30-month complete response serves as PFS surrogate for follicular lymphoma

CHICAGO — The evaluation of complete response rate at 30 months acted as a surrogate endpoint for PFS in patients with follicular lymphoma, according to the results of a meta-analysis presented at ASCO Annual Meeting.

Perspective from Brian J. Bolwell, MD

The use of 30-month complete response (CR30) as a surrogate endpoint may help expedite therapeutic development, according to the researchers.

“Currently available treatments for follicular lymphoma have been effective in delaying disease progression,” Daniel J. Sargent, PhD, the primary consulting statistician of the Mayo Clinic in Rochester, Minnesota, said during a presentation. “Median PFS in first-line follicular lymphoma is now approximately 7 years, indicating that clinical trials may take 8 to 10 years to complete when using the traditional endpoint of PFS. This led us to explore whether surrogate endpoints existed to allow trials to be completed in a timelier manner.”

Sargent and colleagues evaluated data from 13 randomized first-line trials (8 induction trials and 5 maintenance trials) that included 3,837 patients with follicular lymphoma. Researchers excluded studies which evaluated induction vs. observation therapy and studies with insufficient quantity or quality of data.

Sargent and colleagues defined CR30 as being in complete response before 30 months of treatment that was maintained until 30 months following trial induction. Researchers used linear regression and copula bivariate models to correlate the OR of CR30 with the HR of PFS and calculated the minimum CR30 difference to predict significant PFS difference.

Researchers compiled all data analyses in the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) database.

Overall, a minimum 10% absolute CD30 improvement over a control CR30 of 50% predicted significant improvements in PFS for patients with previously untreated follicular lymphoma.

Researchers met the prescribed threshold for surrogacy in both the linear regression model (HR = 0.88; 95% CI, 0.77-0.96) and the copula bivariate model (HR = 0.86; 95% CI, 0.72-1).

In both the linear regression models, researchers observed similar outcomes related to CR30 in trials with rituximab (Rituxan, Genentech/Biogen Idec; HR = 0.85; 95% CI, 0.62-0.97) and without rituximab (HR = 0.91; 95% CI, 0.05-1).

These findings persisted in the copula bivariate model for trials with rituximab (HR = 0.8; 95% CI, 0.56-1) and without rituximab (HR = 0.96; 95% CI, 0.9-1).

Several sensitivity and individual patient data analyses confirmed the finding that CR30 acted as a surrogate endpoint for PFS in first-line follicular lymphoma.

“We must recognize that all surrogacy evaluations are limited to the specific patient population,” Sargent said. “I think we need to think about how these results will play in the future with novel therapies. The assembled FLASH database will provide a rich repository to explore the biology of follicular lymphoma going forward, and the group is already considering multiple additional analyses.” – by Cameron Kelsall

Reference:

Sargent DJ, et al. Abstract 8504. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosure: Sargent reports research funding Celgene and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Brian J. Bolwell, MD

We are continuing to make improvements in follicular lymphoma, and the OS continues to be longer and longer. That is a good thing, obviously, but the question when trying to introduce new drugs is: Are there any other markers that might be of a shorter duration that can predict how patients are going to do?
Researchers looked at a 2.5-year time point and asked, if a patient was in complete remission 30 months after the start of therapy, was that an equivalent marker of PFS? If a drug is good, and it yields better treatment outcomes, having a shorter time point to assess whether that drug is useful is a positive thing.
At the end of the day, this abstract showed that in fact, yes, looking at whether a patient was in compete response 2.5 years after the initiation of therapy was an equivalent to looking at overall PFS. This is important because it will allow a more immediate drug therapy and more immediate introduction of new drugs into the marketplace in the field of follicular lymphoma.

Brian J. Bolwell, MD

Taussig Cancer Institute

Cleveland Clinic

Disclosures: Bolwell reports no relevant financial disclosures.