cetuximab
Regulatory sources consulted
Approved indications
- Squamous cell carcinoma of the head and neck: with radiotherapy for locoregionally advanced disease, with platinum- and fluorouracil-based treatment for recurrent or metastatic disease, or as monotherapy after platinum failure.
- Metastatic colorectal cancer with wild-type RAS and EGFR expression: with FOLFIRI first-line, with irinotecan after irinotecan-refractory disease, or as monotherapy after failure or intolerance of oxaliplatin and irinotecan.
- BRAF V600E-mutated metastatic colorectal cancer in combination with encorafenib after prior therapy.
Clinical warnings
- Boxed warning · It can cause severe or fatal infusion reactions; most occur with the first dose. Premedicate, monitor during and for at least 1 hour afterward, and permanently discontinue for Grade 3–4 reactions. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
- Boxed warning · Cardiopulmonary arrest or sudden death has occurred during radiotherapy or platinum- and fluorouracil-based treatment. Monitor electrolytes during and after therapy and closely assess coronary disease, heart failure, or arrhythmias. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
- Major warning · Dermatologic toxicity can lead to infection and sepsis. Monitor skin and soft tissues, limit sun exposure, and adjust or discontinue for severe complications. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
- Major warning · Do not use in colorectal cancer with mutant RAS or unknown RAS status; it may lack benefit or increase progression and mortality. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
- Major warning · ERBITUX is not indicated with radiotherapy and cisplatin for squamous cell head and neck cancer: it did not improve progression-free survival and increased mucositis, dermatologic toxicity, cardiac events, electrolyte disturbances, and deaths. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
- Major warning · It can cause interstitial lung disease, severe hypomagnesemia and hypocalcemia, and ocular toxicity. Discontinue for confirmed lung disease and monitor electrolytes and ocular symptoms. — DailyMed, ERBITUX set_id 8bc6397e-4bd8-4d37-a007-a327e4da34d9
Adverse events
Common (≥1%)
acneiform rash · pruritus · dry skin · paronychia · diarrhea · nausea · fatigue · hypomagnesemia
Rare but serious
anaphylaxis or fatal infusion reaction · cardiopulmonary arrest or sudden death · sepsis · interstitial lung disease · ulcerative keratitis
Pregnancy and lactation
It can cause embryo-fetal harm. Use effective contraception during treatment and for 2 months after the last dose. Do not breastfeed during treatment or for 2 months afterward.
Recent literature (PubMed)
First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available. We randomly assigned patients with untreated BRAF V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival. Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent. This trial showed significantly longer progression-free survival and overall survival with first-line treat
Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent tre
Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .
Results from the phase III KEYNOTE-177 study established pembrolizumab as a new first-line standard of care for microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Previous results from KEYNOTE-177 showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with pembrolizumab versus chemotherapy ± bevacizumab/cetuximab in MSI-H/dMMR mCRC. Results after >5 years of follow-up are reported. Adults with untreated MSI-H/dMMR mCRC were randomly assigned 1 : 1 to receive pembrolizumab 200 mg intravenously every 3 weeks or chemotherapy. Patients assigned to chemotherapy could cross over to pembrolizumab after centrally confirmed progressive disease. Dual primary endpoints were PFS per RECIST v1.1 and overall survival (OS). Secondary endpoints included duration of response and safety. At data cut-off (17 July 2023), median follow-up was 73.3 months (range, 64.9-89.2 months). Overall, 307 patients were assigned to receive pembrolizumab (n = 153) or chemotherapy (n = 154). Fifty-seven (37.0%) patients assigned to chemotherapy crossed over to pembrolizumab per protocol; 39 (25.3%) received a programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitor off protocol (effective crossover rate, 62%). Median OS was 77.5 months with pembrolizumab versus 36.7 months with chemotherapy (hazard ratio, 0.73; 95% confidence interval 0.53-0.99); 5-year OS rates were 54.8% versus 44.2%. Median PFS was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio, 0.60; 95% confidence interval 0.45-0.79). Median duration of response was 75.4 months (range, 2.3+ to 80.1+ months) with pembrolizumab versus 10.6 months (range, 2.8 to 71.5+ months) with chemotherapy. Compared with chemotherapy, fewer patients in the pembrolizumab arm experienced adverse events (80% versus 99%; grade 3-5, 22% versus 67%). With >5 years of follow-up, responses to pembrolizumab r
Most patients diagnosed with head and neck squamous cell carcinoma (HNSCC) will present with locally advanced disease, requiring multimodality therapy. While this approach has a curative intent, a significant subset of these patients will develop locoregional failure and/or distant metastases. The prognosis of these patients is poor, and therapeutic options other than palliative chemotherapy are urgently needed. Epidermal growth factor receptor (EGFR) overexpression is an important factor in the pathogenesis of HNSCC, and a decade ago, the EGFR targeting monoclonal antibody cetuximab was approved for the treatment of late-stage HNSCC in different settings. In 2016, the anti-programmed death-1 (PD-1) immune checkpoint inhibitors nivolumab and pembrolizumab were both approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy, and in 2019, pembrolizumab was approved for first-line treatment (either as monotherapy in PD-L1 expressing tumors, or in combination with chemotherapy). Currently, trials are ongoing to include immune checkpoint inhibition in the (neo)adjuvant treatment of HNSCC as well as in novel combinations with other drugs in the recurrent/metastatic setting to improve response rates and survival and help overcome resistance mechanisms to immune checkpoint blockade. This article provides a comprehensive review of the management of head and neck cancers in the current era of immunotherapy.