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FDA Decision Alerts July 9, 2021

CDER-Approved sBLA for ERBITUX® (cetuximab)

Nick Honig and Mandy Patrick
Contributing writers, Aetion

On April 6, 2021, FDA approved a new biweekly dosing regimen for Eli Lilly’s ERBITUX® (cetuximab). The supplemental approval allows for a 500 mg/m² dose administered every two weeks for cetuximab’s existing indications: metastatic colorectal cancer (mCRC) and squamous cell carcinoma of the head and neck (SCCHN).

Key findings from FDA’s Clinical Reviews documents:

Cetuximab’s original dosing regimen was a 400 mg/m² initial loading dose followed by a weekly maintenance dose of 250 mg/m² (Q1W). The applicant proposed a dosing change to 500 mg/m² dose administered every two weeks (Q2W). The applicant used a model-informed drug development (MIDD) approach to support this request. The applicant also submitted a meta-analysis of published clinical data and an RWE study to provide supportive clinical evidence.

Intent of the RWE study 
The applicant conducted an RWE study to compare the efficacy and safety outcomes of Q1W and Q2W regimens.

Protocols for RWE generation
The applicant conducted a retrospective, observational, comparative effectiveness study on survival outcomes in mCRC between the two dose regimens. The sole endpoint was overall survival (OS). The applicant used the Flatiron EHR database to initially identify 23,681 patients, then refined the population to patients over 18 years old with stage 4 or recurrent mCRC with K-Ras wild-type status who received one of four therapy regimens as first, second, or third line of therapy. These criteria narrowed the population to 1,074 patients, 61% of whom received Q1W and 39% received Q2W. The applicant used 1:1 propensity score matching to balance the demographic and clinical characteristics of the patient population. The propensity score model included a number of demographic factors, such as age, gender, race, ethnicity, region, and clinical characteristics such as cancer stage at diagnosis, ECOG, mutation type, backbone chemotherapy received, index date, and lines of therapy. The applicant conducted analyses by line of therapy and overall, treating line of therapy as a categorical variable in the overall analysis.

Comparing Q2W to Q1W dosing by line of therapy and for the overall population, the hazard ratios for OS ranged from 0.86 to 0.97 with the 95% confidence intervals for all hazard ratios including the null value of 1, indicating no evidence of a substantial difference in overall survival between Q2W and Q1W regimens.

Outcome of the RWE submission 
FDA concluded that the new dosing regimen was approved based on the MIDD approach and that “the supplemental clinical data from the… RWE are considered supportive.”

FDA noted a few limitations and statistical considerations related to the RWE study. First, the reviewer noted that patients were identified as Q1W or Q2W based on receiving 70% of the planned cetuximab dose within 4-10 days (Q1W) or 11-18 days (Q2W) of the prior administration. The range of actual dosing time intervals for the patients in the Q1W and Q2W cohorts may have impacted the observed differences between the dosing regimens.

FDA also noted the potential for selection bias and confounding in RWE stating, “statistical methods, which in this case was propensity score matching, cannot entirely resolve the issues of selection bias and confounding variables that are intrinsic to observational data, particularly with respect to unmeasured or mis-specified factors.”

Third, FDA noted that overall survival presents issues for RWD. The agency stated that misspecification or inaccurate data with regards to death may “lead to biased results, particularly if this is linked to treatment groups. Though this is unlikely to be the case, in an observational and retrospective analysis, this possibility cannot be completely ruled out.”

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