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FUTURE ONCOLOGYAHEAD OF PRINTSHORT COMMUNICATIONOpen Accesscc iconby iconnc iconnd icon
Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries
George Kafatos , Victoria Banks , Peter Burdon , David Neasham , Kimberly A Lowe , Caroline Anger, Fil Manuguid & Jörg Trojan
Published Online:19 Jan 2021https://doi.org/10.2217/fon-2020-0976
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Abstract
Background: Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors have impacted treatment decisions. Materials & methods: This study used a large oncology database to investigate patterns of monoclonal antibody (mAb) plus chemotherapy treatment in France, Germany, Italy, Spain and the UK in mCRC patients treated in first line in 2018. Results: Anti-EGFR mAbs were most often administered to patients with RAS wild-type mCRC and those with left-sided tumors, while anti-VEGF mAbs were preferred in RAS mutant and right-sided tumors. Adopted treatment strategies differed between countries, largely due to reimbursement. Conclusion: Biomarker status and primary tumor location steered treatment decisions in first line. Adopted treatment strategies differed between participating countries.
Lay abstract
Each patient's cancer is unique. For example, colon cancer on the left side is different from colon cancer on the right side. Colon cancer is different from cancer of the rectum. Cancers also have changes in their genes, which means some treatments should work, while others may not. Doctors can select among different medicines to find the drug that works best for each patient. We looked at patients with cancer of the colon or rectum that has spread to other organs. We tried to find out how doctors in Europe select drugs for their patients after performing tests called RAS or BRAF. We found that doctors make different choices in different countries.
Keywords:
BRAFEGFRmCRCprimary tumor locationRAStumor sidednessVEGF
During the last decade, improvements in the treatment of metastatic colorectal cancer (mCRC) have increased median survival time for patients from 12 months to approximately 3 years [1,2]. Major drivers of this success were the development of an antiangiogenic agent, the VEGF inhibitor bevacizumab, of monoclonal antibodies (mAbs) that inhibit the EGFR namely panitumumab and cetuximab, and a better understanding of prognostic and predictive biomarkers and of the different molecular profiles of left- and right-sided tumors [3,4,5]. Further important factors were the improvements in the adoption of multi-disciplinary teams/tumor boards, new surgical techniques, or local ablative therapies [6].
Chemotherapy, anti-VEGF mAbs and anti-EGFR mAbs are now the mainstay of systemic mCRC therapy. In the first line following diagnosis of mCRC, treatment is planned according to patient fitness, resectability of the tumor and/or metastases, and the tumor's biomarker status [7]. The European Society for Medical Oncology (ESMO) recommends the use of biologicals (targeted agents) as first line of treatment for most patients unless contraindicated [7]. According to European Medicines Agency (EMA) label, the anti-VEGF mAb bevacizumab should be used in combination with fluoropyrimidine-based chemotherapy [8]. Anti-EGFR mAbs should be used in combination with FOLFOX or FOLFIRI or as monotherapy in patients who have failed oxaliplatin- or irinotecan-based therapy, are intolerant of irinotecan (cetuximab) or have failed fluoropyrimidine-based therapy (panitumumab). Both are limited to patients with RAS wild-type tumors [9,10]. There is strong evidence that BRAF mutation is predictive for a la ck of benefit from anti-EGFR mAbs, although some discussions remain [7,11]. Evidence from the BEACON trial suggests some benefit of adding anti-EGFR mAb-based therapy to BRAF/MEK inhibitors. Anti-EGFR mAbs are thought to block the anticipated escape mechanism resulting from BRAF/MEK inhibition [12].
