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A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial

Published:November 25, 2021DOI:https://doi.org/10.1016/j.annonc.2021.11.010

      Highlights

      • A randomised trial comparing bevacizumab plus osimertinib versus osimertinib alone in EGFR-mutant NSCLC with T790M mutations.
      • The primary endpoint was investigator-assessed PFS.
      • No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone.
      • TRAEs of grade ≥3 were more common in patients on combination than osimertinib alone.

      Background

      While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance.

      Patients and methods

      BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs).

      Results

      Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively.

      Conclusions

      No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

      Key words

      Introduction

      The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionised the management of patients with advanced non-small-cell lung cancer (NSCLC) harbouring somatic sensitising EGFR mutations. While the first- and second-generation EGFR TKIs are effective in the first-line treatment of advanced NSCLC harbouring EGFR mutations,
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      Osimertinib, a third-generation EGFR TKI, is highly active in tumours harbouring common sensitising EGFR mutations and a T790M mutation. In AURA3, osimertinib was associated with a prolonged progression-free survival (PFS) when compared to platinum-doublet chemotherapy in patients with advanced NSCLC with common sensitising EGFR mutations and an acquired T790M mutation.
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      Vascular endothelial growth factor (VEGF) plays a critical role in tumour angiogenesis and has been shown to interact with EGFR-signalling pathways. Increased VEGF levels in EGFR-mutant NSCLC were associated with resistance to EGFR inhibition.
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      The objective of this randomised phase II study was to assess the efficacy of the combination of osimertinib and bevacizumab versus osimertinib in terms of PFS, in patients with advanced EGFR-mutant NSCLC with an acquired T790M mutation, after failure of previous EGFR TKI treatment.

      Methods

       Patients

      The main eligibility criteria were as follows: pathologically confirmed non-squamous NSCLC harbouring a common sensitising EGFR mutation (exon 19 deletion or exon 21 L858R), stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to American Joint Committee on Cancer 8th edition, confirmed T790M mutation detected in tumour tissue or circulating tumour DNA (ctDNA) after disease progression upon EGFR TKI therapy as the most recent treatment regimen, previous exposure to a maximum of one line of platinum-based chemotherapy, World Health Organization (WHO) performance status 0-2, presence of measurable or evaluable disease and adequate organ function. Main exclusion criteria were: presence of mixed-type NSCLC with predominantly squamous cell, or any small cell lung cancer components, symptomatic or active central nervous system (CNS) metastases, history of interstitial lung disease and a recent history of significant haemoptysis.

       Trial design and treatment

      Patients were randomly assigned (1 : 1) to receive osimertinib, 80 mg once daily, plus intravenous bevacizumab, 15 mg/kg on day 1 of every 3-week cycle, or osimertinib 80 mg once daily alone. Study treatment was administered until disease progression, lack of tolerability to osimertinib and/or bevacizumab, or patient refusal. Treatment beyond progression was permitted for patients who were still deriving clinical benefit.

       Randomisation and masking

      Block-stratified randomisation balanced by institution has been carried out centrally, stratified by ethnicity (Asian versus non-Asian) and material used for T790M testing (tumour versus ctDNA). Patients and investigators were not masked to treatment assignment.

       Endpoints

      The primary endpoint was PFS, defined as the time from the date of randomisation until documented progression (assessed by RECIST v1.1) or death. Tumour assessments were conducted by computed tomography scans of the thorax and upper abdomen at baseline and every 9 weeks from randomisation until progression of disease. Secondary endpoints were objective response rate (ORR), defined as the percentage of patients reaching a complete or partial response (CR or PR); disease control rate (DCR), defined as CR or PR or stable disease (SD) confirmed at subsequent radiological assessment; overall survival (OS), defined as the time from date of randomisation until death from any cause and safety assessed according to the Common Terminology Criteria for Adverse Events (AEs) version 4.0. Other exploratory endpoints were time to treatment failure (TTF), defined as time from the date of randomisation until discontinuation or failure of protocol treatment for any reason; drug-specific time to drug discontinuation or failure of protocol treatment considered for each drug separately; duration of response (DOR), defined as the time from objective response (CR or PR) to disease progression or death and duration of clinical benefit (DOCB), defined as the time from clinical benefit (CR or PR or SD) to disease progression or death.

