Abstract
Background/Aim: Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAFV600E-mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAFV600E-mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland. Patients and Methods: Anonymized data from BRAFV600E-mutant mCRC patients were analyzed retrospectively regarding 1st-, 2nd- and 3rd-line treatment using descriptive statistics. Results: Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1st-line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy. Conclusion: Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAFV600E-mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and – for MSI-H tumors – pembrolizumab represent urgently needed options for future mCRC patients.
At an incidence of approximately 140,000 new cases for both men and women in 2020, colorectal cancer (CRC) is among the three leading cancer entities in Western Europe (1) and represents a leading cause of cancer death in Germany (ca. 24,800 in 2016) (2). Austria (ca. 2,100 in 2018) (3), and Switzerland (ca. 1,700 in 2013-2017) (4). Across all stages, the five-year survival rate is approximately 60% (5). However, at diagnosis approximately 20% of the patients present with distant metastases (6, 7) and almost 50% develop metastatic disease (mCRC) during disease course (8). Within this population, the median overall survival (mOS) is around 30 months (9) with a five-year survival rate below 10% (6). In the current European Society for Medical Oncology (ESMO) guidelines, combination regimens with cytotoxic and targeted therapy are recommended for the treatment of patients with unresectable mCRC. These include folinic acid plus 5-fluoruracil (FOLF), irinotecan (IRI), oxaliplatin (OX), anti-VEGF/VEGFR agents (bevacizumab, aflibercept, ramucirumab) and anti-EGFR antibodies (cetuximab and panitumumab) (9).
The BRAFV600E-mutation, which leads to constitutive activation of the BRAF-kinase and sustained RAS/RAF/MEK/ERK pathway signaling, resulting in increased cell proliferation, is described in approximately 8-12% of mCRC-cases (10-12). The presence of a BRAFV600E mutation as the predominant BRAF alteration is considered a marker of poor prognosis in patients with mCRC and is associated (in the 1st-line setting of metastatic disease) with a mOS of approximately 12 months (13, 14). In addition, in 2nd- and later lines, treatment outcomes with current therapy options are poor in patients with BRAF-mutated mCRC, with overall response rates (ORR) ≤11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months and a mOS between 4.1 and 6.2 months (15-23).
Factors that are associated with an increased probability of mutated BRAF include female sex, age above 60 years, right-sided tumor localization, higher-grade anaplasia, metastases, and microsatellite instability (9, 24-27). The ESMO guidelines recommend to molecularly assess the BRAF mutation status in all patients at the time of mCRC diagnosis (9).
For the treatment of BRAF-mutant mCRC patients, the ESMO consensus guidelines recommend a polychemotherapy based regimen of FOLF, OX and IRI (FOLFOXIRI) with or without bevacizumab as preferred choice in the 1st-line setting (9). Recently, however, a meta-analysis of five randomized trials (n=1.697) concluded that in the BRAF-mutated subgroup (6.8%) there is rather no increased benefit from intensified 1st-line combination therapy (28). Second and third choices in the 1st-line setting consist of a cytotoxic doublet together with bevacizumab or FOLFOXIRI alone, respectively. In the 2nd-line, the use of a cytotoxic doublet with bevacizumab is recommended as first choice, followed by FOLF plus IRI (FOLFIRI) together with aflibercept or ramucirumab as second choice. In the 3rd-line, regorafenib or trifluridine/tipiracil are recommended.
Of note, if patients are “unfit” and, thus, not eligible for these treatment regimens, no alternative recommendations are provided. In general, the ESMO guidelines state that mCRC patients should receive all three available cytotoxic agents (fluoropyrimidine, OX and IRI) and all targeted treatments [anti-vascular endothelial growth factor (Receptor) (VEGF(R)) and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR)] treatment while concluding that the optimal therapy sequence remains elusive (9).
