SYMPATICO Trial of Ibrutinib Plus Venetoclax Boosts PFS in MCL

Matthew Matasar, MD

In the phase 3 SYMPATICO study (NCT03112174), the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) given in combination with venetoclax (Venclexta) led to a statistically significant improvement in progression-free survival (PFS) and complete response (CR) rate vs ibrutinib and placebo in patients with relapsed/refractory mantle cell lymphoma (MCL).¹

The multinational, double-blind study enrolled patients with relapsed/refractory MCL who received 1 to 5 prior therapies and randomly assigned them in a 1:1 fashion to receive ibrutinib 560 mg once daily for 24 months in combination with venetoclax or placebo. Among the 134 patients treated with ibrutinib plus venetoclax, the primary end point, median investigator-assessed PFS with global censoring, was 31.9 months vs 22.1 months in the 133 patients in the ibrutinib plus placebo arm.

The combination arm was favored vs the placebo arm in regard to median PFS per independent review committee (IRC) with global censoring (HR, 0.67; 95% CI, 0.49-0.91; log-rank P = .0108), by investigator assessment with US FDA censoring (HR, 0.60; 95% CI, 0.44-0.83; log-rank P = .0021), and by IRC assessment with US FDA censoring (HR, 0.63; 95% CI, 0.45-0.87; log-rank P = .0057).

With the combination, the overall response rate was 82% vs 74% with placebo, and the CR rates were 54% vs 32%. The median duration of response was 42.1 months vs 27.6 months across arms, respectively, and the overall survival (OS) was numerically improved among those who received the combination vs placebo with a median OS of 44.9 months vs 38.6 months, respectively (HR, 0.85; 95% CI, 0.62-1.19; log-rank P =.3465).

“We see an improvement in clinical end points with the combination treatment both in terms of overall response rate, progression-free survival, and depth of response. We hope to continue to follow these patients over time and see whether this combination translates to improvements in overall outcomes and overall survival,” Matthew Matasar, MD, told Targeted Oncology^TM, in an interview.

In the interview, Matasar, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discussed the rationale and findings of the doublet consisting of ibrutinib and venetoclax for the treatment of MCL.

Targeted Oncology: Can you discuss the SYMPATICO study?

Matasar: The standard-of-care for patients with relapsed mantle cell lymphoma continues to evolve. Ibrutinib or BTK monotherapy has been a long-standing standard-of-care in these patients. The question is whether we can do better than monotherapy at providing deeper and more durable responses. This has been our goal, to develop combination therapy in this context. To that end, we see data from SYMPATICO, which was a randomized trial of ibrutinib continuously, with or without the addition of 2 years of venetoclax at initiation, with an attempt to improve these very clinical end points.

lymphoma cells : © Dr_Microbe - stock.adobe.com

We see the results are favorable. In terms of activity, we see definite improvements in response and progression-free survival for the patients treated with the doublet. What we do not yet know is whether this is going to translate to improvements in survival. We do not yet have a full and clear picture about the incremental impact of combination therapy.

How does the mechanism of action of this combination differ from other treatment options in the space?

Ibrutinib plus venetoclax is an attractive combination because it is a dual oral program. That's important both for the patient journey, as well as for logistics and operational considerations when we take care of our patients in a variety of health care contexts.

How does the combination therapy compare with ibrutinib and placebo?

We see an improvement in clinical end points with the combination treatment both in terms of overall response rate, progression-free survival, and depth of response. We hope to continue to follow these patients over time and see whether this combination translates to improvements in overall outcomes and overall survival. Due to setting, relapsed/refractory mantle cell lymphoma is a moving target. We have other drugs emerging in the space, but the availability of a potent and well-tolerated oral combination approach is very attractive.

What are the potential implications of these findings?

The potential implications are that we may see a new option emerging for patients with a higher-risk of relapsed/refractory mantle cell lymphoma where we may be able to get more benefit out of our line of BTK-inhibiting therapy with this combination approach, deferring the potential toxicities of other later live interventions, such as [chimeric antigen receptor] T-cell therapy and allogeneic stem cell transplantation.

What are the next steps for the development of this combination? Are there any plans to investigate it in earlier lines of treatment for other types of lymphoma?

Most importantly, we need to continue to follow these data and watch them mature. Mantle cell lymphoma is sometimes a marathon and not a sprint, and following these patients to learn their subsequent outcomes, impact of the next line of therapy, and responses to the next line of therapy will better clarify the impact of having a doublet in this clinical context. The combination was very well-tolerated with no new safety signal outside of that which is expected from its constituent components. That certainly does give us an opportunity to think about other combinations both in relapse setting as well as whether they're optimal partners. to enhance their activity and enable it to move to the first-line setting.

What are some of the challenges in MCL?

One challenge in this field is that we have a number of BTK inhibitors that are available currently. When SYMPATICO was designed, it leveraged ibrutinib, which was an even more relevant consideration because of a relative paucity of alternatives. Now, we find the therapeutic landscape with multiple approved BTK inhibitors, both covalent and noncovalent. It remains an interesting question for us in the community of lymphoma doctors, whether ibrutinib or other BTK-inhibiting approaches may be the optimal partner for venetoclax.

REFERENCE:

1. Wang M, Jurczak W, Trněný M, et al. Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma: primary analysis results from the randomized phase 3 SYMPATICO study. Blood. 2023;142(suppl 2):LBA2. doi:10.1182/blood-2023-191921