       Statistical analysis

      The aim of the study was to detect a hazard ratio (HR) of 0.64, that is, a 36% improvement in PFS hazard rate under the combination of osimertinib and bevacizumab. This corresponded to an increase in the median PFS from 11 months under osimertinib to 17.2 months under the combination. A total of 126 PFS events and 154 randomised patients were required to provide 80% power at 5% one-sided significance level, with an interim analysis planned at 50% information time.
      The baseline characteristics were compared between the two treatment arms via Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. Time-to-event endpoints were estimated by the Kaplan–Meier method and comparisons between the two treatment arms were based on log-rank tests and Cox model Wald tests. For the primary efficacy analysis, PFS was compared between the two arms with the log-rank test, stratified by ethnicity and material used for T790M testing. In the pre-planned interim efficacy analysis carried out after 76 of 126 events had occurred, the corresponding O' Brien-Fleming boundary was not crossed, and the study continued to final analysis.
      In addition, the treatment effect on PFS was also explored within subgroups defined by the stratification factors and other variables of clinical interest. Cox proportional hazards models were fitted in order to assess the effect of treatment on PFS, alone or adjusting for the stratification factors and variables of clinical interest [sex, age, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage and sensitising EGFR mutation]. Treatment interactions, if significant at 10% in unadjusted analyses, were also included in the multivariable model. The backward elimination method, with removal criterion P ≥ 10%, was applied for the selection of statistically significant predictors. OS was analysed analogously to PFS. ORR and DCR were compared between the two treatment groups with Fisher's exact test and Cochran–Mantel–Haenszel test, accounting for the stratification factors. The efficacy analysis was carried out in the intention-to-treat (ITT) population, which consisted of all randomised patients, including patients who were randomised but did not receive any trial treatment.
      An interim safety evaluation was conducted after the randomisation of the first 10 patients to the combination and repeated every 6 months.
      All statistical results were produced using SAS version 9.4 and all reported P values are two-sided.
      The trial was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by the institutional review board at each participating centre. All the patients provided written informed consent. The study was overseen by the European Thoracic Oncology Platform (ETOP) independent data monitoring committee (IDMC). This trial is registered with ClinicalTrials.gov, number NCT03133546, and with the European Medicines Agency's European Clinical Trials database, number 2016-002029-12.

      Results

       Patients

      A total of 155 patients from 22 study sites in six countries were randomised from May 2017 to February 2019 (combination: 78; osimertinib: 77). Two patients randomised in the combination arm did not start the assigned therapy and were included in the ITT population. The median age was 67 years and the majority were female (62%), non-Asian (59%) and never smokers (60%), with ECOG performance status of 1 in 64% at randomisation. In total, 70% of the patients had stage IVa disease. EGFR exon 19 deletion was detected in 109 patients (70%). At baseline, 14% of the patients had brain metastasis, 14% had liver metastasis and 10% had pleural effusion and ascites. Platinum-based chemotherapy was administered as previous treatment before randomisation in 15.5% of the patients. Patient baseline demographic and disease characteristics were well balanced between the two treatment groups (Table 1).
      Table 1Baseline patient characteristics
      CharacteristicOsimertinib/bevacizumab (n = 78)Osimertinib (n = 77)All patients (N = 155)P value
      Age at randomisation, years0.76
      Mann–Whitney U test.
       Median (range)68 (34-85)66 (41-83)67 (34-85)
      Sex, n (%)0.74
      Fisher's exact test.
       Male31 (39.7)28 (36.4)59 (38.1)
       Female47 (60.3)49 (63.6)96 (61.9)
      Ethnicity, n (%)>0.99
      Fisher's exact test.
       Asian32 (41.0)31 (40.3)63 (40.6)
       Non-Asian46 (59.0)46 (59.7)92 (59.4)
      ECOG performance status, n (%)0.60
      Fisher's exact test.
      ,
      Categories ‘1’ and ‘2’ were combined.
       022 (28.2)25 (32.5)47 (30.3)
       151 (65.4)48 (62.3)99 (63.9)
       25 (6.4)4 (5.2)9 (5.8)
      Smoking status, n (%)0.41
      Fisher's exact test.
      ,
      Categories ‘Current’ and ‘Former’ were combined.
       Current (still smokes cigarettes)4 (5.1)1 (1.3)5 (3.2)
       Former (smoked ≥100 cigarettes in the past during the whole life)30 (38.5)27 (35.1)57 (36.8)
       Never smoker (smoked 0-99 cigarettes during the whole life)44 (56.4)49 (63.6)93 (60.0)
      Stage
      According to the American Joint Committee on Cancer 8th TNM classification.
      , n (%)
      0.50
      Fisher's exact test.
      ,
      Excluding ‘Missing’ category.
       IIIB/C2 (2.6)2 (1.3)
       IVA/B76 (97.4)76 (98.7)152 (98.1)
       Missing1 (1.3)1 (0.6)
      Use of prior platinum-based chemotherapy, n (%)11 (14.1)13 (16.9)24 (15.5)
      Prior EGFR TKI, n (%)
       Erlotinib/gefitinib57 (73.1)57 (74.0)114 (73.5)
       Afatinib/dacomitinib21 (26.9)19 (24.7)40 (25.8)
       Other
      Category ‘Other’ includes gefitinib and olaparib.
      1 (1.3)1 (0.6)
      EGFR mutation type, n (%)0.30
      Fisher's exact test.
       Exon 19 deletion58 (74.4)51 (66.2)109 (70.3)
       Exon 21 L858R20 (25.6)26 (33.8)46 (29.7)
      T790M testing material, n (%)>0.99
      Fisher's exact test.
       ctDNA38 (48.7)37 (48.1)75 (48.4)
       Tumour40 (51.3)40 (51.9)80 (51.6)
      Brain metastasis, n (%)0.35
      Fisher's exact test.
       Yes13 (16.7)8 (10.4)21 (13.5)
       No65 (83.3)69 (89.6)134 (86.5)
      Liver metastasis, n (%)0.25
      Fisher's exact test.
       Yes14 (18.0)8 (10.4)22 (14.2)
       No64 (82.0)69 (89.6)133 (85.8)
      Pleural effusion and ascites, n (%)0.61
      Fisher's exact test.
       Yes7 (9.0)9 (11.7)16 (10.3)
       No71 (91.0)68 (88.3)139 (89.7)
      ctDNA, circulating tumour DNA; ECOG, Eastern Cooperative Oncology Group, EGFR, epidermal growth factor receptor, TKI, tyrosine kinase inhibitor.
      a Mann–Whitney U test.
      b Fisher's exact test.
      c Categories ‘1’ and ‘2’ were combined.
      d Categories ‘Current’ and ‘Former’ were combined.
      e According to the American Joint Committee on Cancer 8th TNM classification.
      f Excluding ‘Missing’ category.
      g Category ‘Other’ includes gefitinib and olaparib.