Primary tumor location, a surrogate of the different molecular profiles of left- and right-sided tumors, although first described in 2001 [13], has gained increasing attention after a 2017 meta-analysis of its prognostic and predictive value in patients with RAS wild-type mCRC [14]. In this retrospective analysis, six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181) were pooled, comparing chemotherapy plus anti-EGFR mAb therapy with chemotherapy or chemotherapy plus bevacizumab. A worse prognosis for overall survival, progression-free survival and objective response rate (ORR) was found for patients with right-sided primary tumors. Tumor side was also found to be predictive of treatment efficacy, with the greatest effect in patients with left-sided tumors receiving anti-EGFR mAb in combination with chemotherapy. Similar results were found when analyzing the anti-EGFR mAbs separately in the panitumumab trials PRIME [4,15,16] and PEAK [4,16,17] and the cetuxim ab trials CRYSTAL and FIRE-3 [18].
The present study aimed to capture the treatment patterns in the first line of therapy of mCRC patients actively treated in 2018 in real-world clinical practice in five European countries by tumor sidedness and biomarker status.
Materials & methods
Database
This was a retrospective analysis using a large oncology database (Oncology Dynamics™, IQVIA Ltd., London, UK). The database was designed as a cross-sectional physician survey that collects anonymized individual-level information on drug-treated cancer patients in Europe (and other non-European countries) regardless of cancer type, disease stage and/or treatment [19,20,21,22,23,24,25,26]. The database has been described in detail elsewhere [27].
In brief, the database includes data from oncology centers in 10 countries (France, Germany, Italy, Spain, UK, China, Japan, South Korea, Saudi Arabia and Mexico). It is designed as repeated quarterly cross-sectional cohorts and contains more than 167,000 cancer cases per year and over 35 cancer indications. The database captures patient information via a standardized electronic case report form entered by the treating physician from patients' health records. Stratified random sampling is used to select physicians to represent the distribution of specialties for each cancer indication and country. It is limited to patients treated with a cancer drug at the time of data collection and excludes patients solely treated with radiotherapy, surgery, supportive care or on active surveillance.
Objectives
The study objective was to describe the demographic and clinical characteristics, as well as treatment patterns, i.e. anti-EGFR mAbs, anti-VEGF mAbs and/or chemotherapy, for patients treated for mCRC in first line during 2018 by tumor sidedness and biomarker status.
Eligibility criteria
All mCRC patients from the participating countries recorded in the database who received active anti-cancer first-line treatment in the advanced/metastatic setting in 2018, fulfilled the International Classification of Diseases, Tenth Revision codes used to define the mCRC population, and had a diagnosis date between July 2013 and December 2018, were included. Patients with unknown RAS or BRAF status, or unknown primary tumor location were excluded. Clinical trial participants were excluded.
Demographic & clinical characteristics
Description of demographics included country, age, sex, treatment facility site type and subtype. Clinical characteristics included the quarter of diagnosis, the BMI, Eastern Cooperative Oncology Group performance status, stage at diagnosis, site of metastasis and location of primary tumor.
Left-sided tumors were defined as those originating in the splenic flexure, descending colon, sigmoid colon or rectum. Right-sided tumors were defined as those originating in the appendix, cecum, ascending colon or hepatic flexure as well as the transversum – between the hepatic and splenic flexure; this is in line with previous analyses, such as the meta-analysis of six trials mentioned above [14]. Tumor sidedness was determined by the treating physician. Where tumor sidedness was recorded as unknown by the physician, the International Classification of Diseases, Tenth Revision code, from which anatomy of tumor location could be determined, was used where available.
Statistical considerations
Frequencies and proportions were provided for mCRC patients within the selected cohorts with their corresponding 95% Binomial Exact CIs. SAS Software was used (SAS Enterprise Guide 7.1.; SAS Institute Inc., NC, USA).
