Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings
Open accessAbstract
Background ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Patients and methods Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.Results Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).Conclusions Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.
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An effective therapeutic strategy for KRAS-mutant colorectal cancer, the most common genetically defined subtype, is still lacking.
“an effective therapeutic strategy for KRASMT colorectal cancer, the most common genetically defined subtype (∼40%–45%) is still lacking.”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in <i>KRASG12C</i> -mutant Colorectal Cancer (2023) · cites this paper as [6]
The Introduction (page unavailable) says KRAS mutations occur in about 40% of patients with metastatic colorectal cancer, consistent with the prevalence in the claim. But the Results (patient population; page unavailable) report significantly prolonged progression-free survival with bevacizumab plus chemotherapy in patients with KRAS-mutant tumors, contrary to the assertion that an effective therapeutic strategy is lacking. Overall survival was not significantly improved in that subgroup. (LLM, conf=0.84)
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Experimental — accuracy not yet measuredIn ECOG 3200, adding bevacizumab to FOLFOX4 chemotherapy significantly prolonged mOS and mPFS compared to control.
“In the ECOG 3200 study, the addition of bevacizumab to chemotherapy, specifically FOLFOX 4 and chemotherapy alone, demonstrated significantly prolonged mOS and mPFS compared to the control groups [31,32].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [31]
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- Authors
- Kubicka, S., Greil, R., André, T., Bennouna, J., Sastre, J., Van Cutsem, E., von Moos, R., Österlund, P., Reyes-Rivera, I., Müller, T., Makrutzki, M., Arnold, D., Andel, J., Balcke, P., Benedicic, B., Eisterer, W., Fridrik, M., Jagdt, B., Keil, F., Kretschmer, A., Krippl, P., Oexle, H., Pecherstorfer, M., Samonigg, H., Schmid, M., Thaler, J., Tinchon, C., Weiss, H., Arts, J., De Man, M., Demolin, G., Janssens, J., Polus, M., Benczikova, B., Melichar, B., Prausova, J., Vitek, P., Andersen, F. Z., Jensen, B. B., Keldsen, N., Østerlind, K., Vistisen, K., Elme, A., Magi, A., Ojamaa, K., Ristamäki, R., Salminen, T., Ben Abdelghani, M., Bouche, O., Borg, C., Bouhier-Leporrier, K., Breysacher, G., Chone, L., Clavero Fabri, M.-C., Deplanque, G., Desseigne, F., Dourthe, L.-M., Ezenfis, J., Faroux, R., François, E., Garnier, C., Gaspard, M.-H., Hebbar, M., Illory, J. F., Kaminsky, M.-C., Lecomte, T., Legoux, J.-L., Levache, B., Lobry, C., Lotz, J.-P., Mabro, M., Manet-Lacombe, S., Manfredi, S., Matysiak Budnik, T., Miglianico, L., Mineur, L., Moullet, I., Naman, H., Nouyrigat, P., Oziel-Taieb, S., Perrier, H., Pezet, D., Philip, J., Pottier, V., Porneuf, M., Ramdani, M., Re, D., Rinaldi, Y., Spaeth, D., Taieb, J., Terrebonne, E., Texereau, P., Thirot Bidault, A., Tournigand, C., Tubiana-Mathieu, N., Vantelon, J.-M., Viret, F., Ychou, M., Bangerter, M., Bertram, M. E., Bohnsteen, B., Brinkmann, L., Caca, K., Constantin, C., Cordes, H.-J., Dietrich, G., Eggert, J., Engel, E., Fahlke, J., Fensterer, H., Florschütz, A., Folprecht, G., Forstbauer, H., Freier, W., Freund, M., Frickhofen, N., Gäbele, E., Geißler, M., Gieseler, F., Göhler, T., Graeven, U., Groschek, M., Grundeis, M., Hacker, U., Hagen, V., Hebart, H. F., Hegewisch-Becker, S., Heike, M., Herrmann, T., Hildebrandt, B., Höffkes, H.