Post-ibrutinib management in MCL unclear, speaker says

So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.

A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.

Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.

“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”

Overcoming ibrutinib resistance

Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”

Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers. 

A number of trials are underway to hit some of these pathways, Dr Martin said.

Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.

The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.

There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.  

“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”

Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination. 

He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed. 

“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”