Results
Patient & tumor characteristics
There were 4455 mCRC patients within the database who were actively drug treated in 2018. A full description of all 4455 patients can be found elsewhere [27]. Of these, 42.0% (n = 1871) were receiving their first advanced/metastatic line of therapy and thus eligible for the present analysis; their RAS and BRAF status as well as their primary tumor location were known. Of these 1871 patients, two were excluded from the analysis as they received therapy other than anti-EGFR mAbs plus chemotherapy, anti-VEGF mAbs plus chemotherapy or only chemotherapy (see CONSORT [Consolidated Standards of Reporting Trials] flow diagram in Figure 1); 635 patients were from Italy, 337 from Germany, 318 each from France and the UK and 261 from Spain. The oncology center characteristics for the 1869 analyzed patients are provided in the supplemental material (Supplementary Table 1). Of patients, 60.8% (n = 1136) were male, 68.6% (n = 1282) were older than 60 years of age. Overall, 52.6% (n = 983) had RAS wild-type tumors and 6.5% (n = 122) had BRAF mutant tumors; 62.7% (n = 1172) had left-sided and 37.3% (n = 697) had right-sided or transverse primary tumors (summarized as right-sided). Left-sided tumors were RAS wild type in 55.8% of patients (n = 654). Of right-sided tumors, slightly fewer than half, 47.2% (n = 329), were RAS wild type. BRAF wild type status was found in 95.7% (n = 1122) of left-sided and 89.7% (n = 625) of right-sided tumors (Table 1). Further patient and tumor characteristics are listed in Table 1.
Figure 1. CONSORT flow diagram describing the primary tumor location and biomarker status of first line of therapy for metastatic colorectal cancer patients.
CONSORT: Consolidated standards of reporting trials; CRC: colorectal cancer; mCRC: Metastatic colorectal cancer.
Table 1. Patient demographics and disease characteristics.
Parameters, n (%) Left-sided tumors
(n = 1172) Right-sided tumors†
(n = 697) Overall
(n = 1869)
Sex
– Female 445 (38.0) 288 (41.3) 733 (39.2)
– Male 727 (62.0) 409 (58.7) 1136 (60.8)
Age group at current line of therapy
– <16 – – –
– 16–50 102 (8.7) 73 (10.5) 175 (9.4)
– 51–60 286 (24.4) 126 (18.1) 412 (22.0)
– 61–75 591 (50.4) 355 (50.9) 946 (50.6)
– ≥76 193 (16.5) 143 (20.5) 336 (18.0)
ECOG status at current line of therapy
– 0 390 (33.3) 219 (31.4) 609 (32.6)
– 1 649 (55.4) 408 (58.5) 1057 (56.6)
– 2 120 (10.2) 60 (8.6) 180 (9.6)
– 3 3 (0.3) 6 (0.9) 9 (0.5)
– 4 1 (0.1) 1 (0.1) 2 (0.1)
– Unknown 9 (0.8) 3 (0.4) 12 (0.6)
Stage at diagnosis
– Stage I 10 (0.9) 4 (0.6) 14 (0.7)
– Stage II 61 (5.2) 29 (4.2) 90 (4.8)
– Stage III 156 (13.3) 84 (12.1) 240 (12.8)
– Stage IV 905 (77.2) 558 (80.1) 1463 (78.3)
– Unknown 40 (3.4) 22 (3.2) 62 (3.3)
Primary tumor location
– Left-sided 1172 (100.0) – 1172 (62.7)
– Right-sided – 593 (85.1) 593 (31.7)
– Transverse – 104 (14.9) 104 (5.6)
RAS status