-G., Hübner, G., Hübner, J., Kettner, E., Kneba, M., Kohnke, J. W., Kojouharoff, G., König, C., Kretzschmar, A., Kröning, H., Kürner, K., Lammert, F., Lerchenmüller, C., Lück, A., Meiler, J., Mergenthaler, H.-G., Müller, L., Müller-Naendrup, C., Nusch, A., Papke, J., Porschen, R., Rädle, J., Reddemann, C., Ridwelski, K., Riera-Knorrenschild, J., Rudi, J., Schmalenberger, A., Schimanski, C.-C., Schlegel, F., Schlichting, C., Schmidt, P., Schmiegel, W., Schmitz, S., Schulze-Bergkamen, H., Schwaner, I., Schwarzer, A., Schwerdtfeger, M., Selbach, J., Sieber, M., Siebler, J., Staib, P., Stauch, M., Steffens, C.-C., Stübs, P., Tischendorf, J., Trarbach, T., Tummes, D., Valdix, A.-R., Vogel, A., Von Wichert, G. P. L., Walther, M., Welslau, W., Wilhelm, G., Wobster, H., Wolf, T., Zeigenhagen, N., Zomorodbaksch, B., Batman, E., Bloemendal, H. J., Kehrer, D. F. S., Guren, T., Indrebø, G., Kersten, C., Soerbye, H., Fragoso, M., Fragoso, R., Mellidez, J. C., Sa, A., Aljobran, A., Darwish, T., Alonso-Orduna, V., Aparicio, J., Aranda, E., Bosch, C., Galan-Brotons, A., Busquier Hernandez, I., Camara, J. C., Campos Cervera, J. M., Carlos Garcia Giron, C., Del Prado, P. M., Donnay, O., Escudero, P., Falco, E., Gallego Plazas, J., Garcia Alfonso, P., Gonzalez Flores, E., Gravalos, C., Guardeno, R., Juárez, A., Lopez Ladron, A., Losa Gaspa, F., MªVicent Vergé, J., Marcuello Gaspar, E., Massuti Sureda, B., Molina, J., Montero, I. C., Muñoa, A. L., Naranjo, M. B., Oruezabal Moreno, M. J., Pachón Olmos, V., Pericay, C., Reina Zoilo, J. J., Rivera, F., Ruiz Casado, A., Safont, M. J., Salud Salvia, A., Tobena, M., Toral, J. C., Valenti, V., Valladares Ayerbes, M., Vieitez, J. M., Vera, R., Vieitez, J. M., Berglund, A., Fernebro, E., Hess-Umbricht, V., Pless, M., Popescu, R., & Winterhalder, R.
- Affiliations
- Hôpital Saint-Antoine (FR)
- Institut de Cancérologie de l'Ouest (FR)
- Hospital Clínico San Carlos (ES)
- Genentech (US)
- F. Hoffmann-La Roche AG (CH)
- University of Freiburg (DE)
- KU Leuven (BE)
- Corresponding author
- Kubicka, S.
- ORCID
- Greil, R.
- André, T.
- Bennouna, J.
- Sastre, J.
- Müller, T.
- Arnold, D.
- Eisterer, W.
- Fridrik, M.
- Keil, F.
- Kretschmer, A.
- Pecherstorfer, M.
- Schmid, M.
- Thaler, J.
- Polus, M.
- Melichar, B.
- Elme, A.
- Ojamaa, K.
- Salminen, T.
- Borg, C.
- Faroux, R.
- Hebbar, M.
- Kaminsky, M.-C.
- Lecomte, T.
- Lotz, J.-P.
- Mineur, L.
- Pezet, D.
- Philip, J.
- Tournigand, C.
- Tubiana-Mathieu, N.
- Ychou, M.
- Florschütz, A.
- Folprecht, G.
- Freier, W.
- Geißler, M.
- Gieseler, F.
- Hacker, U.
- Hebart, H.F.
- Herrmann, T.
- König, C.
- Kretzschmar, A.
- Lammert, F.
- Meiler, J.
- Schmiegel, W.
- Schwaner, I.
- Trarbach, T.
- Vogel, A.
- Walther, M.
- Bloemendal, H.J.
- Guren, T.
- Kersten, C.
- Aparicio, J.
- Aranda, E.
- Donnay, O.
- Falco, E.
- Pericay, C.
- Rivera, F.
- Vera, R.
- Popescu, R.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 24
- Issue
- 9
- Pages
- 2342-2349
- ISSN
- 0923-7534 (ISSN-L)
- OpenAlex
- W2081238655
- Cited by
- 104
- References
- 20
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 11 · 2015: 15 · 2014: 2 · 2013: 5 · 2012: 1
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- F. Hoffmann-La Roche
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- bevacizumab, metastatic colorectal cancer, KRAS mutation status, second-line chemotherapy, progression-free survival, overall survival, anti-VEGF therapy
- MeSH terms
- Bevacizumab, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Prospective Studies, Proto-Oncogene Proteins, Survival, Biomarkers, Tumor, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Disease-Free Survival, ras Proteins, Vascular Endothelial Growth Factor A, Young Adult, Antibodies, Monoclonal, Humanized
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