BRAF and RAS mutations are reportedly almost mutually exclusive in mCRC (9). Against this background, the effectiveness of anti-EGFR-based therapy in BRAF-mutant mCRC is currently under debate. Two meta-analyses from 2015 are drawing different conclusions. Pietrantonio et al. stated that addition of cetuximab or panitumumab in the BRAF-mutant subgroup did not significantly improve progression-free survival (PFS) (HR=0.88, p=0.33) or OS (HR=0.91, p=0.63) (29). However, Rowland et al. concluded that there is insufficient evidence to definitively state that BRAF-mutant mCRC patients attain a different treatment benefit from anti-EGFR-based therapy than the BRAF wild-type population (30). More recently, a meta-analysis with pooled data from two studies directly comparing chemotherapy plus anti-EGFR against chemotherapy plus anti-VEGF in 1st-line mCRC showed that regarding the BRAF-mutant subgroup there is no relevant difference in overall survival between bevacizumab- and cetuximab-based treatment (n=138; HR=1.01, 95%CI=0.69-1.48) (31).
Objective. This retrospective data analysis was designed to evaluate the approved therapeutic approaches and treatment pathways in BRAFV600E-mutant mCRC at specialized colon-cancer centers before approved availability of the targeted combination of encorafenib plus cetuximab in Germany, Austria, and Switzerland.
Further objectives were: i) Descriptive rationale for treatment decision making in the 1st, 2nd- and 3rd-line setting; ii) Description of treatment algorithms.
Patients and Methods
In this retrospective, cross-sectional documentation based on anonymized data from fourteen specialized colon-cancer centers in Germany, Austria, and Switzerland regarding male or female patients, at least 18 years of age, with metastatic BRAFV600E-mutated colorectal cancer according to the 8th American joint Commission on Cancer (AJCC) classification and confirmed by valid test method treated between January 2016 and May 2020 in the 1st-, 2nd- and 3rd-line setting with substances registered in the respective country at the time of treatment was collected retrospectively and analyzed using descriptive statistics. To be eligible for data documentation, at least the 2nd-line systemic treatment as per local standard had to be initiated.
The exclusion criteria were: i) BRAF test performed after initiation of 2nd-line treatment, ii) other secondary stage III-IV tumor diseases or concomitant systemic treatment of any secondary tumor disease, iii) pregnant or lactating patient during the documented treatment lines, and iv) participation in a clinical trial during the documented treatment lines.
The analysis was carried out using epidemiological statistical methods. All data were summarized by frequency tables and sample statistics and interpreted descriptively only. All analyses were performed with the Analysis Set, which contained all documented patients who meet all inclusion criteria and none of the exclusion criteria and for whom at least the 1st- and 2nd-treatment line were documented. The datasets included demographic and baseline characteristics, effectiveness and safety observations.
Most analyses were performed overall, by treatment line, by treatment type (all treatment lines and separately for each treatment line), by treatment type of targeted therapy (all treatment lines and separately for each treatment line), and by treatment regimen (all treatment lines and separately for each treatment line).
Before the start of the study, the project received a positive ethics committee (EC) vote in Germany (reference number: EA4/044/20) and Austria (reference number: 32-233 ex 19/20) and was confirmed to be no subject for EC evaluation in Switzerland (reference number: 2020-00142). An informed consent process was not required in this anonymized, retrospective data analysis. Moreover, before project start, the study was registered in the publicly accessible German Clinical Trials Register (number DRKS00020982). The clinical investigations detailed in the manuscript submitted were conducted in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Results
Study sites. Half of the patients (21, 50.0%) were documented in Germany, 9 patients (21.4%) in Austria and 12 patients (28.6%) in Switzerland. All patients in Germany were documented in private practices; all patients in Austria and Switzerland were documented in hospitals.