– Wild type 654 (55.8) 329 (47.2) 983 (52.6)
– Mutant 518 (44.2) 368 (52.8) 886 (47.4)
BRAF status
– Wild type 1122 (95.7) 625 (89.7) 1747 (93.5)
– Mutant 50 (4.3) 72 (10.3) 122 (6.5)
Site of metastasis
– Liver & lung combination 281 (24.0) 164 (23.5) 445 (23.8)
– Liver only 343 (29.3) 193 (27.7) 536 (28.7)
– Liver with other combination 303 (25.9) 171 (24.5) 474 (25.4)
– Lung only 63 (5.4) 31 (4.4) 94 (5.0)
– Lung with other combination 59 (5.0) 26 (3.7) 85 (4.5)
– Other 123 (10.5) 112 (16.1) 235 (12.6)
Pre-existing comorbidities
– No 541 (46.2) 334 (47.9) 875 (46.8)
– Yes 631 (53.8) 363 (52.1) 994 (53.2)
Type of comorbidities
– Auto-immune disease 15 (1.3) 4 (0.6) 19 (1.0)
– Bone disease 12 (1.0) 10 (1.4) 22 (1.2)
– Cardiovascular 215 (18.3) 119 (17.1) 334 (17.9)
– Gastrointestinal 29 (2.5) 12 (1.7) 41 (2.2)
– Infection 5 (0.4) 1 (0.1) 6 (0.3)
– Metabolic 224 (19.1) 134 (19.2) 358 (19.2)
– Neurological 36 (3.1) 21 (3.0) 57 (3.0)
– Renal 41 (3.5) 34 (4.9) 75 (4.0)
– Respiratory 155 (13.2) 97 (13.9) 252 (13.5)
– Other 223 (19.0) 114 (16.4) 337 (18.0)
– None 513 (43.8) 309 (44.3) 822 (44.0)
– NA 28 (2.4) 25 (3.6) 53 (2.8)
CRC-related surgery
– No surgery 548 (46.8) 308 (44.2) 856 (45.8)
– Surgery 624 (53.2) 389 (55.8) 1013 (54.2)
†Right-sided tumors include tumors of the transverse colon.
CRC: Colorectal cancer; ECOG: Eastern cooperative oncology group; NA: Not available.
Treatment landscape
Patients with RAS wild-type tumors were most commonly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%). The remaining patients were treated equally with anti-VEGF mAbs plus chemotherapy (18.4%; 95% CI: 16.0%, 21.0%) or chemotherapy-only (19.0%; 95% CI: 16.6%, 21.6%). Patients with RAS mutant tumors were most commonly prescribed anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%) followed by chemotherapy-only (38.1%; 95% CI: 34.9%, 41.4%). There were 12 patients (out of 886 RAS mutant patients) documented as receiving anti-EGFR mAbs plus chemotherapy (1.4%; 95% CI: 0.7%, 2.4%; Table 2).
Table 2. Treatments received overall and by RAS mutation status and primary tumor location, n (%) (95% CI).
Treatment RAS wild type RAS mutant
Left-sided Right-sided Total Left-sided Right-sided Total
Anti-EGFR mAbs 468 (71.6)
[67.9, 75.0] 147 (44.7)
[39.2, 50.2] 615 (62.6)
[59.5, 65.6] 11 (2.1)
[1, 3.8] 1 (0.3)
[0.0, 1.5] 12 (1.4)
[0.7, 2.4]
Anti-VEGF mAbs 76 (11.6)
[9.3, 14.3] 105 (31.9)
[26.9, 37.3] 181 (18.4)
[16.0, 21.0] 308 (59.5)
[55.1, 63.7] 228 (62.0)
[56.8, 66.9] 536 (60.5)
[57.2, 63.7]
Chemo only 110 (16.8)
[14.0, 19.9] 77 (23.4)
[18.9, 28.4] 187 (19.0)
[16.6, 21.6] 199 (38.4)
[34.2, 42.8] 139 (37.8)
[32.8, 42.9] 338 (38.1)
[34.9, 41.4]
Total 654 (100.0)
[99.4, 100.0] 329 (100.0)
[98.9, 100.0] 983 (100.0)
[99.6, 100.0] 518 (100.0)
[99.3, 100.0] 368 (100.0)
[99.0, 100.0] 886 (100.0)
[99.6, 100.0]
Chemo: Chemotherapy; mAbs: Monoclonal antibodies.
