Tobias Heintges

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial

BACKGROUND Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. METHODS In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. FINDINGS Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2-67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1-63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85-1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). INTERPRETATION Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. FUNDING Merck KGaA.

Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3).

LBA3506 Background: In patients (pts) with KRAS, wild-type metastatic colorectal cancer (mCRC) a head to head comparison of anti-EGFR- and anti-VEGF-directed first-line therapy has not been reported with regard to the FOLFIRI backbone. The AIO KRK-0306 study was therefore designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC pts not pretreated for metastatic disease. METHODS Pts were randomized to FOLFIRI (Tournigand regimen) every two wks plus cetuximab (400 mg/m² day 1, followed by 250 mg/m² wkly = arm A) or bevacizumab (5 mg/kg every two wks = arm B). The intent-to-treat (ITT) population comprised all pts who had at least completed one application of therapy. While recruitment initially was independent of KRAS status, an amendment confined inclusion to KRAS wildtype (WT) tumors. Recruitment was completed in October 2012. The primary study endpoint was objective response rate (ORR, investigators read). RESULTS Among 735 pts of the ITT-population, KRAS-WT was identified in 592. Of these, 297 pts were randomized to arm A and 295 to arm B. Median age was 64 years, 66% of pts were male, and ECOG PS 0-1 was observed in 98% of pts. Median duration of treatment was 4.7 mo vs 5.3 mo, respectively. While in the ITT analysis, ORR was comparable in arms A vs B (62% vs 57%, odds ratio 1.249), a significant superiority was found for assessable pts in arm A. Median PFS of the ITT population was nearly identical (10.3 vs 10.4 mo, HR 1.04, p=0.69), however, overall survival (OS) showed a significantly better outcome in arm A vs arm B (28.8 vs 25.0 mo, HR 0.77, p=0.0164, 95% CI: 0.620-0.953). Sixty-day mortality was low in both arms (1.01% vs 2.71%). CONCLUSIONS ORR was comparable between arms in the ITT analysis, but favored arm A in assessable pts. Significantly superior OS was observed in KRAS-WT patients receiving cetuximab plus FOLFIRI as first-line treatment. CLINICAL TRIAL INFORMATION NCT00433927.

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.

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 Fishers 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. FUNDING Merck KGaA and Pfizer.

Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer

PURPOSE We investigated choice and efficacy of subsequent treatment, with special focus on second-line therapy, in the FIRE-3 trial (FOLFIRI plus cetuximab [arm A] or bevacizumab [arm B]) for patients with KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS Start of subsequent-line (second or third) therapy was defined as use of an antitumor drug that was not part of the previous regimen. We evaluated choice, duration, and efficacy of subsequent therapy and determined the impact of subsequent-line treatment on outcome of patients in FIRE-3. RESULTS Of 592 patients in the intent-to-treat population, 414 (69.9%) received second-line and 256 (43.2%) received third-line therapy. In subsequent treatment lines, 47.1% of patients originally assigned to arm A received bevacizumab, and 52.2% originally assigned to arm B received either cetuximab or panitumumab. Oxaliplatin was subsequently used in 55.9% (arm A) and 53.2% (arm B) of patients. Second-line therapy was administered for a median duration of 5.0 versus 3.2 months (P < .001) in study arm A versus B. Progression-free (6.5 v 4.7 months; hazard ratio, 0.68; 95% CI, 0.54 to 0.85; P < .001) and overall survival (16.3 v 13.2 months; hazard ratio, 0.70; 95% CI, 0.55 to 0.88; P = .0021) from start of second-line therapy were longer in patients in arm A compared with arm B. CONCLUSION Our data suggest that the sequence of drug application might be more important than exposure to single agents. In patients with RAS wild-type tumors, first-line application of anti-epidermal growth factor receptor-directed therapy may represent a favorable condition for promoting effective subsequent therapy including antiangiogenic agents.

Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306)

Purpose To assess the impact of primary tumor sidedness on outcome of patients with metastatic colorectal cancer (mCRC) across treatment lines. Patients and Methods Patients of the FIRE-3 trial (initial FOLFIRI plus either cetuximab or bevacizumab) were separately evaluated according to primary tumor site differentiating left-sided (LPT) from right-sided primary tumors (RPT). Efficacy (i.e. progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) was evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression analyses. All analyses were also reported according to drug sequences. Results 411 of 592 patients (69%) with KRAS exon 2 wild-type tumors received 2nd-line therapy has and had available information on primary tumor location, of those 309 patients (75%) presented with LPT. In patients with LPT, PFS2nd was markedly longer than in patients with RPT (6.0 months [95% CI 5.5-6.5] versus 3.8 months [95% CI 2.5-5.2], hazard ratio: 0.61 [95% CI 0.47-0.78], P<0.001). Differences in PFS2nd between study-arms were evident in patients with LPT, but not in patients with RPT (Cox model interaction test, P=0.12). Consistent observations were also made for OS2nd. Conclusion This retrospective analysis of FIRE-3 indicates that efficacy of second-line therapy was significantly greater in patients with left-sided tumors as compared to right-sided tumors. This difference was driven by superior activity of second-line regimens of the initial cetuximab-arm as compared to the initial bevacizumab-arm in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in second-line therapy of mCRC.

Relation of early tumor shrinkage (ETS) observed in first-line treatment to efficacy parameters of subsequent treatment in FIRE-3 (AIOKRK0306)

We explored the association of early tumor shrinkage (ETS) and non‐ETS with efficacy of first‐line and consecutive second‐line treatment in patients with KRAS wild‐type metastatic colorectal cancer treated in FIRE‐3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to <20%), mPD (minor progression >0 to <20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0–38.4) months in ETS patients, while non‐ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2–26.9) months, mPD 19.0 (95% CI 13.0–25.0) months, PD 12.8 (95% CI 11.1–14.5) months). Differences in PFS of first‐line therapy were less pronounced. ETS subgroups defined in first‐line therapy also correlated with efficacy of second‐line therapy. Progression‐free survival in second‐line (PFS2nd) was 6.5 months (5.8–7.2) for ETS, and was 5.6 (95% CI 4.7–6.5) months for mETS, 4.9 (95% CI 3.7–6.1) months for mPD and 3.3 (95% CI 2.3–4.3) months for PD. PFS of first‐line and PFS2nd showed a linear correlation (Bravais–Pearson coefficient: 0.16, p = 0.006). While ETS is associated with the most favorable outcome, non‐ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment. This is the first analysis to demonstrate that early tumor response observed during first‐line FOLFIRI‐based therapy may also relate to efficacy of second‐line treatment. Early response parameters may serve as stratification factors in trials recruiting pretreated patients.

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial)

BACKGROUND To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.

Relevance of liver-limited disease in metastatic colorectal cancer: Subgroup findings of the FIRE-3/AIO KRK0306 trial

In metastatic colorectal cancer (mCRC), liver‐limited disease (LLD) is associated with a higher chance of metastectomy leading to long‐term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first‐line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE‐3, a randomized phase III trial comparing first‐line chemotherapy with FOLFIRI plus either cetuximab (anti‐EGFR) or bevacizumab (anti‐VEGF) in RAS wild‐type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non‐LLD. Median overall survival (OS) was significantly longer in LLD compared to non‐LLD patients (36.0 vs. 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51–0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time‐dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50–0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS‐WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.

Anti-infective prophylaxis with aciclovir and cotrimoxazole significantly reduces the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy

gutachter Stefan Paul Aebi, Salah-Eddin Al-Batran, Walter Autlitzky, Claudia Baldus, Thomas Bauernhofer, Walter Baumann, Lothar Bergmann, Wolfgang Bethge, Jörg Beyer, Mascha Binder, FrankDietmar Böhmer, Carsten Bokemeyer, Markus Maximilian Borner, Martin Bornhäuser, Jan Braess, Thomas Brodowicz, Peter Brossart, Tim Henrik Brümmendorf, Lars Bullinger, Christian Buske, Nathan Cantoni, Richard Cathomas, Joachim Clement, Claudio Denzlinger, Stefan Diem, Christian Dittrich, Konstanze Döhner, Martin Dreyling, Ulrich Dührsen, Justus Duyster, Alexander Egle, Barbara Eichhorst, Ekkehard Eigendorff, Wolfgang Eisterer, Monika Engelhardt, Jürgen Finke, Thomas Fischer, Gunnar Folprecht, Norbert Frickhofen, Michael Fridrik, Michael Fuchs, Alois Günther Gastl, Klaus Geissler, Dietmar Geissler, Armin Gerger, Nicola Gökbuget, Hartmut Goldschmidt, Katharina Götze, Ullrich Graeven, Martin Gramatzki, Jochen Greiner, Martin Griesshammer, Viktor Grünwald, Dominik Heim, Susanna Hegewisch-Becker, Wolfgang Herr, Pia Heußner, Inken Hilgendorf, Felicitas Hitz, Andreas Hochhaus, Britta Höchsmann, Silvia Hofer, Ralf-Dieter Hofheinz, WolfKarsten Hofmann, Friedemann Honecker, Jutta Hübner, Gerald Illerhaus, Dirk Jäger, Ulrich Jäger, Martin Janz, Karin Jordan, Constanze Junghans, Christian Junghanß, Lothar Kanz, Felix Keil, Ulrich Keilholz, Michael Kiehl, Michael Kneba, Maren Knödler, Michael Köhler, Gerald Kolb, Hans-Georg Kopp, Michael Krainer, Stefan W. Krause, Frank Kroschinsky, Volker Kunzmann, Paul Graf La Rosée, Florian Langer, Claudia Lengerke, Eva Lengfelder, Georg Lenz, Anne Letsch, Lars H. Lindner, Hartmut Link, Anja Lorch, Florian Lordick, Michael Lübbert, Heinz Ludwig, Diana Lüftner, Andreas Mackensen, Christoph Mamot, Markus G. Manz, Norbert Marschner, Georg Maschmeyer, Axel Matzdorff, Georgia Metzgeroth, Robert Möhle, Ulrike Mößner, Lars-Olof Mügge, Andreas Müller, Lothar Müller, Martin Müller, Andrea Nätscher, Andreas Neubauer, Urban Novak, Karin Oechsle, Helmut Oettle, Friedrich Overkamp, Jakob Passweg, Christian Peschel, Andrea Petermann-Meyer, Andreas Petzer, Michael Pfeilstöcker, Robert Pirker, Uwe Platzbecker, Lisa Pleyer, Tobias Pukrop, Mirko Radloff, Peter Reichardt, Andreas Reiter, Christoph Renner, Hanno Riess, Alexander Röth, Thomas Ruhstaller, Niklaus Schäfer, Markus Schaich, Markus Schaich, Werner Scheithauer, Peter Schellongowski, Jan Schildmann, Kristina Schilling, Marcus Schittenhelm, Harald Schmalenberg, Manuela Schmidinger, Silke Schmidt, Clemens Schmitt, Norbert Schmitz, Sebastian Scholl, Karin Schrenk, Martin Schuler, Ulrich Schuler, Holger Schulz, Ulf Seifart, Hubert Serve, Heinz Sill, Ernst Späth-Schwalbe, Michael Stahl, Reinhard Stauder, Frank Stenner-Liewen, Michael Steurer, Stephan Stilgenbauer, Georg Stüssi, Hans Tesch, Josef Thaler, Matthias Theobald, Alexandre Theocharides, Michael Thomas, Peter ThußPatience, Martin Trepel, Lorenz Trümper, Maria Vehreschild, Arndt Vogel, Wichard Vogel, Wichard Vogel, Gunhild von Amsberg, Marie von Lilienfeld-Toal, Roger von Moos, Cornelius Waller, Juliane Walz, Claudia Waskow, Herbert Watzke, Ulrich Wedding, Katja Weisel, Clemens-Martin Wendtner, Martin Wilhelm, Wolfgang Willenbacher, Andreas Willer, Jürgen Wolf, Albert Wölfler, Ewald Wöll, Bernhard Wörmann Angaben ohne Gewähr Disclosure Statement The editor declares no conflict of interest. CONTENTS

Time-course evaluation of survival and treatment in FIRE-3 (AIO KRK0306, first-line therapy of KRAS wild-type metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab).

617 Background: FIRE-3 reported overall survival (OS) difference in favour of arm A (FOLFIRI plus cetuximab, N= 297 pts.) compared to arm B (FOLFIRI plus bevacizumab, N= 295 pts.) in the absence of significant differences in progression-free survival and response rate. Methods: We subdivided the study into six-month time intervals, starting at the time point of randomisation and evaluated OS in a time-wise fashion. Within each interval, OS was analyzed by Cox regression. Furthermore, systemic treatment and local interventions were investigated in the respective time-frames. Results: The time-course hazard ratios of OS are summarized in the Table. Pronounced differences in overall survival by time-interval analysis are observed between 24 and 30 months and between 30 and 36 months. Within the interval of 24-30 months, 24.6% (73/297) of pts in arm A and 25.1% (74/295) of pts in arm B received systemic therapy (any treatment-line). In the subsequent interval of 30-36 months, systemic anti-tumor treatment dec...