NCCN Recommends Zanubrutinib as First-Line, Second-Line Therapy in CLL, SLL

The National Comprehensive Cancer Network (NCCN) recommended zanubrutinib, a tyrosine kinase inhibitor sold as Brukinsa (BeiGene), for treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

While zanubrutinib is approved by the FDA for the treatment of adult patients with mantle cell lymphoma (MCL), recent NCCN guidelines updated on December 3 now recommend the indication as both a first-line and second-line treatment in CLL/SLL:

• First-line therapy of zanubrutinib as a single agent is recommended for the treatment of CLL/SLL with del(17p) and TP53 mutations in patients with contraindication to other bruton tyrosine kinase (BTK) inhibitors who have indications for treatment.
• For second-line treatment and subsequent therapy, the NCCN recommends the indication as a single agent for the treatment of CLL/SLL with or without del(17p) and TP53 mutations in patients with intolerance or contraindication to other BTK inhibitors who have indications for retreatment.

As payers view the NCCN guidelines as a gold standard for making reimbursement decisions, the question lingers whether to adhere to the NCCN guidelines while the FDA has not approved zanubrutinib for the treatment of CLL/SLL. The distinction of the del(17p) mutation as a high-risk genetic characteristic associated with overall survival may warrant the push for treatment of CLL/SLL, as those with CLL have a shorter life expectancy than age- and sex-matched populations.

Recent findings from the arm C, phase 3 SEQUOIA Trial presented at the 62nd American Society of Hematology Annual Meeting and Exposition indicate that zanubrutinib was well tolerated and effective among patients with CLL/SLL with 17p depletion. Including more than 21.9 months of follow-up, treatment-naïve patients with CLL or SLL with del(17p) administered zanubrutinib as a monotherapy exhibited an increased complete response rate from baseline (1.9% to 6.4%).

Additionally, progression-free survival at 18 months was 90.6% (95% CI, 83.3%-94.9%), and the overall response rate was 94.5%, with the drug’s tolerability remaining consistent with what has been reported in previous studies.

So, how should payers handle a situation when the NCCN adds to its treatment guidelines ahead of FDA?

A prior analysis published in BMJ of 113 NCCN recommendations found that the NCCN frequently recommends beyond FDA-approved indications and that the evidence for these recommendations was weak.

In a subsequent study published in the Annals of Oncology examining the level of evidence used in recommendations within NCCN guidelines formed prior to FDA approvals, researchers found that on the contrary, the strength of the evidence supporting these recommendations was “robust, with a significant subset of these drugs later becoming FDA approved or supported by randomized controlled trials.”

Speaking in an email exchange with The American Journal of Managed Care®, Erin Lopata, PharmD, MPh, vice president of the Access Experience Team at PRECISIONvalue, explains the process of managing an indication added to NCCN treatment guidelines ahead of FDA approval.

AJMC®: What is typically the payer response when a drug is added to NCCN guidelines before the FDA approves the indication? Is this common?

Dr Lopata: Most payers consider NCCN Guidelines as a recognized compendium to support coverage decisions for oncology products. While many payers currently manage the oncology class by limiting utilization to FDA-approved indications, a Category 1 or 2a recommendation for a non-approved indication will generally result in coverage for that use.

The new recommendation may trigger a payer policy change for the drug, where the NCCN-supported indication is added to the pharmacy or medical policy clinical criteria. Other payers may have an overarching policy that allows for authorization based on NCCN guideline recommendations.

Additionally, if the payer utilizes a pathway to manage oncology agents, the pathway may also need to be updated to direct approvals of the NCCN-supported indication.

AJMC®: How should providers approach this situation, particularly when it comes to potentially updating respective clinical pathways platforms?

Dr Lopata: Providers may be working with multiple payers with different methods of operationalizing NCCN Guideline recommendations. To support a smooth approval process, the provider should note that the use of the medication is supported by NCCN Guidelines on the prior authorization form or within a medical necessity letter.

This may be particularly helpful when a recommendation has been recently released and payer policies may not yet be updated. Providers should consider updates to their internal tools such as their own clinical pathways, EMRs, and other clinical decision support tools to account for the new recommendation and treatment option.

AJMC®: Any other thoughts?

Dr Lopata: With a significant research effort and robust pipeline, both payers and providers are challenged with keeping up-to-date with advances and updates in this therapeutic area.