FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial
http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(16)30269-8.pdf
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for
metastatic colorectal cancer (FIRE-3): a post-hoc analysis of
tumour dynamics in the final RAS wild-type subgroup of this
randomised open-label phase 3 trial
Sebastian Stintzing, Dominik P Modest, Lisa Rossius, Markus M Lerch, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani,
Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian Lerchenmüller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Swantje Held, Clemens Giessen-Jung, Markus Moehler, Andreas Jagenburg, Thomas Kirchner, Andreas Jung, Volker Heinemann, on behalf of the FIRE-3 investigators
Summary
Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival.
Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher’s exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927.
Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5–39·4] vs 25·0 months [23·0–28·1]; hazard ratio 0·70 [0·54–0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3–78·8] vs 97 of 173, 56·1% [48·3–63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3–75·4] vs 85 of 173, 49·1% [41·5–56·8]; p=0·0005), and median depth of response (–48·9% [–54·3 to –42·0] vs –32·3% [–38·2 to –29·2]; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups.
Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.
Sebastian Stintzing, Dominik P Modest, Lisa Rossius, Markus M Lerch, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani,
Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian Lerchenmüller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Swantje Held, Clemens Giessen-Jung, Markus Moehler, Andreas Jagenburg, Thomas Kirchner, Andreas Jung, Volker Heinemann, on behalf of the FIRE-3 investigators
Summary
Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival.
Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher’s exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927.
Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5–39·4] vs 25·0 months [23·0–28·1]; hazard ratio 0·70 [0·54–0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3–78·8] vs 97 of 173, 56·1% [48·3–63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3–75·4] vs 85 of 173, 49·1% [41·5–56·8]; p=0·0005), and median depth of response (–48·9% [–54·3 to –42·0] vs –32·3% [–38·2 to –29·2]; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups.
Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.
Lancet Oncol 2016
Published Online
August 26, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30269-8
This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on September 1, 2016.
Department of Hematology and Oncology (S Stintzing MD, D P Modest MD, L Rossius,
C Giessen-Jung MD,
Prof V Heinemann MD), and Institute of Pathology
(Prof T Kirchner MD,
Prof A Jung MSc), University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
(S Stintzing, D P Modest,
Prof T Kirchner, Prof A Jung, Prof V Heinemann); Klinik und PoliklinikfürInnereMedizinA, Universitätsmedizin Greifswald, Greifswald, Germany (Prof M M Lerch MD); MVZ Gesundheitszentrum
St. Marien GmbH, Amberg, Germany
(L F von Weikersthal MD); Studienzentrum Onkologie Ravensburg,Ravensburg, Germany (T Decker MD); Klinikum Bayreuth GmbH, Bayreuth, Germany
(A Kiani MD); Praxis Hämatologie/Onkologie/ Palliativmedizin—Tagesklinik, Landshut, Germany
(U Vehling-Kaiser MD); Krankenhaus Nordwest, Medizinische
Klinik II/Onkologie, Frankfurt, Germany
(Prof S-E Al-Batran MD); Lukaskrankenhaus Neuss, Neuss, Germany
(T Heintges MD);
Published Online
August 26, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30269-8
This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on September 1, 2016.
Department of Hematology and Oncology (S Stintzing MD, D P Modest MD, L Rossius,
C Giessen-Jung MD,
Prof V Heinemann MD), and Institute of Pathology
(Prof T Kirchner MD,
Prof A Jung MSc), University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
(S Stintzing, D P Modest,
Prof T Kirchner, Prof A Jung, Prof V Heinemann); Klinik und PoliklinikfürInnereMedizinA, Universitätsmedizin Greifswald, Greifswald, Germany (Prof M M Lerch MD); MVZ Gesundheitszentrum
St. Marien GmbH, Amberg, Germany
(L F von Weikersthal MD); Studienzentrum Onkologie Ravensburg,Ravensburg, Germany (T Decker MD); Klinikum Bayreuth GmbH, Bayreuth, Germany
(A Kiani MD); Praxis Hämatologie/Onkologie/ Palliativmedizin—Tagesklinik, Landshut, Germany
(U Vehling-Kaiser MD); Krankenhaus Nordwest, Medizinische
Klinik II/Onkologie, Frankfurt, Germany
(Prof S-E Al-Batran MD); Lukaskrankenhaus Neuss, Neuss, Germany
(T Heintges MD);
Funding Merck KGaA and Pfizer.
Introduction
The randomised, phase 3, FIRE-3 (AIO KRK-0306) trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO) was, to our knowledge, the first head-to-head comparison of cetuximab (an anti-EGFR agent) versus bevacizumab (an anti-VEGF agent) in combination with standard infusional 5-fluorouracil, leucovorin, and irinotecan
Introduction
The randomised, phase 3, FIRE-3 (AIO KRK-0306) trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO) was, to our knowledge, the first head-to-head comparison of cetuximab (an anti-EGFR agent) versus bevacizumab (an anti-VEGF agent) in combination with standard infusional 5-fluorouracil, leucovorin, and irinotecan
(FOLFIRI) chemotherapy for first-line treatment of
patients with KRAS exon 2 wild-type metastatic colorectal
cancer.1 In the KRAS exon 2 wild-type intention-to-treat
population, overall survival was significantly longer in
FOLFIRI plus cetuximab-treated patients compared with
patients treated with FOLFIRI plus bevacizumab, although
the investigator-assessed objective response according to
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