Of the 983 RAS wild-type patients, 654 (66.5%) had left-sided tumors and 329 (33.4%) had right-sided tumors. For both groups of patients, the most common treatment was anti-EGFR mAbs plus chemotherapy (71.6%; 95% CI: 67.9%, 75.0% and 44.7%; 95% CI: 39.2%, 50.2%) for left- and right-sided tumors, respectively). Of the 886 RAS mutant patients, 518 (58.4%) had left-sided tumors and 368 (41.5%) had right-sided tumors. For both left- and right-sided RAS mutant tumors, the majority were treated with anti-VEGF mAbs plus chemotherapy (59.5%; 95% CI: 55.1%, 63.7%) for left-sided and 62.0%; 95% CI: 56.8%, 66.9% for right-sided) (Table 2).
Of the RAS wild-type patients, 108 (11.0%) were BRAF mutant. For tumors of both RAS and BRAF wild type status, the most common treatment was anti-EGFR mAbs plus chemotherapy (69.3%; 95% CI: 66.1%, 72.4%). For tumors of RAS wild type and BRAF mutant status the most common treatment were anti-VEGF mAbs plus chemotherapy (44.4%; 95% CI: 34.9%, 54.3%). Of the RAS mutant patients, 872 (98.4%) were BRAF wild type and 14 (1.6%) were documented as BRAF mutant. For RAS mutant and BRAF wild-type tumors the most common treatment were anti-VEGF mAbs (61.1%; 95% CI: 57.8%, 64.4%). In the rare case of patients who were reported as having both RAS and BRAF mutant tumor status (n = 14) the great majority was treated with chemotherapy only (78.6%; 95% CI: 49.2%, 95.3%) (Table 3).
Table 3. Treatments received overall and by RAS mutation status and BRAF mutation status, n (%) (95% CI).
Treatment RAS wild type RAS mutant
BRAF wild type BRAF mutant Total BRAF wild type BRAF mutant Total
Anti-EGFR mAbs 589 (69.3)
[66.1, 72.4] 26 (24.1)
[16.4, 33.3] 615 (62.6)
[59.5, 65.6] 12 (1.4)
[0.7, 2.4] 0 (0.0)
[0.0, 23.2] 12 (1.4)
[0.7, 2.4]
Anti-VEGF mAbs 133 (15.6)
[13.3, 18.3] 48 (44.4)
[34.9, 54.3] 181 (18.4)
[16.0, 21.0] 533 (61.1)
[57.8, 64.4] 3 (21.4)
[4.7, 50.8] 536 (60.5)
[57.2, 63.7]
Chemo only 153 (17.5)
[15.0, 20.2] 34 (31.5)
[22.9, 41.1] 187 (19.0)
[16.6, 21.6] 327 (37.5)
[34.3, 40.8] 11 (78.6)
[49.2, 95.3] 338 (38.1)
[34.9, 41.4]
Total 875 (100.0)
[99.6, 100.0] 108 (100)
[96.6, 100.0] 983 (100.0)
[99.6, 100.0] 872 (100.0)
[99.6, 100.0] 14 (100.0)
[76.8, 100.0] 886 (100.0)
[99.6, 100.0]
Chemo: Chemotherapy; mAbs: Monoclonal antibodies.
When looking at the treatment landscape by country, there were differences regarding the adopted treatment strategies. In RAS wild-type mCRC patients, anti-VEGF mAbs plus chemotherapy were not prescribed in the UK as opposed to the other countries, in which anti-VEGF mAb-based combinations ranged from 15.2% in Spain to 25.6% in Italy. Patients with RAS mutant tumors also received anti-VEGF mAbs plus chemotherapy less frequently in the UK (5.1%; 95% CI: 2.2%, 9.8%) compared with other countries which ranged from 66.9% in France to 78.9% in Italy (Supplementary Tables 2 & 3).