       Follow-up

      At the time of data cut-off (22 February 2021), 54 (34.8%) of the total 155 randomised patients were still on follow-up (27 in each arm), while 12 patients (combination: 5; osimertinib: 7) withdrew consent or were lost to follow-up without an observed event (Figure 1). The median follow-up time is 33.8 months [interquartile range (IQR): 26.5 – 37.6 months] (combination: 32.6 months; osimertinib: 34.5 months).

       Efficacy

      A total of 129 (83.2%) PFS events were reported in the ITT population (combination: 64; osimertinib: 65). The 1-year PFS estimate, along with the 95% confidence interval (CI), was 60.3% (48.4% to 70.3%) in the combination and 50.8% (39.1% to 61.5%) in the osimertinib arms. There was no significant difference in median PFS between the combination (15.4 months; 95% CI 9.2-18.0 months) and the osimertinib arms (12.3 months; 95% CI 6.2-17.2 months) [log-rank P = 0.71; HR (95% CI): 0.94 (0.66-1.33)] (Figure 2A). Inference remained the same when accounting for the two stratification factors: ethnicity and material used for T790M testing [stratified long-rank P = 0.83; HR (95% CI): 0.96 (0.68-1.37)].
      Figure thumbnail gr2
      Figure 2(A) Progression-free survival. (B) Forest plot for progression-free survival within subgroups. (C) Progression-free survival by treatment arm and smoking status.
      Subgroup analysis for PFS showed a significant interaction between treatment and smoking status (interaction P = 0.024). Specifically, current and former smokers had a significantly longer PFS under combination treatment [HR: 0.57 (0.33-0.98); Wald test P = 0.043], while the PFS difference was not significant in never smokers (HR: 1.29 (0.82-2.02); Wald test P = 0.28) (Figure 2B and C). The interaction of treatment with smoking status remained significant when adjusting for all other factors in the multivariable PFS analysis, (interaction P = 0.0052; Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      A total of 89 (57.4%) deaths were recorded (combination: 46; osimertinib: 43). The median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm, with no significant difference in OS observed [log-rank P = 0.89; HR: 1.03 (0.68-1.56)] (Figure 3A). Inference remained the same when accounting for the two stratification factors [stratified long-rank P = 0.91; HR: 1.03 (0.67-1.56)]. For OS, in unadjusted analysis, the interaction between treatment and smoking was consistent with the one found for PFS, albeit not reaching significance at the 5% level (interaction P = 0.068). For current and former smokers, the treatment effect on OS was similar to the observation with PFS, with a numerically longer OS in the combination arm, however not reaching statistical significance [HR: 0.64 (0.33-1.22); Wald test P = 0.18]. For never smokers, again there was no significant difference in OS between the two treatment arms (Figure 3B and C). In the multivariable OS analysis, the interaction between treatment and smoking was significant (interaction P = 0.029; Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      Figure thumbnail gr3
      Figure 3(A) Overall survival. (B) Forest plot for overall survival within subgroups. (C) Overall survival by treatment arm and smoking status.
      aUnstratified HRs (95% CI) for Osi/beva vs. Osi.
      bFor smoking history, HR is derived from the unstratified Cox model for treatment, including the interaction of treatment with smoking history.
      cThere are also 2 patients in Beva+Osi arm with stage III (1 with IIIb and 1 with IIIc), both patients died at 20.5 and at 32.1 months after randomization, respectively. Additionally, there is 1 patient in Osi arm with missing information about tumor stage, who is censored for OS at 38.6 months post randomization.
      The ORR was 55% (95% CI 43% to 66%) in both treatment arms and the DCR in the combination and osimertinib arms was 90% (95% CI 81% to 95%) and 82% (95% CI 71% to 90%) (Fisher's exact P = 0.17), respectively (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2021.11.010). In Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2021.11.010, the best percentage change in the targeted tumour size from baseline is presented by best overall response via waterfall plots, separately for each arm. The median DOR in the combination and osimertinib arm was 14.5 months and 16.6 months, respectively (log-rank P = 0.36) (Supplementary Figure S2, available at https://doi.org/10.1016/j.annonc.2021.11.010). Concerning clinical benefit, the median DOCB was 14.5 months in the combination and 12.5 in the osimertinib arm (log-rank P = 0.76) (Supplementary Figure S3, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      Among patients with documented progression, 28 out of 54 (51.9%) in the combination arm and 28 out of 56 (50.0%) in the osimertinib arm experienced metastasis in at least one site. The most common sites for new metastatic lesions in both arms were the lungs [combination: 19 (52.8%); osimertinib: 19 (44.2%)], followed by bones [combination: 3 (8.3%); osimertinib: 8 (18.6%)] (Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2021.11.010).

