Increased Treatment Efficacy in p53-Mutated MCL Remains Elusive

The future of treatment in p53-mutated mantle cell lymphoma (MCL) depends on further research to find more effective therapies for this patient subset, according to Tycel Jovelle Phillips, MD.

For instance, in the phase 3 SHINE trial (NCT01776840), ibrutinib (Imbruvica) in combination with bendamustine plus rituximab (Rituxan; BR) demonstrated a 17.8-month progression-free survival (PFS) benefit over placebo plus BR in this population, with a median PFS of 28.8 months with ibrutinib vs 11.0 months with placebo, Phillips explained in a presentation at the 2022 Pan Pacific Lymphoma Conference.¹ Although investigators observed a PFS benefit, it was lower than the median PFS of 80.6 months for the entire studied population of patients with MCL.

“Right now, the big question is how to best treat these patients and how to best continue to keep them alive,” Phillips said. “More studies are needed with new novel combinations, and we’ll need more new drugs to enter the market that are hopefully agnostic to p53 mutations.”

In an interview with OncLive^®, Phillips, a clinical associate professor in the Division of Hematology and Oncology at the Rogel Cancer Center, Michigan Medicine, University of Michigan Health, outlined the reasons why p53 mutations are difficult to treat and discussed potential future directions for the treatment of this subgroup of MCL .

OncLive^®: Could you provide a general overview of your presentation on p53 mutations in MCL?

Phillips: I discussed the role of p53 mutations, asking the question: Should they affect how we treat patients with MCL? The mutation itself is rare, appearing in about 20% of patients, but it seems to have poor prognostic effects on outcome and treatment response. If we look at all the information we have to date about up-front therapy and salvage therapy, patients who harbor this mutation tend to have worse outcomes than those who don’t. [Additionally, this mutation doesn’t] seem to have any clear treatment modality; it seems to be agnostic [to treatments] other than potentially CAR T-cell therapy.

As a background, p53 is our master tumor suppressor. Patients can have either p53 deletion through loss of chromosome 17p, or mutations in the p53 protein. It does appear that the mutation tends to be a bit more detrimental to a patient’s outcome than the deletion, because there are 2 copies of the gene, so if a patient loses 1 copy [through deletion], there’s always the possibility that they have another intact copy. Patients can have monoallelic or biallelic deletions. However, the p53 mutation is a dominant negative, so if a patient has a mutated copy, it affects and inactivates the normal copy, and they lose all complete function in p53.

What are some of the factors within p53-mutated disease that might contribute to worse patient outcomes?

The biggest issue is that these patients don’t seem to be responsive to chemotherapy. If we look at most clinical trials, we see a 2-year PFS and overall survival [OS] rate that’s normal for what we’ve historically seen in MCL [of] 3-5 years. [This is less than] what we’re seeing in more contemporary times with patients who are living a decade or longer.

What potential therapies are still needed to increase the benefit of treatment in patients with p53-mutated disease?

These are probably our highest-risk patients. Identifying a treatment regimen that can give a durable remission [would be ideal]. MCL is incurable, so we’re not curing any of these patients.

However, the end goal in this disease is to prolong the remission as long as possible. We need to come up with new induction therapies that will provide remissions in most of these patients beyond 24 months, and then move on to better salvage therapies to continue to extend the OS of these patients.

What ongoing studies within this patient population would you like to highlight?

A [phase 2] trial [NCT03824483] at Memorial Sloan Kettering Cancer Center is looking at a combination of obinutuzumab [Gazyva], venetoclax [Venclexta], and zanubrutinib [Brukinsa], which is a second-generation BTK inhibitor. That trial is immature, as we still don’t have the 24-month readout on the patients who received that induction therapy.

Other than that, unfortunately, most studies that have been published have not shown effective results, at least in the up-front setting for these patients with p53-mutated disease. A study that was done in the Netherlands that looked at combining ibrutinib and lenalidomide [Revlimid] in this patient population seemed to have a decent outcome. [However, that is not reflective of] the way the field is going as far as combining these 2 agents in the relapsed/refractory setting.

Another direction may be combining BTK inhibitors with the BCL2 inhibitor venetoclax, although most of the studies so far with a BCL2 inhibitor plus a BTK inhibitor haven’t demonstrated any substantial impact in p53-mutated cases.

What main message from your presentation would you like colleagues to walk away with?

We need better studies, whether that’s by moving CAR T-cell therapy into the frontline setting or using the wave of bispecific antibodies that are entering the field. We’ll need to wait to see how future studies read out to determine whether these therapies will move up to the up-front setting and be useful for these patients.

[The situation with these patients with p53-mutations is] unfortunate because we’ve come so far with MCL. [In MCL as a whole,] we’ve improved survival quite a bit, and most of these patients can expect to live a decade or longer. We need to play catch-up with this high-risk group. We can identify these patients, now we just need to find the best way to treat them.

Reference

Phillips TJ. Impact of p53 mutations in patients with mantle cell lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI. https://bit.ly/3yMGygE