Discussion
This study aimed to capture the treatment patterns in mCRC patients in real-world clinical practice in five European countries. There were large differences in treatment patterns by biomarker status and primary tumor location. RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%) whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%). For RAS wild-type patients, anti-EGFR mAbs plus chemotherapy were more frequently prescribed in patients with left-sided compared with right-sided tumors (71.6%; 95% CI: 67.9%, 75.0% vs 44.7%; 95% CI: 39.2%, 50.2%, respectively). In RAS and BRAF wild-type patients, the most common treatment was anti-EGFR mAb plus chemotherapy (69.3%, 95% CI: 66.1%, 72.4%). RAS wild-type/BRAF mutant patients preferably received anti-VEGF mAbs (44.4%; 95% CI: 34.9%, 54.3%). For RAS mutant/BRAF wild-type patients, anti-VEGF mAbs plus chemotherapy was most commonly prescribed (61.1%; 95% CI: 57.8%, 64.4%).
Studies with a broad focus evaluating the patterns of mCRC treatment, especially in first line, are rare; the authors are not aware of any studies using a similarly broad research angle as theirs. The predecessor of the database that was used in the present study (Oncology Analyzer™), was previously used to evaluate treatment patterns in the USA, the EU (France, Germany, Italy, Spain), UK and Japan using data from 2007 [21], and in France, Germany, Italy and Spain using a 2009 data snapshot [28]. In 2007, treatment combinations including targeted therapy (bevacizumab) accounted for a limited proportion of administered regimens in the first-line mCRC setting, with the highest uptake in France with <20%, followed by Italy and Germany with <10% [21]. By 2009, the proportion of bevacizumab-containing regimens had increased to approximately 40% in France, Germany and Italy, and 30% in Spain; cetuximab-containing regimens accounted for 7–14% [28]. Approved indications have changed subs tantially since these studies were conducted, generally allowing for refined use of these agents. The anti-EGFR mAbs labels changed several times over the last years, including changes in mandatory wild type status of KRAS to RAS and of allowed chemotherapy backbone (Figure 2). Panitumumab was initially approved as monotherapy, then in combination with FOLFOX in first line and with FOLFIRI in second-line; the combination with FOLFIRI in first line followed in 2015 [29]. Additionally, ESMO guidelines were continuously updated to incorporate new clinical evidence [7] and entailed considerable shifts in treatment practices.
Figure 2. Selected European union label changes relating to the patient population eligible for anti-EGFR monoclonal antibody therapy.
†And intolerant to irinotecan.
‡FOLFOX4 subsequently revised to FOLFOX (first line) in 2012.
§For patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
Therapeutic indications have been abbreviated; please see product labels for full details [9,10].
CTx: Chemotherapy; CTxR: Chemotherapy refractory; FOLFOX: Folinic acid, fluorouracil and oxaliplatin; FOLFIRI: Folinic acid, fluorouracil and irinotecan; IRI: Irinotecan; mAb: Monoclonal antibody; WT: Wild type.