       Treatment administration

      Based on the 76 (97.4%) patients who started treatment, in the combination arm, the median number of osimertinib and bevacizumab cycles was 20 (range 1-54 cycles) and 11.5 cycles (range 1-48 cycles), respectively, whereas 18 (range 1-57) cycles were administered in the osimertinib arm (Supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      Median TTF was significantly shorter in the combination than in the osimertinib arm, 8.2 months (95% CI 5.5-9.1 months) versus 10.8 months (95% CI 6.2-14.5 months; P = 0.0074), respectively (Supplementary Table S6, Supplementary Figure S4, available at https://doi.org/10.1016/j.annonc.2021.11.010). Separately, in the combination arm, the median TTF (essentially, time to drug discontinuation or treatment failure) for bevacizumab and osimertinib was 8.2 months (95% CI 5.5-9.1 months) and 12.4 months (95% CI 8.1-16.4 months), respectively. A comparison of TTF for osimertinib revealed no significant difference between the two treatment arms (P = 0.96) (Supplementary Table S6, Supplementary Figure S4, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      The most common reasons for treatment failure are summarised in Supplementary Table S7, available at https://doi.org/10.1016/j.annonc.2021.11.010. In the combination arm, the major reasons for bevacizumab discontinuation were toxicity (46%) and disease progression (39%) while for osimertinib, disease progression (70%), toxicity (11%) and patient decision (7%) were reported. For osimertinib monotherapy, the main reasons were progression (77%), death (10%) and patient decision (6%) (Supplementary Table S7, available at https://doi.org/10.1016/j.annonc.2021.11.010).
      Treatment beyond disease progression continued in 24 (44%) of the 54 patients with documented progression in the combination arm and in 28 (50%) of the 56 patients in the osimertinib-alone arm. In the combination arm, the median number of bevacizumab and osimertinib cycles administered after disease progression was 4 (range 1-18 cycles) and 3.5 cycles (range 1-32 cycles), respectively. In the osimertinib arm, the median number of osimertinib cycles received after disease progression was 3.5 (range 1-23 cycles) (Supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2021.11.010). Of the patients who had progressed (combination: 54; osimertinib: 56, as mentioned above), 27 (50%) in the combination and 28 (50%) in the osimertinib arm received further lines of treatment.
      The most common further-line treatment was chemotherapy, administered in 23 and 21 (85% and 75% among 27 and 28 that received further lines of treatment) patients in the combination and osimertinib arms, respectively (Supplementary Table S8, available at https://doi.org/10.1016/j.annonc.2021.11.010).

       Safety

      In the safety cohort, 152 (99%) of 153 patients experienced at least one AE of any grade (76 patients in each arm). The percentage of patients who experienced any grade TRAEs in the combination arm and osimertinib arm was 96% and 87%, respectively, while grade ≥3 TRAEs were reported in 47% and 18% of patients, respectively. TRAEs leading to treatment discontinuation were reported in 25% of patients in the combination and in 4% in the osimertinib-alone arm (Table 2). TRAEs leading to dose interruption or dose reduction were reported, respectively, in 30% and 2.6% of patients in the combination, as well as in 9% and 2.6% in the osimertinib arm. TRAEs leading to death were reported only in three (4%) patients in the osimertinib, while no such event was reported in the combination arm (Table 2).
      Table 2Safety overview and adverse events
      Safety overviewOsimertinib/bevacizumab n (%)Osimertinib n (%)
      Safety cohort7677
      Patients experienced:
       Any AE76 (100.0)76 (98.7)
       Treatment-related AEs73 (96.1)67 (87.0)
       Treatment-related AEs grade 3-536 (47.4)14 (18.2)
       Treatment-related AEs leading to dose interruption
      For 9/23 patients in osimertinib/bevacizumab and 2/7 patients in osimertinib, the dose interruption was followed by permanent treatment discontinuation. In osimertinib/bevacizumab: 7 patients had a dose interruption for both drugs, 11 had bevacizumab dose interruption and 5 had osimertinib dose interruption.
      23 (30.3)7 (9.1)
       Treatment-related AEs leading to dose reduction
      The dose reduction did not lead to permanent treatment discontinuation, for any of these patients.
      2 (2.6)2 (2.6)
       Treatment-related AEs leading to treatment discontinuation
      In osimertinib/bevacizumab: 16/19 patients continued with osimertinib alone after bevacizumab discontinuation, while only 3/19 stopped both drugs at the same time due to treatment-related adverse events. Regarding the 16 patients who continued with osimertinib, 5 patients were still on treatment at the database cut-off, while 11 patients stopped osimertinib treatment (seven due to PD, and one each due to death, toxicity, investigator decision and other reason).
      19 (25.0)3 (3.9)
       Treatment-related AEs leading to death3 (3.9)
      Treatment-related AEs occurring in ≥ 10% of patients:
       Diarrhoea33 (43.4)31 (40.3)
       Rash acneiform27 (35.5)19 (24.7)
       Fatigue21 (27.6)18 (23.4)
       Proteinuria
      Statistically significant risk differences at 5% between the two treatment arms (i.e., differences in the % of patients experiencing a specific adverse event) are indicated in bold.
      34 (44.7)1 (1.3)
       Hypertension
      Statistically significant risk differences at 5% between the two treatment arms (i.e., differences in the % of patients experiencing a specific adverse event) are indicated in bold.
      30 (39.5)1 (1.3)
       Anorexia
      Statistically significant risk differences at 5% between the two treatment arms (i.e., differences in the % of patients experiencing a specific adverse event) are indicated in bold.
      20 (26.3)8 (10.4)
       Dry skin15 (19.7)13 (16.9)
       Oral mucositis
      Statistically significant risk differences at 5% between the two treatment arms (i.e., differences in the % of patients experiencing a specific adverse event) are indicated in bold.
      18 (23.7)7 (9.1)
       Paronychia12 (15.8)10 (13.0)
       Platelet count decreased14 (18.4)8 (10.4)
       Pruritus6 (7.9)13 (16.9)
       Lipase increased9 (11.8)7 (9.1)
       Nausea10 (13.2)6 (7.8)
      Note: Treatment-related are considered the events that are possible/probable/definite related to bevacizumab and/or osimertinib.
      AEs, adverse events.
      a For 9/23 patients in osimertinib/bevacizumab and 2/7 patients in osimertinib, the dose interruption was followed by permanent treatment discontinuation. In osimertinib/bevacizumab: 7 patients had a dose interruption for both drugs, 11 had bevacizumab dose interruption and 5 had osimertinib dose interruption.
      b The dose reduction did not lead to permanent treatment discontinuation, for any of these patients.
      c In osimertinib/bevacizumab: 16/19 patients continued with osimertinib alone after bevacizumab discontinuation, while only 3/19 stopped both drugs at the same time due to treatment-related adverse events. Regarding the 16 patients who continued with osimertinib, 5 patients were still on treatment at the database cut-off, while 11 patients stopped osimertinib treatment (seven due to PD, and one each due to death, toxicity, investigator decision and other reason).
      d Statistically significant risk differences at 5% between the two treatment arms (i.e., differences in the % of patients experiencing a specific adverse event) are indicated in bold.
      The most frequent TRAEs in all patients were diarrhoea and acneiform rash, reported in 42% and 30% of patients overall, respectively. Proteinuria, hypertension, anorexia and oral mucositis were significantly more frequent in patients treated with the combination than with osimertinib alone (Table 2, Supplementary Figure S5, available at https://doi.org/10.1016/j.annonc.2021.11.010).

