meeting & Exposition were dominated by advancements in the treatment of chronic lymphocytic leukemia.
Jennifer A. Woyach, MD
Presentations at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition were dominated by advancements in the treatment of chronic lymphocytic leukemia (CLL). Searches for CLL among oral presentations and poster sessions yield 371 entries.1High on the list of discussions was the efficacy of standard-of-care ibrutinib (Imbruvica) and novel immunotherapy combination regimens.
“This was a big year at ASH for targeted therapy,” said Jennifer A. Woyach, MD, associate professor at The Ohio State University Comprehensive Cancer Center in Columbus, who presented her own research at the meeting. The paradigm for frontline therapy is moving away from chemotherapy to targeted agents given alone or in combination. “Some of the biggest news this year [included] the results of 2 trials of frontline therapy showing superior efficacy of ibrutinib alone or with rituximab [Rituxan] versus chemoimmunotherapy,” she said.
Woyach was also interested in updates on the combination targeted therapy trials and the extended follow-up from the MURANO trial of venetoclax (Venclexta) plus rituximab.2This study, along with trials of ibrutinib plus venetoclax with or without other immunotherapy agents, involved patients treated with novel targeted combination therapies. All these studies, however, have relatively limited follow-up, so updates at future meetings when the data have further matured will be of interest, she said.
Alliance A041202: Ibrutinib in Older, Untreated Patients With CLL
Woyach presented data from the phase III Alliance A041202 study, which she said was designed to investigate the optimal treatment for older patients with CLL.3The study compared the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib as monotherapy and in combination with rituximab, as well as the combination of bendamustine and rituximab, for patients ≥65 years with previously untreated CLL. Investigators found that ibrutinib alone or in combination with rituximab produced superior progression-free survival (PFS) versus bendamustine plus rituximab, but there was no significant difference between ibrutinib and ibrutinib plus rituximab.
The 24-month PFS rate was 87% (95% CI, 81%-92%) for ibrutinib monotherapy, 88% (95% CI, 81%-92%) for ibrutinib plus rituximab, and 74% (95% CI, 66%-80%) for bendamustine plus rituximab.4Results of the study showed no overall survival (OS) difference between the 2 ibrutinib arms, which investigators attributed to a short follow-up and a crossover study design. Patients who progressed on bendamustine plus rituximab were allowed to cross over to ibrutinib.
The results were not particularly surprising, Woyach said. “From the initial data from PCYC-1102-CA [NCT01105247] and RESONATE-2 [NCT01722487], frontline ibrutinib did appear to be more effective than chemoimmunotherapy, but it remains very important to do these large studies to establish this,” she said. In 2017, randomized phase II data presented at ASH comparing ibrutinib alone with the combination of ibrutinib and rituximab also did not show an advantage to adding rituximab,5but this was a smaller trial in a different group of patients.
Ibrutinib was granted an expanded approval in 2016 to include single-agent ibrutinib therapy as a valid frontline therapy option; the FDA based its decision on data from the RESONATE-2 trial, which compared ibrutinib with chlorambucil.6This trial is the first comparing ibrutinib with a commonly used and very effective chemotherapy regimen.
Woyach said that their findings suggest that ibrutinib monotherapy should be the efficacy standard against which to measure other drugs in CLL trials for older patients.
iLLUMINATE: Up-front Ibrutinib Plus Obinutuzumab in CLL/SLL
Results from the phase III iLLUMINATE trial (NCT02264574) showed that ibrutinib plus obinutuzumab (Gazyva) was an effective chemotherapy-free treatment regimen compared with the chemoimmunotherapy regimen chlorambucil and obinutuzumab in patients with treatment-naïve CLL or small lymphocytic lymphoma (SLL).7This study included a genomically defined high-risk CLL population, according to the investigators.
“Similar to the Alliance trial, [results from] this study show that ibrutinib plus a CD20[-directed] antibodyin this case, obinutuzumab—is superior to chemoimmunotherapy,” Woyach said.
The chemotherapy-free arm showed a 77% reduction in risk of disease progression or death for patients with CLL or SLL and an 85% reduction for patients with high-risk CLL compared with the chemoimmunotherapy arm. OS had not yet been reached in either study arm.
The minimal residual disease (MRD) analysis for the intention-to-treat population showed that 35% of patients had undetectable MRD on ibrutinib plus obinutuzumab in bone marrow and/or peripheral blood testing versus 25% of those in the chlorambucil plus obinutuzumab arm. In the high-risk population, 27% versus 15% of patients had undetectable MRD in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively.8
Based on the trial findings, the FDA granted a priority review designation in October 2018 to a supplemental new drug application for the front-line regimen of ibrutinib plus obinutuzumab in this patient population.9
“[Results from] this study do not show that ibrutinib plus obinutuzumab is better than ibrutinib alone, but [the data] are promising. In the absence of a head-to-head trial, it would be reasonable to use this regimen,” she noted.
