| On April 6, 2021, the FDA approved a new dosage regimen of 500 mg/m2 as a 120-minute intravenous infusion every two weeks (Q2W) for ERBITUX (cetuximab) for patients with K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) or squamous cell carcinoma of the head and neck (SCCHN). This approval provides a biweekly dosage regimen option in addition to the previously approved weekly (QW) dosage regimen (initial dose of 400 mg/m2 as a 120-minute intravenous infusion, and subsequent doses of 250 mg/m2 infused over 60 minutes once weekly) as a single agent or in combination with chemotherapy. The new dosage approval was based on population pharmacokinetic (pop-PK) modeling analyses that compared the predicted exposures of cetuximab 500 mg/m2 Q2W to observed cetuximab exposures in patients who received cetuximab 250 mg/m2 QW. Pop-PK modeling applies mathematical models to draw conclusions about clinical scenarios by describing PK characteristics and variability based on limited concentration-time data pooled from more than one study. Although the concentration-time profiles of cetuximab Q2W and QW regimens were overlapping, the geometric mean of steady-state cetuximab Cmin achieved with 500 mg/m2 Q2W were 25% and 23% lower compared to QW dosage regimen in patients with SCCHN and mCRC, respectively. The potential impact of lower Cmin at steady state was assessed by determining the duration at steady state where the proposed 500 mg/m2 Q2W dosage regimen would have concentrations lower than that of the previously approved 250 mg/m2 QW dosage. The estimation showed that, on average, approximately 6% of the patients who received the 500 mg/m2 Q2W dosage regimen would have their concentrations below the lower bound of 90% prediction interval of Cmin,ss at 250 mg/m2 QW for approximately 1-2 days out of the proposed 2-week dosing interval. This difference in Cmin,ss was deemed unlikely to have a clinically significant impact on the effectiveness of ERBITUX therapy for the approved indications. This conclusion was also supported by pooled analyses of overall response rates (ORR), progression-free survival (PFS), and overall survival (OS) from published literature in patients with CRC and SCCHN, and contextualized by OS analyses using real-world data (RWD) in patients with mCRC who received either the cetuximab QW or Q2W regimens. In these exploratory RWD analyses, the observed efficacy results were consistent across dosage regimens and supported the findings from the pop-PK modeling analyses. Additional information about the pop-PK modeling analyses can be found at https://go.usa.gov/x6xkm. ERBITUX is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced SCCHN; in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN; as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed; and for the treatment of K-Ras wild-type, EGFR-expressing mCRC as determined by an FDA-approved test in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment, in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, and as a single-agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown. The most common adverse reactions (incidence ≥ 25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. Additional information regarding ERBITUX dosage and administration, and warnings and precautions can be found in the full prescribing information linked below. The Prescription Drug User Fee Act (PDUFA) VI Model-Informed Drug Development (MIDD) Paired Meeting Pilot Program played a key role in the development program for this supplemental New Drug Application (sNDA). MIDD is an approach that involves developing and applying exposure-based, biological and statistical models derived from preclinical and clinical data sources to inform drug development and decision-making. It aims to integrate information from diverse data sources to help decrease uncertainty and lower failure rates, and to develop information that cannot or would not be generated experimentally. For additional information on the MIDD Paired Meeting Pilot Program, please visit https://go.usa.gov/xdtdP. |
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