      Discussion

      In the BOOSTER trial, the addition of bevacizumab to osimertinib after failure of previous EGFR TKI treatment in patients with EGFR-mutant NSCLC and acquired T790M mutations was not associated with an improvement in PFS, OS or ORR. Two other studies have examined the role of second-line anti-angiogenic therapy plus osimertinib in this patient population. In the first study, a similar but smaller randomised phase II study (n = 81) conducted by the West Japan Oncology Group (WJOG) 8715L, the median PFS for the combination and for osimertinib was 9.4 months versus 13.5 months, respectively (HR 1.44; 80% CI 1.00-2.08; P = 0.20).
      • Akamatsu H.
      • Toi Y.
      • Hayashi H.
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
      In contrast to the WJOG study, the PFS in the BOOSTER study was numerically not worse for the combination. In a phase I study of osimertinib and ramucirumab, the PFS and ORR were 11 months and 76%, respectively.
      • Yu H.A.
      • Paz-Ares L.G.
      • Yang J.C.
      • et al.
      Phase I study of the efficacy and safety of ramucirumab in combination with osimertinib in advanced T790M-positive EGFR-mutant non-small cell lung cancer.
      Patients in the combination arm of BOOSTER encountered more treatment-related toxicities than those in the osimertinib-only arm (grade ≥3 TRAEs 47% versus 18%) and also TRAEs leading to treatment discontinuation were more frequent in the combination arm (25% versus 4%). Although the frequency of diarrhoea and acneiform rash was similar in both treatment groups, unsurprisingly, proteinuria and hypertension, side effects associated with bevacizumab, were significantly more frequent in the combination arm with grade ≥3 proteinuria and hypertension reported in 4% and 24%, respectively. This observation was also reported in the WJOG study, where the most frequent grade ≥3 AEs were proteinuria (23%) and hypertension (20%).
      • Akamatsu H.
      • Toi Y.
      • Hayashi H.
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
      In first-line studies of erlotinib with and without anti-angiogenic therapy, grade ≥3 proteinuria and hypertension were also more common in the combination arm, with a frequency of 3%-12% and 18.5%-60%, respectively.
      • Nakagawa K.
      • Garon E.B.
      • Seto T.
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Saito H.
      • Fukuhara T.
      • Furuya N.
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
      • Seto T.
      • Kato T.
      • Nishio M.
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
      • Zhou Q.
      • Wu Y.L.
      • Cheng Y.
      • et al.
      1480O - CTONG 1509: phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      ,
      • Stinchcombe T.E.
      • Jänne P.A.
      • Wang X.
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial.
      Although patients in the combination arm had more grade 3/4 TRAEs, the discontinuation of bevacizumab due to toxicity in 35 patients did not seem to adversely affect PFS, noting the caveat of the purely descriptive retrospective nature of this analysis in a restricted number of patients.
      In the combination arm, the TTF was significantly shorter, reflecting the combined impact of TRAEs and disease progression. Early treatment discontinuation, 51 patients in the first 12 months, was mainly due to toxicity (24 patients) and progression (18 patients). TTF was also noted to be numerically shorter in the combination arm in the WJOG 8715L study.
      • Akamatsu H.
      • Toi Y.
      • Hayashi H.
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
      The incidence of brain metastases in this patient population with pre-treated EGFR-mutant NSCLC, was 14%. In other osimertinib studies in the second-line setting, the incidence of CNS metastases was reported to be between 24% and 41%.
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      ,
      • Akamatsu H.
      • Toi Y.
      • Hayashi H.
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
      ,
      • Goss G.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.
      The fact that brain MRI was not mandated at screening before randomisation might have resulted in an underestimation of the incidence of CNS metastasis in this study population.
      A significant interaction of smoking history with treatment was observed, with smokers and former smokers showing a statistically significant improvement in PFS under combination treatment, while non-smokers did not show improvement. The interaction of smoking history with treatment was also observed for OS (multivariable model), with the treatment effect on OS showing the same trend although not reaching statistical significance in the subgroup of smokers. This can be partially due to the smaller number of deaths observed so far as compared to the number of PFS events. In WJOG 8715L, the PFS in smokers or former smokers was not significantly different between the two arms, with an HR of 1.06 (95% CI 0.5-2.5). In studies of first-line EGFR TKI with or without anti-angiogenic therapy, the PFS benefit of combination therapy was seen in both smokers or former smokers and never smokers.