In January 2019, the FDA approved the combination of ibrutinib plus obinutuzumab for the treatment of patients with CLL/SLL in the first-line setting based on these trial data, making it the first chemotherapy-free regimen that includes an anti-CD20 antibody approved in the United States to treat this patient population.
ECOG-ACRIN Study E1912: Ibrutinib Plus Rituximab Versus FCR
The phase III ECOG-ACRIN study E1912 (NCT02048813) compared ibrutinib and rituximab with standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated patients ≤70 years.10The study found OS and PFS advantages for ibrutinib plus rituximab versus FCR.
This trial, as well as the Alliance and iLLUMI- NATE trials, was designed to span the entire population of patients with CLL and broadly compare chemoimmunotherapy with targeted therapy, said Woyach.
“That was really unexpected to see a survival advantage, especially so early on,” said Woyach. “[Results from] iLLUMINATE, Alliance, and [E1912] show us that for most patients, a targeted therapy should be the frontline standard of care.”
These agents are not perfect for all patients, Woyach added. “In older patients, there are associated toxicities that make it unappealing to give ibrutinib to everybody for the rest of their lives, but certainly these trials establish ibrutinib alone or with antibodies as the standard of care from which we need to build on, to move the field forward. It also tells us, for patients with a higher-risk CLL, that chemoimmunotherapy as frontline therapy should not be the go-to.”
The E1912 investigators noted in their abstract that the findings have immediate practice-changing implications, “establishing ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL.”
CLARITY: Ibrutinib Plus Venetoclax in R/R CLL
Findings from the phase II CLARITY study showed that combination ibrutinib plus venetoclax was tolerable in patients with relapsed/refractory CLL.11In 39% of patients, the combination induced MRD negativity in the bone marrow after 12 months.12More than 90% of patients achieved an objective response, with 54% in complete remission (CR) or CR with incomplete marrow recovery after 12 months of treatment.
This was one of 3 studies presented at ASH with this drug combination, said Woyach; the other studies were from The University of Texas MD Anderson Cancer Center and The Ohio State University.
“Looking at them all together, they show that these combinations are extremely effective for CLLboth up front and in the relapsed/refractory setting. They have high rates of complete response, [meaning] MRD negative. These trials justify moving these regimens to phase III trials, to compare [them] to the standard of care,” Woyach said.
Investigators on the CLARITY study said results showed deep remission in patients who are relapsed/refractory, and the drug combination can possibly be discontinued for those who achieve MRD eradication. In the trial, both ibrutinib and venetoclax were discontinued at 14 months if patients were MRD negative at 8 months; those who were MRD negative at 14 or 26 months discontinued therapy at month 26.
As single agents, ibrutinib and venetoclax are both successful in improving survival in CLL; however, they rarely induce MRD eradication asmonotherapies.
PCYC-1102-CA: 7-Year Ibrutinib Follow-up
Seven-year efficacy results from the phase Ib/II PCYC-1102 trial and extension study (PCYC- 1103-CA; NCT01109069) examining ibrutinib monotherapy administered in both frontline and heavily pretreated populations with CLL and SLL showed sustained activity with the single-agent BTK inhibitor.13The median PFS and OS rates for the first-line setting had not yet been reached, whereas the 7-year PFS rate was 80% and the OS rate was 75%. For the relapsed/ refractory setting, the 7-year PFS rate was 32% and the OS rate was 52%. A median PFS of 51 months was observed, and the median OS had not yet been reached for this group.
Investigators suggested that the data were promising, showing that patients with remissions are living longer with this treatment. Starting ibrutinib treatment early for both CLL and SLL provides the best long-term efficacy, according to current data.
Ibrutinib Plus CAR T-Cell Combo
The retrospective phase I/II study (NCT01865617) induced an 80% response rate in patients with relapsed/refractory CLL with concurrent therapy with ibrutinib and JCAR014, a CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.14,15 Investigators also found higher in vivo expansion of CD4-positive CAR T cells plus lower rates of severe toxicity. That included rates of grade ≥3 cytokine release syndrome (CRS) compared with a similar group of patients receiving only JCAR014.
Rather than giving JCAR014 after patients progressed on ibrutinib, investigators hypothesized that giving ibrutinib during leukapheresis and lymphodepletion, as well as during CAR T-cell therapy, would benefit patients by preventing tumor flare upon withdrawal, improving CAR T-cell function, decreasing CRS and other CAR T-cell treatment toxicity, and moving disease from the lymph nodes and into the blood. The study compared these patients with a previous cohort whose ibrutinib administration ended before infusion of CAR T cells.