Patient population. Treatment sequences of 49 patients were documented. Forty-two patients met all inclusion and none of the exclusion criteria and had started at least two lines of therapy with five 2nd-line treatments not being considered in the analysis as off-label treatments. Fifteen patients were eligible for analysis in the 3rd-line setting, accounting for a total of 94 treatment lines. At initiation of the 1st-line treatment, 22 patients (52.4%) were male and 20 were female (47.6%). The mean age for both sexes was 62.1 years at the time when the 1st-line treatment was initiated. At the time of the initial diagnosis, the primary tumor was located in the colon/cecum in 37 patients (88.1% of total with most diagnoses in colon ascendens: 16 patients, 38.1%) and in 5 patients (11.9%) rectal carcinoma was diagnosed. In terms of tumor sidedness, 20 patients (47.6%) presented with right sided colorectal cancer and 8 patients (19.0%) with left sided colorectal cancer. Three or more organs were involved in 4 patients (9.8%), i.e., in the majority of patients (37 patients, 90.2%; one patient with missing data) a maximum of two organs were affected by the tumor disease. At this point, 17 patients (40.5%) presented with stage IV-M1c, i.e., with peritoneal metastasis. Liver metastases were present in 27 patients (64.3%). As required by the project inclusion criteria, all patients eligible for data documentation were tested positive for BRAFV600E mutation. Most of the patients [34 (81.0%)] were tested prior to the start of 1st-line treatment. At the time of metastatic stage diagnosis, 31 and 29 patients (73.8% vs. 69.0%) underwent molecular testing for KRAS and/or NRAS mutations, respectively. Most of these tests were performed simultaneously to BRAF testing (87.1% for KRAS, 93.1% for NRAS). One out of all patients tested (3.2%) presented with additionally mutated KRAS. The test on microsatellite instability (MSI) status was performed in 24 patients (57.1%) at time of diagnosis of the metastatic stage and in 2 patients (5.4%) at start of 2nd-line treatment. Four patients (9.5% based on all 42 patients) displayed high microsatellite instability (MSI-H). Key patient characteristics at the time of initiation of each treatment line are presented in Table I.
Key patient characteristics at the time of initiation of 1st-line treatment (if not stated otherwise).
Treatments administered. Among all 94 treatment lines, chemotherapy in combination with TT was the treatment type chosen in most cases (58 treatment lines) representing 61.7% of the regimens administered followed by chemotherapy alone (18 lines; 19.1%) and other treatment types (13 lines, 13.8%) (Figure 1). (OF NOTE: Treatments that were summarized as “other treatment type” (2nd-line: 8 patients, 21.6%; 3rd-line: 5 patients, 33.3%) included in the 2nd-line “regorafenib alone” in 1 patient, “unknown treatment” in 6 patients and “unknown targeted therapy” in 1 patient and in the 3rd-line “other treatment type” comprised “unknown treatment” in 4 patients and “unknown targeted therapy” in 1 patient).
Treatment types administered. The percentage of treatment types are shown by treatment line and overall. The bars underneath the chemo/TT combinations break down to the two combination partners, VEGF(R)i and EGFRi, respectively. In this group, one patient in the 1st-line setting (2.4%) and one patient in the 2nd-line (2.7%) were treated with chemo. +VEGF(R)i+EGFRi (triple combination) depicted by the hatched area (overall: 2.1%). Chemo.: Chemotherapy; TT: targeted therapy; VEGF(R)i: vascular endothelial growth factor (Receptor) inhibitor; EGFRi: epidermal growth factor receptor inhibitor.
Overall, chemotherapy backbones were mostly FOLFOXIRI (26 treatments, 27.7%) or doublet (overall: 40 treatments, 42.6%; FOLFOX/CAPOX: 21 treatments, 22.3%; FOLFIRI: 19 treatments, 20.2%). The frequency of chemotherapy alone decreased with later treatment lines (Figure 1).
Targeted agents–either in combination with chemotherapy or in monotherapy – were used in approximately two thirds of the treatment lines administered [63 treatment lines (67.0%)] Among these patients, the majority received a VEGF(R)i treatment (43 treatment lines, 45.7%). An EGFR inhibitor (EGFRi) was chosen in 22 treatment lines (23.4%). Among these, one patient in both, the 1st and the 2nd treatment line (2.4% and 2.7%, respectively), was treated with VEGF(R)i plus EGFRi plus chemotherapy. In monotherapy, EGFRi was used in four patients (4.3%) and VEGF(R)i in one patient (1.1% - bevacizumab). Accordingly, when administered in combination, VEGF(R)i therapy was chosen more frequently than EGFRi (Figure 1) and EGFRi was the preferred choice when TT was administered in monotherapy [EGFRi: 4 patients (4.3%); VEGF(R)i: 1 patient (1.1%)]. Bevacizumab was the preferred VEGF(R) targeted therapy when combined with chemotherapy (over all treatment lines: 40.4%) and the only compound chosen when VEGF(R)i was administered in monotherapy. Regarding 1st-line treatment, 22 patients (52.4%) received the VEGFi bevacizumab (all of them in combination with chemotherapy), while 7 patients (16.7%) and 2 patients (4.8%) were treated with the anti-EGFR antibodies panitumumab and cetuximab, respectively (all of them in combination with chemotherapy). Table II provides details on the treatment types, regimen, and active combinations/substances, overall and by treatment line.