      Although the current study demonstrated that smokers and former smokers benefitted from the combination treatment, given the post-hoc nature of our analysis, these results are hypothesis generating and should be interpreted with caution.
      The rationale supporting a PFS benefit under the combination in current or former smokers remains unclear, but a possible explanation is that bevacizumab may be more effective in tumours with TP53 mutations. It is well recognised that tobacco exposure produces a heavy burden of genomic mutations in lung cancer, including TP53 mutations.
      • Gibbons D.L.
      • Byers L.A.
      • Kurie J.M.
      Smoking, p53 mutation, and lung cancer.
      TP53 mutations are associated with increased VEGF expression in multiple solid tumours, including NSCLC,
      • Li A.M.
      • Boichard A.
      • Kurzrock R.
      Mutated TP53 is a marker of increased VEGF expression: analysis of 7,525 pan-cancer tissues.
      ,
      • Schwaederle M.
      • Lazar V.
      • Validire P.
      • et al.
      VEGF-a expression correlates with TP53 mutations in non-small cell lung cancer: implications for antiangiogenesis therapy.
      and tumours harbouring TP53 mutations are associated with improved outcomes with VEGF or VEGF receptor inhibitors.
      • Schwaederle M.
      • Lazar V.
      • Validire P.
      • et al.
      VEGF-a expression correlates with TP53 mutations in non-small cell lung cancer: implications for antiangiogenesis therapy.
      • Said R.
      • Hong D.S.
      • Warneke C.L.
      • et al.
      P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy.
      • Wheler J.J.
      • Janku F.
      • Naing A.
      • et al.
      TP53 alterations correlate with response to VEGF/VEGFR inhibitors: implications for targeted therapeutics.
      Furthermore, subgroup analysis from the RELAY study reported TP53 mutations were associated with improved outcomes in patients with EGFR-mutant NSCLC treated with erlotinib and ramucirumab compared with erlotinib alone, supporting the concept of improved efficacy with anti-angiogenic therapy in tumours harbouring TP53 mutations.
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY subgroup analyses by EGFR Ex19del and Ex21L858R mutations for ramucirumab plus erlotinib in metastatic non-small cell lung cancer.
      However, our explanation remains speculative and an assessment of TP53 mutation status would be required to support this hypothesis. Translational studies of tumour tissue and plasma samples with next-generation sequencing are planned and may inform on the molecular basis for the benefit seen with combination treatment in smokers. In addition, whilst the mechanisms of acquired resistance to single-agent osimertinib have been well described,
      • Leonetti A.
      • Sharma S.
      • Minari R.
      • Perego P.
      • Giovannetti E.
      • Tiseo M.
      Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer.
      ,
      • Papadimitrakopoulou V.A.
      • Wu Y.L.
      • Han J.Y.
      • et al.
      Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study.
      genomic profiling of prospectively collected tumour and plasma samples would provide a unique opportunity to ascertain the molecular patterns of resistance in patients treated with osimertinib and bevacizumab.
      The results from this current study as well as from the WJOG8715L study do not support further efforts to pursue the combination of osimertinib and bevacizumab in patients with EGFR-mutant NSCLC harbouring acquired T790M mutations. Furthermore, based on the OS and PFS benefits reported in the FLAURA study, the use of osimertinib has shifted from second-line post EGFR T790M-acquired resistance to first-line in the treatment-naive setting.
      • Ramalingam S.S.
      • Vansteenkiste J.
      • Planchard D.
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      ,
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      Given the pivot to first-line, the addition of an anti-angiogenic therapy to osimertinib in patients with untreated EGFR-mutant advanced NSCLC has also been studied. In a single arm phase I/II study of bevacizumab and osimertinib, the PFS was 19 months,
      • Yu H.A.
      • Schoenfeld A.J.
      • Makhnin A.
      • et al.
      Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
      similar to the PFS reported in the FLAURA study. More recently in a randomised phase II study (WJOG9717L), the addition of bevacizumab to first-line osimertinib did not improve PFS (HR 0.86; 95% CI 0.70-1.06; P = 0.21).
      • Kenmotsu H.
      • Wakuda K.
      • Mori K.
      • et al.
      LBA44 Primary results of a randomized phase II study of osimertinib plus bevacizumab versus osimertinib monotherapy for untreated patients with non-squamous non-small cell lung cancer harboring EGFR mutations: WJOG9717L study.
      Taken together, the results to date suggest that the combination of bevacizumab and osimertinib is not associated with increased efficacy over osimertinib monotherapy in any clinical setting.
      Results from ongoing studies in the EGFR TKI-naive patient population receiving osimertinib with ramucirumab (NCT03909334) or with bevacizumab (NCT04181060, JapicCTI-184146) may further elucidate the role of this combination.