Investigators said the results were the most encouraging they had seen in human subjects for a targeted agent and CAR T-cell combination. The CAR T cells expanded robustly in both the concurrent ibrutinib and no-ibrutinib groups, but the ibrutinib group had no severe CRS cases during CAR T-cell treatment while still showing a high response.
“There are preclinical data showing that ibrutinib’s inhibitory effects on ITK [interleukin 2inducible T-cell kinase] can actually help with the expansion of T cells in vitrowith the initial expansion of T cells to allow the CAR to be generated in the first place,” Woyach said.
Ibrutinib is an immunomodulatory agent for the same reasonit inhibits ITK and can normalize parts of the immune microenvironment. “It is exciting and makes sense with the preclinical data and what we know about the effects of ibrutinib in normal cells,” Woyach noted. The immune system of someone with CLL is so suppressed that adding ibrutinib, which modulates the immune system in a way to make it function more normally, can improve its function with CAR T cells, she said.
TRANSCEND-CLL-004: Liso-cel in Heavily Pretreated, High-Risk CLL
Patients who were previously treated with ≥2 prior lines of therapy, including a BTK inhibitor, were treated with the investigational CD19- directed 4-1BB CAR T-cell product lisocabtagene maraleucel (liso-cel; JCAR017), administered in a defined CD4 and CD8 composition.16
Results from the TRANSCEND-CLL-004 study (NCT03331198) found that liso-cel induced an 81.3% best overall response rate and a 43.8% CR rate.17Toxicities were seen as manageable, including CRS and neurologic events. Investigators noted a rapid achievement of CR and undetectable MRD in high-risk and standard-risk patients with CLL who previously received ibrutinib, the majority of whom also received venetoclax.
Investigators noted that in general, CR rates are low for CLL with continuous therapy required. Increasingly, MRD is seen as an important endpoint and as an independent predictor of improved survival. They said data from this study support continued development of single-dose liso-cel in the treatment of CLL.
Newer products are being developed and modifications are being made to CAR T-cell therapies and adjuvants such as ibrutinib. “We are getting close to learning how best to use CAR with CLL. The CLL immune system is unique compared with what is seen in other hematologic diseases,” in terms of making these products effective, said Woyach.
Novel Immunotherapy Triplet Regimen
Results from a phase I/II study of the triplet regimen combining pembrolizumab (Keytruda) with novel agents umbralisib and ublituximab showed a 90% response rate in relapsed/ refractory CLL and a 50% response rate in patients with Richter transformation.18,19The median PFS was not reached for patients with CLL at 15.6 months, and the PFS rate at 12.0 months was 89%.
Investigators noted that clinical data show pembrolizumab is ineffective as monotherapy for relapsed or refractory CLL and has a 90% failure rate for Richter transformation, with a median OS of 2 months. They hypothesized that antiPD-1 therapy combinations will be successful in treating CLL and Richter transformation, especially in patients who are relapsed/refractory to ibrutinib, and suggested that PD-1 and PI3K blockade would be synergistic.
The triplet was well tolerated, with durable responses in patients who are BTK refractory and high risk. The study had 2 CRs in patients with Richter transformation. Patients did not have higher immune-mediated toxicities than would be expected with pembrolizumab or umbralisib alone. It is thought to be the first PD-1, anti-CD20, and PI3Kδ inhibitor combination for this patient population.
The study is continuing to enroll patients with BTK-refractory CLL, as well as Richter transformation. Investigators are also amending the protocol to replace pembrolizumab with TG-1501, a novel antiPD-L1 agent.
“This was an interesting regimen,” said Woyach. “We have not seen PD-1 inhibitors to be very effective prior to this in CLL.” Although the study had only a few patients with Richter transformation, she said it was exciting to see some success.
As for other continuations, Woyach said the successor phase III trials to several studies presented at the meeting this year have just opened. These are the Alliance trial A041702 (NCT03737981) and the ECOG-ACRIN trial EA9161 (NCT03701282). Both use the same agents: ibrutinib plus obinutuzumab with or without venetoclax but for different age groups and with different rules for therapy discontinuation. The Alliance trial is for patients ≥70 years, whereas the ECOG-ACRIN trial is for patients aged 18 to 69 years. The primary endpoint in both trials is PFS, with secondary endpoints of OS and safety.
As for take-home lessons from ASH, Woyach reiterated the importance of targeted therapies. “Most patients with previously untreated CLL should not see chemotherapy as part of their treatment plan. The data presented at ASH this year, along with a number of other trials that have previously been reported, tell us that the standard of care for frontline CLL is now ibrutinib, and we should focus our efforts now on improving upon this standard of care,” she concluded.