Cetuximab Plus Chemotherapy Worsens Survival in Resectable Colorectal Liver Metastases

Despite demonstrating improvement in overall survival (OS) as treatment of patients with advanced inoperable metastatic colorectal cancer (mCRC), cetuximab (Erbitux) plus chemotherapy led to significantly worse OS for patients with operable colorectal liver metastases in the perioperative setting, according to findings from a randomized phase III clinical trial.

“Overall, we have shown that survival in patients with operable colorectal liver metastases is significantly worse with the use of cetuximab in combination with chemotherapy in the perioperative setting than with chemotherapy alone,” wrote John A. Bridgewater et al. They also advised that cetuximab should not be used in the neoadjuvant setting for patients with operable colorectal liver metastases.

Patients were randomized 1:1 to receive chemotherapy with or without cetuximab before and after liver resection. Chemotherapy included an intravenous oxaliplatin regimen with 5-fluororacil and folinic acid, capecitabine with oxaliplatin, or irinotecan with 5-FU and folinic acid. Cetuximab was given intravenously at 500 mg/m²every 2 weeks with regimen 1 and 3 or a loading dose of 400 mg/m²followed by a weekly infusion of 250 mg/m²with regimen 2.

Overall, 257 patients were eligible and randomly assigned to chemotherapy plus cetuximab (n = 129) or chemotherapy alone (n = 128). The primary end point of the study was progression-free survival (PFS), which was published previously. Secondary end points included OS, preoperative response, pathological resection status, and safety. However, all analyses, with the exception of safety, were done on the intent-to-treat population following a recruitment halt advised by the Trial Steering Committee on November 1, 2012.

The median PFS was 22.2 months (95% CI, 18.3-26.8) in the chemotherapy alone arm compared with 15.5 months (95% CI, 13.8-19.0) in the combination arm (HR, 1.17; 95% CI, 0.87-1.56;P=.304). The median OS was 81.0 months with chemotherapy alone (95% CI, 59.6-not reached) compared with 55.4 months (95% CI, 43.5-71.5) in the combination arm (HR, 1.45; 95% CI, 1.02-2.05; P=.036).

Most deaths out of 130 were related to disease, which included 54 of 58 (93%) in the chemotherapy arm versus 67 of 72 (93%) in the combination arm. The remaining 9 deaths (7%) were due to other causes. The combination of cetuximab plus chemotherapy resulted in an unadjusted HR for OS of 1.45 (95% CI, 1.02-2.05;P=.036).

Complete or partial responses were observed in 61% of patients in the chemotherapy arm versus 72% in the combination arm. However, there was no significant difference in the proportion of patients who achieved a response.

Overall, 86% of the patients underwent an operation, including 96% of those in the chemotherapy arm and 93% of patients in the combination arm. Most patients (82%) underwent an R0 resection in the chemotherapy arm compared with 79% in the combination arm.

Median post-progression survival was 33.5 months in the chemotherapy arm (95% CI, 25.3-41.2) versus 23.5 months (95% CI, 16.0-31.3) in the combination arm (HR, 1.55; 95% CI, 1.07-2.24;P-.020).

In the chemotherapy arm, 45% in the preoperative period and 43% in the postoperative period required at least 1 dose modification compared with 47% and 44% in the combination arm, respectively. The proportion of patients requiring at least 1 dose delay was similar among the 2 groups as well, including 51% in the preoperative period and 34% in the postoperative period in the chemotherapy arm compared with 49% and 36% in the combination arm, respectively. Overall, there were 14 premature withdrawals from treatment due to adverse events (AEs), 4% in the chemotherapy arm and 6% in the combination arm.

In the chemotherapy alone arm, 47% of patients in the preoperative setting and 22% in the postoperative setting had at least 1 grade 3 or greater toxicity compared with 53% and 30% in the combination arm, respectively. The most common grade 3/4 AEs included decreased neutrophil count in 19% of the chemotherapy arm and 15% in the combination arm, diarrhea in 10% and 10%, skin rash in 1% and 16%, thromboembolic events in 7% and 8%, lethargy in 7% and 7%, oral mucositis in 2% and 10%, vomiting in 5% and 5%, peripheral neuropathy in 6% and 4%, and pain in 4% and 4%, respectively.

The most common serious AEs included diarrhea (7% in the chemotherapy and 5% in combination arm), thromboembolic events (7% and 5%), vomiting (5% and 4%), fever (4% and 2%), sepsis (1% and 4%), and device-related infection (1% and 4%), respectively. Twenty-six drug-related serious AEs were observed in the chemotherapy arm versus 32 in the combination arm. Doses of chemotherapy were reduced in 20% of patients due to gastrointestinal and hematologic toxicities. In addition, 2-week delays of cetuximab were made a result of toxicity in some patients.

Five deaths were potentially related to treatment, of which 3 were related to systemic treatment, including 1 in the chemotherapy arm due to heart failure and 2 in the combination arm due to pulmonary embolism and interstitial lung disease and pulmonary embolism.

One patient died within 30 days of surgery due to bronchopneumonia in the combination arm, while 1 patient died of cardiac arrest within 90 days of surgery in the same arm. Investigators noted that the latter death may have been related to surgery. Surgical complications were observed in 25% of patients in the chemotherapy arm versus 25% in the combination arm.

In the multicenter, open-label trial, patients with a WHO status of 2 or lower and either resectable or suboptimally resectable colorectal liver metastasis without detectable extrahepatic distant mCRC were included to the study. There was no limit on the number of metastases a patient could have. There was a protocol that mandated the primary cancer should be resected prior to trial entry.

If patients had any uncontrolled medical comorbidity that could interfere with treatment or assessment of response, they were ineligible to participate in the study. Patients were also excluded if they had any psychiatric or neurological disorder affecting the ability to consent or comply with medication, partial or complete bowel obstruction, or pre-existing peripheral neuropathy of grade 1 or rose in severity, among other exclusion criteria.

“This finding is robust, with no apparent confounding variables, and suggests that biological intervention in molecularly complex cancers might have unintended consequences,” study authors wrote. “Cetuximab should not be used as neoadjuvant therapy in patients with operable colorectal liver metastases.”

Reference:

Bridgewayer JA, Pugh SA, Maishman T, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (new EPOC): long-term results of a multicenter, randomized, controlled, phase 3 trial [Published Online January 31, 2020].Lancet. DOI:https://doi.org/10.1016/S1470-2045(19)30798-3.