      Conclusions

      Single-agent osimertinib remains the standard treatment in pretreated patients with EGFR-mutant NSCLC with acquired EGFR TKI resistance harbouring a T790M mutation.

      Acknowledgements

      We thank the 155 patients who participated in the trial and their families and caregivers, the BOOSTER investigators at the 23 clinical sites and their teams, Cancer Trials Ireland, the Spanish Lung Cancer Group (SLCG), the Swiss Group for Clinical Cancer Research (SAKK), the Central laboratory in Lausanne, the European Thoracic Oncology Platform Independent Data Monitoring Committee (IDMC), the coworkers at the ETOP Coordinating Office and the ETOP Statistical Office and AstraZeneca and F. Hoffmann-La Roche for supporting the trial.

      Funding

      The BOOSTER trial was sponsored and coordinated by ETOP , in collaboration with Cancer Trials Ireland , the SLCG and the SAKK . BOOSTER received financial support for trial conduct from AstraZeneca , who also provided osimertinib for this study [grant number ESR-15-11666 ]. Bevacizumab was provided by F. Hoffmann-La Roche [grant number MO39447 ].

      Disclosure

      RAS reports advisory role for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda and Yuhan and grants from AstraZeneca, Boehringer Ingelheim, outside the submitted work. UD reports honorarium as Member of the Tumor Agnostic Evidence Generation working Group of Roche, outside the submitted work. BCC reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Abbvie, Medpacto, GI Innovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp, personal fees from Novartis, AstraZeneca, Champions Oncology, Janssen, Yuhan, Ono, MSD, Medpacto, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp, Boehringer Ingelheim, Roche, BMS, Pfizer, Takeda, KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Joseah BIO, Gencurix Inc., and other from Interpark Bio Convergence Corp, KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Gencurix Inc, DAAN, TheraCanVac Inc., outside the submitted work. EN reports grants, personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Bristol-Myers-Squibb, personal fees and non-financial support from Merck Sharp Dohme, grants and personal fees from Merck Serono, personal fees from Takeda, grants, personal fees and non-financial support from Pfizer, personal fees from Lilly, personal fees from Bayer, personal fees from Amgen, personal fees from Boehringer Ingelheim, outside the submitted work. EC reports personal fees from AstraZeneca, Amgen, BMS, MSD and Roche, outside the submitted work. JdC reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme and Hoffmann-La Roche, personal fees from Bayer, Boehringer Ingelheim, Glaxosmithkline, Jansen-Cilag, Lilly, Novartis, Pfizer and Takeda, outside the submitted work. MAS reports advisory role for Roche and Boehringer Ingelheim, speaker role for Pierre Fabre and travel grants from Roche and PharmaMar, outside the submitted work. RB reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Roche, AstraZeneca, BMS, AMGEN and MSD, participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, BMS and Roche. LC reports advisory role for AstraZeneca, Roche and Daichi, outside the submitted work. MPP reports grants, personal fees and non-financial support from AstraZeneca, BMS and ROCHE, personal fees from MSD and TAKEDA, outside the submitted work. RGC reports Advisory Board, Consultancy or Speaker honoraria from MSD, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen and Sanofi. SC reports non-financial support from Pfizer, Roche, MSD and BMS, outside the submitted work. MF reports grants from Astra Zeneca and BMS and other support from AstraZeneca, BMS, Boehringer Ingelheim, Janssen, MSD, Pfizer, Roche and Takeda, outside the submitted work. JGS reports grants for consulting or advisory role from Roche, Boehringer Ingelheim, EUSA Pharma, research funding from Roche and travel, and accommodation expenses from Roche, BMS, Merck Sharp & Dohme and Pfizer, outside the submitted work. MD reports personal fees from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Pfizer, Roche and Takeda, outside the submitted work. MM reports grants and personal fees from Bristol-Myers Squibb, Pierre Fabre, personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, F. Hoffman – La Roche, Merck Sharp and Dohme, and personal fees from Kyowa Kirin, outside the submitted work. JMST reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche, Takeda and MSD, outside the submitted work. CB reports consulting or advisory role for AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag and Boehringer Ingelheim, as well as travel support from AstraZeneca and Takeda, outside the submitted work. MP reports grants from AstraZeneca, BMS, Boehringer Ingelheim, Roche, Takeda, Vifor, and personal fees from Abbvie, AstraZeneca, BMS, Boehringer Ingelheim, Eisei, MSD, Novartis, Pfizer, Roche, Takeda, Merck and Janssen, outside the submitted work. RAS reports consultant or advisory role for AstraZeneca, BMS, Janssen, MSD, Pfizer, Regeneron, Roche, Seattle Genetics and Takeda, speaker honoraria from Amgen, AstraZeneca, Blueprint, Eli Lilly, GSK, MSD, Novartis, Roche and Sandoz, DMC role from Genentech/Roche and Takeda, and financial support for ETOP and IBCSG trials, where he is president and scientific chair, from AstraZeneca, BMS, Ipsen, MSD, Novartis, Pierre Fabre, Roche and Pfizer. SP reports grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffman – La Roche, Illumina, Novartis, Pfizer, Merck Sharp and Dohme, personal fees from Amgen, Abbvie, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman – La Roche, Foundations Medicine, Illumina, Janssen, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Merck Sharp and Dohme, Merck Serono, Merrimack, Medscape, Phosphoplatin Therapeutics, Beigene and Imedex, outside the submitted work. All other authors have declared no conflicts of interest.