Treatment types, regimen, and active combinations/substances, overall and by treatment line.
Most of the patients were treated consecutively with a combination regimen chemotherapy plus TT in both, the 1st- and the 2nd-line setting, changing one or more of the combination compounds within the types administered (n=16, 53.3% of the 30 patients having been treated with chemotherapy+TT in 1st-line). In the rest of the cases, the treatment types were usually switched to the remaining treatment types. Out of the twelve patients that started treatment with chemotherapy alone, three patients (25%) continued to be treated with chemotherapy alone changing one of the combination partners; the remaining of the patients switched to other treatment types. The treatment sequences (from the 1st-line to 2nd-line to 3rd-line treatment) are shown in Figure 2.
Treatment sequences. The treatment sequences (1st-line to 2nd-line to 3rd-line treatment) for all patients are depicted. Each patient is represented by a single, colored line or dot in case only the 1st-line treatment was considered. Therefore, the therapy sequence of each patient can be followed from left to right with the width of the bar (consisting of several colored lines) indicating the proportion of patients receiving a specific therapy sequence. Chemo.: Chemotherapy; TT: targeted therapy.
Main reasons for treatment choices. To enquire about the main reasons for the treatment choice, a list of six specific options to choose from was provided to the centers (Table III). The most frequently indicated reason to choose any treatment type was – over all treatment lines – remission pressure, i.e., after rapid tumor progress or based on the patients’ tumor load [36 treatment lines (38.3%) followed by BRAF mutation (25 treatment lines, 26.6%] and the physician’s preferences (18 treatment lines, 19.1%). Remission pressure was more prominent in later treatment lines amounting from 28.6% (12 patients) in the 1st-line setting and 45.9% (17 patients) in 2nd-line up to 46.7% (7 patients) in the 3rd treatment line compared to BRAF mutation that played a more dominant role for the treatment choice in the 1st-line setting (35.7%, 15 patients) versus 18.9% (7 patients, 2nd-line) versus 20% (3 patients, 3rd-line)). The decision to choose a specific treatment was motivated by the physician’s preference in around 20% of the patients in each of the treatment lines (1st-line: 8 patients, 19.0%; 2nd-line: 7 patients, 18.9%; 3rd-line: 3 patients, 20.0%). Regimen specific toxicity profiles influenced the treatment decision making in 8 lines (8.5%) in total without trend towards early or later treatment stage.
Main reasons for choosing specific treatment type.
Specific toxicity profiles of the substances administered played a less prominent role in decision making. The main reasons for prescribing a specific treatment type are summarized in Table III.
Treatment discontinuation. Most treatment lines (81 lines, 86.2%) were discontinued by the time of data documentation. To enquire about the main reasons for the treatment discontinuation, a list of nine specific options to choose from was provided to the centers (Table IV; interpretation of any of these options was at the discretion of the study sites).
Main reasons for treatment discontinuation by treatment line.
Within each treatment line as well as for all treatment types across treatment lines, the predominantly documented reason for discontinuation was lack of efficacy (42 treatment lines in total, 51.9%). Planned treatment discontinuation as the number of pre-planned cycles was reached and toxicities (7 treatment lines each, 8.6%) were the next most frequent reasons to discontinue treatment. Best benefit reached was a prominent reason for discontinuation in patients being treated in 1st-line only (5 patients, 12.2%) and death leading to treatment discontinuation became a more prominent reason in later treatment lines (1st-line: 0 patients, 0.0%; 2nd-line: 4 patients, 12.9%; 3rd-line: 2 patients, 22.2%). Table IV and Figure 3 summarize the main reasons for treatment discontinuation by treatment line and treatment type, respectively.
Reasons for discontinuation. The percentages for the reasons to discontinue treatment according to pre-defined response options in all treatment lines by treatment type are shown. Chemo.: Chemotherapy; TT: targeted therapy; VEGF(R)i: vascular endothelial growth factor (Receptor) inhibitor; EGFRi: epidermal growth factor receptor inhibitor.