The meta-analysis of six Phase III trials by Arnold et al. provided strong evidence about the prognostic and predictive value of primary tumor location, which are biologically different [5]. It was shown that the greatest effect was obtained in patients with left-sided tumors receiving anti-EGFR mAbs in combination with chemotherapy [14]. In the present study, 71.6% (95% CI: 67.9%, 75.0%) of patients with left-sided RAS wild-type tumors and 44.7% (95% CI: 39.2%, 50.2%) of patients with right-sided RAS wild-type tumors received anti-EGFR mAb-based therapy, using a chemotherapy backbone. In the UK, the great majority of RAS mutant patients were treated with chemotherapy only (93.6%; 95% CI: 88.6%, 96.9%) whereas in the other European countries most patients were treated with anti-VEGF mAbs plus chemotherapy (between 67.2 and 78.9% in Germany and Italy, respectively). In the UK, National Institute for Health and Care Excellence (NICE) does not recommend the anti-VEGF mAb bevacizumab in combination with FOLFOX or oxaliplatin plus capecitabine (CAPEOX) for the treatment of mCRC [32] and it was removed from the UK cancer drug fund in November 2016 [33]. Apart from the differences in reimbursement in the different countries, it needs to be highlighted that the scientific evidence supporting a benefit of bevacizumab in patients with RAS mutant tumors is yet unclear, as was shown by a recent systematic review and network meta-analysis of ten papers reporting six randomized-controlled trials [34]. This analysis found a statistically nonsignificant benefit in progression-free survival and no benefit in overall survival for patients with RAS mutant mCRC receiving bevacizumab plus chemotherapy versus those receiving chemotherapy alone [34]. Prospective randomized, controlled clinical trials enrolling solely RAS mutant patients have not been conducted with bevacizumab. Interestingly, 1.4% (95% CI: 0.7%, 2.4%) of patients with RAS mutant tumors were documented to have receive d anti-EGFR mAbs plus chemotherapy. Patients with RAS mutant or unknown status should not receive anti-EGFR mAbs and it thus seems likely that this number is an error in either documentation or treatment choice. The tumors of 14 patients were documented as having both, a RAS and a BRAF mutation. RAS and BRAF mutations are considered as mutually exclusive although some rare cases have been reported in the literature [35,36,37] and there is evidence that with next-generation sequencing (NGS) more such cases might be identified [38,39]. Clinical implications of such concomitant mutations are still undetermined.
The topic of primary tumor location as a surrogate for biologically different tumor entities was accepted on a broader scale after the publication of the large meta-analysis of six clinical trials conducted by Arnold et al. [14]. From that time onwards, extensive research was conducted to investigate the prognostic potential of primary tumor location on outcomes, although much of this research was retrospective. Although the 2016 ESMO recommendations could not yet take into consideration the primary tumor location as they predated the meta-analysis, the ESMO pan-Asian guidelines have been updated to include treatment recommendations including consideration of left- versus right-sided primary tumor location [40]. The pan-Asian ESMO guidelines recommend that for patients with left-sided RAS wild-type disease, a cytotoxic doublet such as FOLFOX or FOLFIRI plus an anti-EGFR mAb should be the treatment of choice, whereas for those with right-sided RAS wild-type tumors, the cytotoxic tripl et FOLFOXIRI plus bevacizumab should be or a cytotoxic doublet plus an anti-EGFR mAb can be, the treatment of choice [40].
There are some limitations to the present analysis. This study focused on describing the treatment patterns by biomarker status and tumor sidedness. However, there was less focus on the impact on clinical characteristics, such as resectability of the metastases or patient fitness of the choice of treatment. The database does not capture data on hospitalizations or survival. Observed country differences might be partly explained by differences in local treatment guidelines, physician prescribing behaviors, or reimbursement policies, some of which have been outlined above but no systematic analysis of the impact of these factors on treatment choice was conducted. A discussion of the database itself can be found elsewhere [27] .
Conclusion
In clinical practice in the five participating European countries, RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy in all countries except for the UK, where they were more commonly treated with chemotherapy-only in the UK. In RAS wild-type patients, the presence of a BRAF mutation diversified the prescribed treatments compared with BRAF wild-type patients.
Future perspective
In the era of precision medicine, there are many biomarker-driven drugs that are under development, especially within the oncology therapeutic area. As these drugs are gradually being introduced, it is important to understand the impact of biomarker status in the physicians' treatment decision making.
Summary points
Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors such as biomarkers or the recognition of the clinical impact of the biological differences between left- and right-sided primary tumors have impacted mCRC treatment patterns.
The present study used a large international oncology database to investigate the treatment landscape of anti-VEGF monoclonal antibodys (mAbs) and anti-EGFR mAbs, both in combination with chemotherapy or chemotherapy alone in the first line of therapy of mCRC patients actively treated in 2018 in real-world clinical practice in five European countries (France, Germany, Italy, Spain, UK) by tumor sidedness and biomarker status.
