Ibrutinib Combos Target Hard-to-Treat CLL and MCL at ASH 2022

Janssen_Editorial_Michael We

Courtesy of Michael Vi/Getty Images

When drug developers start using terms like “functional cure”, the science has arrived – or is at least pretty close. Reaching this point requires tinkering with different combinations and mechanisms of action.

For chronic lymphocytic leukemia and mantle cell lymphoma, many of these combinations include ibrutinib (Imbruvica).

Co-developed by J&J’s Janssen and AbbVie’s Pharmacyclics, ibrutinib stood out across several presentations at the 64th American Society of Hematology (ASH) annual meeting Saturday and Sunday.

In the U.S., the average five-year survival rate for CLL is 87%. While this may sound hopeful, there are still patient populations with high unmet needs, elderly patients in particular.

For MCL, the survival statistics aren’t as rosy. Janssen characterizes MCL, a form of non-Hodgkin’s lymphoma, as “an aggressive and incurable blood cancer of the white blood cells.”

Mark Wildgust_JanssenIn an interview with BioSpace, Mark Wildgust, vice president, global medical affairs, oncology at Janssen said ibrutinib is the only Bruton's tyrosine kinase (BTK) inhibitor that has shown single agent overall survival benefit for patients with newly diagnosed CLL. The therapy won FDA approval as a single agent to treat second-line CLL in 2014.

A Functional Cure?

Of note, an oral presentation Saturday highlighted four-year follow-up data from the Phase III GLOW study. This trial tested a combination of ibrutinib plus AbbVie’s venetoclax versus chlorambucil plus obinutuzumab in 211 older adults with previously untreated CLL. These patients had comorbidities such as renal impairment.  

The data showed ibrutinib plus venetoclax reduced the risk of progression or death by 79%. It is the first fixed-duration novel combination to demonstrate an overall survival advantage compared to chlorambucil plus obinutuzumab in the first-line treatment of CLL, Janssen reported.

Venetoclax is approved as a second-line treatment for CLL. It is also approved to treat adults 75 and older with newly diagnosed acute myeloid leukemia, in combination with azacitidine or decitabine or low-dose cytarabine.

Wildgust said the OS curve overlaps with an age-matched U.S. general population.

“The curve speaks thousands of words, in my mind,” he said. “To be able to return survival back to potentially what we would see in the normal patient population, I think speaks to the transformational outcomes we've been hoping for. In many regards, it's almost like a functional cure.”

Carsten Niemann_Rigshospitalet Study investigator Carsten Niemann, M.D., Ph.D. told BioSpace that adults 65-plus with comorbidities are the most common CLL patient population at his outpatient clinic.

“This may address an important question for this frail patient population, that we can actually give them a very effective treatment without jeopardizing their health in terms of adverse events,” said Niemann, who is a clinical associate professor and principal investigator at Rigshospitalet in Copenhagen.

Niemann said that there was a “small subgroup of patients who had a risk of fatal events early on” in the treatment, though this didn't equate to a “statistical significance.”

Imbruvica’s label warns of a risk of fatal and serious cardiac arrhythmias and cardiac failure.

The therapy’s current development portfolio is emblematic of the refinement occurring in cancer treatment today.

A glance at ClinicalTrials.gov shows 82 active studies involving the therapy in CLL alone.

Ibrutinib Bests Transplant in MCL

Leading off the Sunday plenary session, Martin Dreyling, M.D., co-chair of the European Mantle Cell Lymphoma Network presented data from the TRIANGLE study, where ibrutinib was added to autologous stem cell transplantation (ASCT) in younger adults with untreated MCL. The study of 870 patients ran from July 2016 to December 2020. 

Ibrutinib given during induction and as maintenance with or without ASCT showed strong efficacy with acceptable toxicity, Dreyling et. al wrote.

It's the first time he’s seen a small molecule tyrosine kinase inhibitor beat transplant, Wildgust said.

Ibrutinib has also had success in adults 65-plus with newly diagnosed MCL.

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in June, Janssen reported the therapy plus bendamustine-rituximab (BR) and rituximab maintenance significantly reduced the risk of disease progression or death by 25% compared to placebo plus BR and rituximab maintenance in this patient population.

After 84.7 months of follow-up, the ibrutinib combo led to a median PFS of 6.7 years versus 4.4 years in the comparator arm.

The SHINE trial was the first front-line Phase III study of a BTK inhibitor in MCL.

Ibrutinib is currently approved as a second-line therapy for MCL in the U.S. under the accelerated approval pathway.

Ibrutinib Boosted by Anti-ROR1 Antibody 

Ibrutinib was also featured in tandem with Oncternal Therapeutics' zilovertamab in both MCL and CLL in the Phase I/II CIRM-0001 study. Zilovertamab, an investigational anti-ROR1 monoclonal antibody, is the San Diego-based company’s lead asset.

In MCL, the combination elicited an ORR of 89% and a complete response rate of 43% compared with a historical ORR of 66% and CR of 20% for ibrutinib alone. After 19.5 months of follow-up, PFS and OS have not yet been reached.

Historically, patients have reached PFS at 12.8 months and OS at 25 months with ibrutinib monotherapy.

PFS was achieved in 100% of patients with relapsed/refractory CLL expressing the p53 mutation/17p deletion. T

he numbers have been nowhere near as robust for either therapy alone. In a statement, Saturday, Oncternal President and CEO James Breitmeyer, M.D., Ph.D. said MCL and CLL patients with the p53 mutation/17p deletion are “underserved by current standard of care treatments.”

“We continue to believe that the inhibition of ROR1 with zilovertamab can play a key role in addressing important unmet medical needs in difficult-to-treat patients across various hematological malignancies,” he said.

The duo is currently being assessed in a Phase III trial in R/R MCL.

Back to news