      Supplementary data

      Appendix 1: ETOP 10-16 BOOSTER Collaborators

      BOOSTER Steering Committee: Rolf Stahel, Solange Peters, Ross Soo, Ji-Youn Han, Martin Früh, Mariano Provencio, Linda Coate, Urania Dafni, Anita Hiltbrunner, Barbara Ruepp, Heidi Roschitzki-Voser.
      European Thoracic Oncology Platform Coordinating Office, Bern, Switzerland: Anita Hiltbrunner, Adriana Gasca-Ruchti, Nino Giacomelli, Rosita Kammler, Nesa Marti, Lionel Nobs, Mariana Pardo-Contreras, Rita Pfister, Anne-Christine Piguet, Sabrina Ribeli-Hofmann, Virginia Rodriguez Martinez, Heidi Roschitzki-Voser, Susanne Roux, Barbara Ruepp, Magdalena Sanchez-Hohl, Mirjam Schneider, Robin Schweri, Sandra Troesch, Isabel Zigomo.
      European Thoracic Oncology Platform Statistical Office, Frontier Science Foundation Hellas, Athens, Greece: Urania Dafni, Zoi Tsourti, Panagiota Zygoura, Marie Kassapian, Katerina Vervita, Georgia Dimopoulou, Charitini Andriakopoulou.
      BOOSTER participating groups:
      Spanish Lung Cancer Group (SLGC): Maria Fernandez, Eva Pereira, Carolina Simona
      Cancer Trials Ireland: Lisa Tucker, Jillian Burnes, Aisling Barrett, Meghan McGrillen
      Swiss Group for Clinical Cancer Research (SAKK): Catherine Berset, Christine Biaggi, Martin Reist, Priska Rentsch
      BOOSTER participating centres:
      Ireland (under the Cancer Trials Ireland umbrella)
      Mid-Western Cancer Centre, Limerick, Principal Investigator: Linda Coate
      St. James's Hospital, Dublin, Principal Investigator: Sinead Cuffe
      The Netherlands
      VUMC Amsterdam, Amsterdam, Principal Investigator: Sayed Hashemi
      Spain (under the SLCG umbrella)
      ICO L'Hospitalet, Barcelona, Spain, Principal Investigator: Ernest Nadal
      ICO Hospital Germans Trias i Pujol, Badalona Hospital, Principal Investigator: Enric Carcereny
      Hospital Universitario La Paz, La Paz, Principal Investigator: Javier de Castro
      Hospital Universitario Basurto, Bilbao, Principal Investigator: Maria Angeles Sala
      Hospital Virgen del Rocio, Sevilla, Principal Investigator: Bernabé Reyes
      Hospital Puerta de Hierro, Madrid, Principal Investigator: Mariano Provencio Pulla
      Hospital Teresa Herrera, La Coruña, Principal Investigator: Rosario Garcia Campelo
      Hospital General Universitario Alicante, Alicante, Principal Investigator: Bartomeu Massutí
      Hospital Arnau de Vilanova, Valencia, Principal Investigator: Jose Garcia
      Hospital Universitario Fundacion Jimenez Díaz, Madrid, Principal Investigator: Manuel Dómine
      Hospital De La Santa Creu I Sant Pau, Barcelona, Principal Investigator: Margarita Majem
      Hospital Universitario de la Princesa, Madrid, Principal Investigator: Jose Miguel Sanchez
      Switzerland (unter the SAKK umbrella)
      Cantonal Hospital St. Gallen, St. Gallen, Principal Investigator: Martin Früh
      University Hospital Zurich, Zurich, Principal Investigator: Christian Britschgi
      Cantonal Hospital Winterthur, Winterthur, Principal Investigator: Miklos Pless
      Centre Hospitalier Universitaire Vaudois, Lausanne, Principal Investigator: Solange Peters
      Singapore
      National University Hospital, Singapore, Principal Investigator: Ross Soo
      Tan Tock Seng Hospital, Singapore, Principal Investigator: Chong Ming YEO
      Republic of Korea
      National Cancer Center, Goyang, Principal Investigator: Ji-Youn Han
      Yonsei Cancer Center, Seoul, Principal Investigator: Byoung Chul Cho

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