Of the 1869 analyzed patients, RAS wild-type patients were mainly treated with anti-EGFR mAbs plus chemotherapy (62.6%; 95% CI: 59.5%, 65.6%) whereas RAS mutant patients were most commonly treated with anti-VEGF mAbs plus chemotherapy (60.5%; 95% CI: 57.2%, 63.7%).
Of RAS wild-type patients with left-sided primary tumors, 71.6% (95% CI: 67.9%, 75.0%) received anti-EGFR mAbs plus chemotherapy, as did 44.7% (95% CI: 39.2%, 50.2%) of RAS wild-type patients with right-sided primary tumors.
For RAS wild-type/BRAF mutant as well as RAS mutant/BRAF wild-type patients, the most common treatment was anti-VEGF mAbs plus chemotherapy with 44.4% (95% CI: 34.9%, 54.3%) and 61.1% (95% CI: 57.8%, 64.4%), respectively.
There were differences between countries regarding the adopted treatment strategies with the UK generally prescribing less frequently anti-VEGF mAb plus chemotherapy compared with the other countries.
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0976
Author contributions
All authors were involved in, and contributed to, the drafting and critical review of this manuscript.
Financial & competing interests disclosure
This research project was funded by Amgen Ltd. G Kafatos, D Neasham and KA Lowe are compensated employees of Amgen, Inc. and stockholders of Amgen, Inc. P Burdon was an employee of Amgen (Europe) GmbH at the time the research was conducted and owns shares in Amgen Inc.; he is currently an employee of MSD International GmbH. V Banks was a contract worker for Amgen, Ltd. at the time the research was conducted. C Anger and F Manuguid are compensated employees of IQVIA Ltd. J Trojan received consulting fees from Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Onkowissen TV, Pierre Fabre, PCI Biotech, Roche and Servier. He is serving on the speaker's bureau of Amgen, Bioprojet, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Roche, Servier and streammedup! and he received research grants from Roche and Ipsen. 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.
The authors would like to thank and acknowledge M Hemetsberger of hemetsberger medical services, Vienna, Austria, for medical writing support, funded by Amgen.
Ethical conduct of research
The Oncology Dynamics database (IQVIA Ltd.) used in this study is fully anonymized and complies with relevant regulations for protecting patient privacy.
Data sharing statement
The data that support the findings of this study are available from IQVIA Ltd, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA Ltd.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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History
Received 23 September 2020
Accepted 11 December 2020
Published online 19 January 2021
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© 2021 Amgen Ltd.
Keywords
BRAFEGFRmCRCprimary tumor locationRAStumor sidednessVEGF
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0976
Author contributions
All authors were involved in, and contributed to, the drafting and critical review of this manuscript.
Financial & competing interests disclosure
This research project was funded by Amgen Ltd. G Kafatos, D Neasham and KA Lowe are compensated employees of Amgen, Inc. and stockholders of Amgen, Inc. P Burdon was an employee of Amgen (Europe) GmbH at the time the research was conducted and owns shares in Amgen Inc.; he is currently an employee of MSD International GmbH. V Banks was a contract worker for Amgen, Ltd. at the time the research was conducted. C Anger and F Manuguid are compensated employees of IQVIA Ltd. J Trojan received consulting fees from Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Onkowissen TV, Pierre Fabre, PCI Biotech, Roche and Servier. He is serving on the speaker's bureau of Amgen, Bioprojet, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Roche, Servier and streammedup! and he received research grants from Roche and Ipsen. 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.
The authors would like to thank and acknowledge M Hemetsberger of hemetsberger medical services, Vienna, Austria, for medical writing support, funded by Amgen.
Ethical conduct of research
The Oncology Dynamics database (IQVIA Ltd.) used in this study is fully anonymized and complies with relevant regulations for protecting patient privacy.
Data sharing statement
The data that support the findings of this study are available from IQVIA Ltd, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA Ltd.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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