Addition of cetuximab to chemotherapy shortens OS in advanced colorectal cancer subset
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Cetuximab plus chemotherapy resulted in shorter PFS and OS compared with chemotherapy alone among patients with resectable KRAS exon 2 wild-type colorectal liver metastases, according to results of the randomized phase 3 New EPOC study published in Lancet Oncology.
The detrimental effects of adding cetuximab (Erbitux, Eli Lilly) — an epidermal growth factor receptor antibody — to perioperative systemic chemotherapy appeared most prominent among patients with more favorable clinical tumor characteristics, researchers noted.
“Although the addition of cetuximab to chemotherapy improves [OS] in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of OS. Cetuximab should not be used in this setting,” John A. Bridgewater, MRCP, PhD, clinical researcher at UCL Cancer Institute at University College London in the U.K., and colleagues wrote.
As Healio previously reported, an interim analysis of the EPOC trial showed an unexpected decline in PFS with the addition of cetuximab to perioperative systemic chemotherapy for this patient population.
The current analysis, with long-term follow-up and a more complete data set, evaluated the effect of the combination on OS among 257 adults with KRAS wild-type resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0 to 2. Researchers assigned 128 patients (median age, 65 years; interquartile range [IQR], 59-70; 63% men) to chemotherapy with oxaliplatin, folonic acid and fluorouracil, or oxaliplatin and capecitabine. Patients who had received adjuvant oxaliplatin were eligible to receive IV irinotecan with fluorouracil instead of oxaliplatin.
The other 129 patients (median age, 64 years; IQR, 59-69; 71% men) received chemotherapy plus cetuximab for 12 weeks before and 12 weeks after liver resection. Researchers administered cetuximab in one of two doses — either an IV dose of 500 mg/m² every 2 weeks, or a loading dose of 400 mg/m² followed by weekly infusion of 250 mg/m².
PFS served as the primary endpoint. OS, preoperative response, pathological resection status and safety served as secondary endpoints.
The Trial Steering Committee halted the trial prematurely on Nov. 1, 2012. Analyses, other than safety, were conducted in the intention-to-treat population. Safety analyses included all patients.
During median follow-up of 66.7 months (IQR, 58-77.5), 180 events occurred.
Patients assigned cetuximab demonstrated significantly shorter median PFS than those assigned chemotherapy alone (15.5 months vs. 22.2 months; HR = 1.17; 95% CI, 0.87-1.56). Moreover, median OS was significantly shorter among those assigned cetuximab (55.4 months vs. 81 months; HR = 1.45; 95% CI, 1.02-2.05).
Researchers observed no significant differences in preoperative response, pathological resection status or in the distribution of extended RAS/RAF mutations between the treatment groups.
Of the 130 patient deaths that occurred during follow-up, 54 deaths in chemotherapy alone group were disease related vs. 67 disease-related deaths in the cetuximab group.
Those in the chemotherapy-only group had a higher rate of grade 3 or grade 4 low neutrophil count (19% vs. 15%), whereas those assigned cetuximab experienced higher rates of skin rash (16% vs. 1%), thromboembolic events (8% vs. 7%) and oral mucositis (10% vs. 2%).
“This mature analysis shows that in the perioperative setting, cetuximab shortens OS by 2 years compared with chemotherapy alone,” Bridgewater and colleagues wrote. “This detriment was most notable in patients who had features suggestive of a better prognosis and, crucially, post-progression survival was significantly worse. Toxicity from systemic therapy and complications of surgery could not explain these findings.”
Limitations of the study, including imbalances in the number of patients who did not undergo surgery and the use of ablation rather than resection, probably do not affect the final outcomes of the study, according to a related editorial by Sepideh Gholami, MD, assistant professor of surgery in the department of surgery at UC Davis Health, and Axel Grothey, MD, consultant in the division of medical oncology in the department of oncology at Mayo Clinic in Rochester, Minnesota.
“At this point in time, EGFR antibodies should not be used as a component of neoadjuvant or perioperative therapy in resectable stage IV colorectal cancer,” the editorial authors wrote. “Although we believe that EGFR antibodies added to chemotherapy still play a role in the preoperative conversion setting, when high anatomical responses are desired, we caution against their use as postoperative therapy after resection of metastatic disease. As the field of molecular targeting treatment and understanding of resistance mechanisms continue to evolve, novel combination treatment strategies should be explored.”
Perspective
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Mohamed E. Salem, MD
Studies have shown no added benefit of anti-EGFR therapies in the adjuvant setting for patients with colon cancer. However, EGFR-directed therapy improves outcomes when added to systemic chemotherapy in the metastatic setting.
Bridgewater and colleagues presented the mature analysis of the New EPOC trial. It is difficult to explain the exact reason for these new results. Over the past few years, several studies have shed light on the prognostic value of primary tumor location. Patients with left-sided primary tumors were consistently shown to have a better prognosis and improved treatment outcomes with the use of EGFR inhibitors in addition to combination chemotherapy, especially in the first-line setting. Conversely, patients with RAS wild-type right-sided primary tumors derived no benefit from anti-EGFR therapy when added to combination chemotherapy.
However, in the forest plot for OS of patients in the New EPOC study, individuals with either right- or left-sided tumors did not appear to benefit from adding cetuximab to standard chemotherapy — although only a few patients in both groups had right-sided tumors.
Beyond the well-established, predictive RAS and BRAF mutations, several other factors that determine resistance to anti-EGFR therapy have been discovered since the launch of the New EPOC trial. However, it is unlikely that the final outcomes of the study were affected by these factors.
The overall data were driven by more multisite progressions and shorter survival after recurrence in the chemotherapy-plus-cetuximab group, potentially due to the development of a more aggressive disease phenotype or imbalances in post-recurrence treatment approaches (only 10% of patients in the cetuximab group received cetuximab after recurrence compared with 30% of patients in the chemotherapy-alone group).
In summary, the New EPOC results show that anti-EGFR treatment should not be used for patients with resectable colorectal liver-limited metastases as a neoadjuvant or perioperative strategy, but anti-EGFRs may still have a role in the preoperative conversion setting when a deep objective response is needed.
The New EPOC trial is similar to several other studies conducted in metastatic colorectal cancer in that it raised more questions than answers, demonstrating that perhaps we still know very little about metastatic colorectal cancer and its biology; hence, we definitely need to continue research into this complex disease.
References:
Alberts SR, et al. JAMA. 2012;doi:10.1001/jama.2012.385.
Gholami S and Grothey A. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30003-6.
Nordlinger B, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.3989.
Taieb J, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70227-X.
Tejpar S, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2016.3797.
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Bridgewater JA, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(19)30798-3.
Gholami S and Grothey A. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30003-6.
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