Allergic reaction (2 cases) was the most frequent cause of treatment discontinuation due to toxicities. Both patients were treated with chemotherapy in combination with TT (grade 2: FOLFOX plus cetuximab, and grade 3: FOLFOX plus bevacizumab, in this case associated with bronchospasm). In another patient being treated with chemotherapy plus VEGFi (FOLFOXIRI plus bevacizumab) increased bilirubin, grade 3, required treatment discontinuation. In another case when chemotherapy was combined with an EGFRi, the treatment was discontinued upon occurrence of hydronephrosis due to ureter stone, grade 3 (FOLFOXIRI plus panitumumab). Capecitabine used in monotherapy was discontinued due to grade 2 coronary spasm in a single case. Toxicities occurring during therapy with other treatment types that were not otherwise specified required treatment discontinuation due to fever of unknown cause, grade 2, and grade 2 emesis.
Six patients died (three patients while being treated with chemotherapy+VEGF(R)i, two patients while in treatment with chemotherapy+EGFRi and one patient under treatment with other treatment types).
Discussion
In this study, we examined the real-world treatment of metastatic BRAFV600E-mutated colorectal cancer in patients treated at fourteen sites in Germany, Austria, and Switzerland before approved availability of the targeted combination of encorafenib plus cetuximab. The aim of our data analysis was to better understand the treatment landscape and decision-making process. The results of this study include data on patient profiles, treatment patterns and outcomes of patients treated in the real-world setting.
In the three countries involved, the majority of the patients were tested for BRAF, KRAS, and NRAS mutations. BRAF testing usually was performed before systemic 1st-line therapy and simultaneously to KRAS and NRAS testing. This testing strategy is in compliance with the recommendations of applicable clinical practice guidelines as the results of the molecular evaluation constitute a critical requirement to choose the optimal therapy within the given treatment algorithms (9, 10, 32, 33).
In the 1st-line setting, all patients received a chemotherapy regimen with or without TT. Most of these patients were treated with a cytotoxic, platinum-based doublet or triplet. The targeted agent predominantly used as combination partner was bevacizumab. In the 2nd-line setting, the treatment type was either switched or – in case the therapy was continued with the same treatment type – one or more of the combination partner/s within the type was/were replaced. Clinical study results investigating 1st-line regimens have shown that combination chemotherapy with a fluoropyrimidine (such as FOLF or capecitabine) plus OX and/or IRI (FOLFOX or FOLFIRI or FOLFOXIRI) provides higher response rates and better progression-free and (partly) overall survival than a fluoropyrimidine alone (34-37). In addition, monoclonal antibodies such as the VEGFi bevacizumab or the EGFR inhibitors cetuximab and panitumumab have demonstrated an improved clinical outcome of patients with mCRC when combined with chemotherapy regimens in the 1st-line setting (38-47). Accordingly, those intensive 1st-line treatment triplet- or doublet-based regimens are recommended in the treatment algorithms of current national and international clinical practice guidelines in patients in good general health condition, limiting the recommended regimens to FOLF or capecitabin in combination with bevacizumab in patients in deteriorated condition (9, 10, 32). Moreover, according to the ESMO consensus guidelines, in patients in whom the initial chemotherapy backbone has failed, the chemotherapy backbone should be changed and biologics should be considered in 2nd-line if not used in the 1st-line treatment (9).
Our data show that both, the testing strategy and treatment principles in the treatment of mCRC patients within the three countries involved, reflected the recommendations laid out in these guidelines.
Across all treatment lines and types, however, lack of efficacy represented the leading cause for treatment discontinuation. Toxicities played a minor role when the decision was made to discontinue treatment. In general, up to 30% of the patients with mCRC experience disease- and treatment-related toxicities CTC grade III-IV, in particular diarrhea, nausea and vomiting, mucositis/stomatitis, constipation and neuropathy (19). While toxicities were not a major cause for treatment discontinuation in this study, most toxicities reported and attributed to a specific treatment regimen are typical for the substances or combinations used (48-58).
Against this background, molecularly defined approaches including the registration of encorafenib in combination with cetuximab for treatment of BRAFV600E-positive mCRC after systemic therapy as well as the registration of pembrolizumab provide further promising options for future mCRC patients.
Methodological limitations. A general limitation is introduced by the nature of this study with its retrospective, uncontrolled, open design, non-standardized treatment allocations and conditions, as well as its observational character. Therefore, the study data is presented in a descriptive way only, showing the real-life situation during the specified documentation period. Observed treatment trends and tendencies must be interpreted with caution, as these might be influenced by underlying patient and disease characteristics.
