Prospective II phase study on the evaluation of the efficacy of monotherapy with cetuximab as the first-line treatment for patients with metastatic colorectal cancer with wild-type KRas, NRas, and BRAF genes
V.M. Moiseenko (1), F.V. Moiseenko (1, 2, 3), N.M. Volkov (1), G.A. Yanus (2), E.Sh. Kuligina (2), A.P. Sokolenko (2), S.N. Aleksakhina (2), V.A. Chubenko (1), K.S. Kozyreva (2), N.Kh. Abduloeva (1), M.M. Kramchaninov (1), A.S. Zhuravlev (1), V.A. Khinshtein (1), K.V. Shelekhova (1), A.A. Kudryavtsev (1), A.V. Myslik (1), A.O. Ivantsov (2), A.R. Venina (2), E.V. Preobrazhenskaya (2, 4), N.V. Mityushkina (2), A.G. Ievleva (2, 4), E.N. Imyanitov (2, 4)
1 St. Petersburg Clinical Scientific and Practical Center of Specialized Types of Medical Care (Oncological), St. Petersburg, Russia;
2 N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russia;
3 North-Western State Medical University n.a. I.I. Mechnikov, Saint-Petersburg, Russia;
4 St. Petersburg State Pediatric Medical University, St. Petersburg, Russia
Background. The use of a consistent approach to cytostatic therapy in the form of monotherapy as a first-line treatment for 20–25% of patients with metastatic colorectal cancer (mCRC) makes it possible to achieve a similar survival rate, as with polychemotherapy. The list of standard regimens of drug therapy for mCRC for various treatment lines includes monotherapy with fluoropyrimidines and cetuximab. The efficacy of cetuximab and panitumumab is indicated in patients with tumors that do not have KRas, NRas, and BRAF gene mutations. Currently, there is no evidence of the effectiveness of monotherapy with cetuximab as the first-line of therapy for patients selected by molecular factors. Methods. A prospective II phase study of monotherapy with cetuximab in patients with unresectable mCRC without KRas, NRas and BRAF gene mutations and without symptomatic manifestations of the tumor was conducted. After molecular analysis, the study included patients who had not previously received drug therapy for a advanced tumor and without mutation changes in any of the listed tumor genes. Patients received monotherapy with cetuximab in standard mode: loading dose of 400 mg/m2, then – 250 mg/m2
once a week intravenously until progression or intolerable toxicity. The primary endpoint of the study was a 6-month progression-free survival (PFS). For the independent validation of the results, retrospective data on the efficacy of standard monochemotherapy with fluoropyrimidines in a similar population of patients with wild type KRas, NRas and BRAF genes in tumor tissue were used.
Results. Samples of tumor tissue of 73 patients were analyzed for mutations in the KRas, NRas and BRAF genes. In 33 of 73 tumors, no mutations were found in all 3 genes. Cetuximab therapy was initiated in 21 of 33 patients. Data for assessing the effect of treatment and survival were obtained for 19 patients. The median duration of cetuximab therapy was 3.9 months (95% CI, 2.18–5.69). Six months after the start of therapy, 11 (57.9%) of 19 patients had no progression of the disease. Median PFS was 6.4 months (95% CI, 4.31–8.39).
In 2 of 19 patients partial regress of tumor foci was noted, complete responses to therapy were not noted. Control of the disease (partial regression or stabilization) was achieved in 68% of patients. The median overall survival was 14.9 months (95% CI, 13.1–16.7). Subgroup analysis showed no significant correlations of PFS or disease control with any of the clinical characteristics of patients. Compared with retrospective data on the efficacy of monotherapy with fluoropyrimidines as the first-line therapy in 19 patients with wild type KRas, NRas and BRAF genes in tumor tissue, PFS and overall survival of patients treated with cetuximab did not significantly differ in this study. Conclusion. This study showed the efficacy of monotherapy with cetuximab as the 1st-line therapy in patients with unresectable mCRR selected according to known molecular factors and not requiring urgent aggressive chemotherapy. Further research on the factors for the selection of patients with colorectal cancer to increase the effectiveness of therapy with epidermal growth factor receptor antibodies in patients of the selected subgroup is needed.
About the Autors
Corresponding author: V.M. Moiseeenko – MD, Prof., Director of the St. Petersburg Clinical Scientific and Practical Center of Specialized Types of Medical Care (Oncological), St. Petersburg, Russia; Tel. 8 (812) 573-91-91, e-mail: email@example.com