Conclusion
Based on the MORSECRC patient cohort, current treatment practice of BRAFV600E-mutant mCRC patients in Germany, Austria, and Switzerland typically includes combination chemotherapy plus targeted agents- thus reflecting the current clinical practice guidelines. While both anti-VEGF- and anti-EGFR-targeted therapy play a relevant role in this treatment setting, lack of efficacy including progression is the leading cause for treatment discontinuation. In line with the current guideline recommendations for upfront molecular testing at the time of mCRC diagnosis, recently approved molecularly defined therapies represent promising treatment options for mCRC patients.
Acknowledgements
The Authors wish to thank all the patients, family members and staff from all the study centers that participated in the study. The Authors would like to acknowledge editorial support provided by Andreas Zähringer, Freiburg. The Authors would also like to express their gratitude to Monika Schwager (Winicker Norimed GmbH, Nuremberg, Germany) for providing the statistical support in this project. Support for this assistance was funded by Pierre Fabre GmbH (Freiburg, Germany; Wels, Austria; Allschwil, Switzerland).
Footnotes
Authors’ Contributions
This project and the analysis were designed and conducted by Pierre Fabre. All named Authors participated in the development of this manuscript and in the decision to submit this manuscript for publication. The Authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the accuracy and integrity of any part of the work as a whole and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, and have given their approval for this version to be published.
Armin Gerger: Conceptualization, methodology, resources (patients), investigation, writing-original draft preparation, writing-review, and editing. Wolfgang Eisterer, Stefan Fuxius, Sara Bastian, Dieter Köberle, Manfred Welslau, Dilara Akhoundova Sanoyan, Christian Maas, Jens Uhlig, Klaus Fenchel, Richard Greil, Eyck von der Heyde, Gaëlle Rhyner, and Rudolf Weide: Resources (patients), investigation, writing-review, and editing. Monika Schwager: Resources (computing), data curation, formal analysis, statistical analysis, software, visualization. Frank Reichenbach: Conceptualization, methodology, project administration, writing-original draft preparation, writing-review and editing, visualization, validation. Dominik Paul Modest: Conceptualization, methodology, writing-original draft preparation, writing-review, and editing. Ralph Fritsch: Conceptualization, methodology, resources (patients), investigation, writing-original draft preparation, writing-review, and editing.
Conflicts of Interest
Armin Gerger disclosed a consulting role for Pierre Fabre; Dieter Koeberle has disclosed a consulting role with Pierre Fabre; Manfred Welslau has disclosed advisory roles for Amgen, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Lilly, medac, Novartis, Roche, and Sanofi. He received honoraria from Amgen, astellas, AstraZeneca, Celgene, Gilead, Hexal, Janssen, Lilly, Novartis, Roche, And Sanofi. Jens Uhlig has disclosed advisory roles in Ad Boards and workshops with Roche, Amgen, Servier, MSD, Bristol-Myers Squibb, Sanofi, Merck, Celgene, Novartis, Janssen-Cilag, Boehringer-Ingelheim, and Bayer. Richard Greil has disclosed a consulting role with Celgene, Novartis, Roche, BMS, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo. He has received honoraria from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo. Eyck von der Heyde has disclosed consulting roles with Bristol-Myers Squibb, AstraZeneca, Merck, Novartis, and Boehringer Ingelheim. Dominik Paul Modest has disclosed a consulting role or honoraria for lectures with Amgen, Merck, Pierre Fabre, Servier, Lilly, MSD, BMS, onkowissen, Taiho, Incyte, AstraZeneca, G1, Transgene and Sanofi. He is currently receiving research grants from Servier and Amgen. Ralph Fritsch has disclosed a consulting role and is on the speaker`s bureau for Pierre Fabre.
Wolfgang Eisterer, Stefan Fuxius, Sara Bastian, Dilara Akhoundova Sanoyan, Christian Maas; Klaus Fenchel, Gaëlle Rhyner Agocs, Rudolf Weide, and Monika Schwager declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Frank Reichenbach is an employee at Pierre Fabre Pharma GmbH.
The Authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
- Received June 29, 2022.
- Revision received July 19, 2022.
- Accepted August 6, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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