Dokumentenserver des LBI-HTA

Wild, C.

HASH(0x558738ee0b78)

Ujeyl, M.

Nachtnebel, A.

HASH(0x558738d71088)

Rothschedl, E.

Horizon Scanning in Oncology    
 
Ergänzende Informationen zu den Arzneistoffen für Priorisierung XXII – HSS Onkologie Seite 1 von 7 
 
 
 
 
 
Horizon Scanning in Oncology 
22nd Prioritization – 1st quarter 2015 
 
General information, efficacy and safety 
data 
 
 
 
 
 
 
Eleen Rothschedl 
Anna Nachtnebel 
 
 
 
Ergänzende Informationen zu den Arzneistoffen für Priorisierung XXII – HSS Onkologie Seite 2 von 7 
  
Introduction 
 
As part of the project „Horizon Scanning in Oncology“ (further information can be found here: 
http://hta.lbg.ac.at/page/horizon-scanning-in-der-onkologie), 9 information sources are scanned 
frequently to identify emerging anticancer drugs. 
Every 3 months, these anticancer therapies are filtered (i.e. in most cases defined as availability of 
phase III results; for orphan drugs also phase II) to identify drugs at/around the same time as the 
accompanying drug licensing decisions of the EMA.  
An expert panel consisting of oncologists and pharmacists then applies 5 prioritisation criteria to elicit 
those anti-cancer therapies which might be associated with either a considerable impact on financial 
resources or a substantial health benefit.  
For the 22nd prioritisation (April 2015), 10 were filteredout of 180 identified drugs and were sent to 
prioritisation. Of these, 4 drugs were ranked as ‘highly relevant’ by the expert panel, 4 as ‘relevant’ and 
2 as ‘not relevant’. For ‘highly relevant’ drugs, further information including, for example, abstracts of 
phase III studies and licensing status is contained in this document. 
The summary judgements of the expert panel for all drugs are provided in the following table. 
No Filtered Drugs – 22nd prioritisation 1st quarter 2015 Overall category 
1.  Bevacizumab (Avastin®) for recurrent, persistent, or metastatic cervical 
cancer Relevant 
2.  Blinatumomab (Blincyto®, MT-103) in patients with relapsed/refractory 
Philadelphia negative B-precursor ALL Relevant 
3.  Carfilzomib (Kyprolis®) in patients with relapsed and refractory multiple 
myeloma Highly relevant 
4.  Ceritinib (Zykadia®, LDK378) in patients with ALK-positive advanced non-
small cell lung cancer (NSCLC) Relevant 
5.  Nab-Paclitaxel (Abraxane®, ABI-007) as first-line therapy for patients with 
advanced NSCLC Highly relevant 
6.  Nivolumab (Opdivo®, BMS-936558, MDX1106, ONO4538) for the 
second-line therapy of squamous cell/ NON-squamous cell NSCLC Highly relevant 
7.  Dinutuximab in high-risk neuroblastoma patients Not relevant 
8.  Lanreotide (Somatuline Autogel®, ITM-014) in patients with non-
functioning entero-pancreatic endocrine tumour Not relevant 
9.  Lenvatinib (Lenvima®, E7080) in patients with differentiated thyroid 
cancer Relevant 
10.  Palbociclib (Ibrance®, PD-0332991) for the treatment of post-menopausal 
women with hormone receptor positive, Her2 negative advanced breast 
cancer 
Highly relevant 
 
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1 Multiple Myeloma 
1.1 Carfilzomib (Kyprolis®) in patients with relapsed and refractory 
multiple myeloma 
Drug description: a proteasome inhibitor, targeting the 20S proteasome 
Incidence in Austria: 4-5/100,000 
EMA/FDA licensingfor this indication: - /FDA: approved for the treatment of patients 
with multiple myeloma who have received at least two prior therapies including bortezomib and an 
immunomodulatory agent and have demonstrated disease progression on or within 60 days of 
completion of the last therapy. 
Phase III results: 
 
Stewart et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. 
NEJM (2015), 372:142-52 
 
Background  
Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The 
combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown 
efficacy in a phase 1 and 2 study in relapsed multiple myeloma. 
 
Methods  
We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide 
and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). 
The primary end point was progression-free survival. 
 
Results 
Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 
months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 
0.57 to 0.83; P = 0.0001). The median overall survival was not reached in either group at the interim 
analysis. The Kaplan–Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib 
and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = 0.04). The 
rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and 
control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a 
complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of 
grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, 
respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in 
the carfilzomib group reported superior health-related quality of life. 
 
 
Conclusion 
In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and 
dexamethasone resulted in significantly improved progression-free survival at the interim analysis and 
had a favorable risk–benefit profile.  
 
 
 
 
 
 
 
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2. Lung cancer 
2.1 Nab-Paclitaxel (Abraxane®, ABI-007) as first-line therapy 
for patients with advanced NSCLC 
Drug description: nab (nanoparticle albumin bound) – paclitaxel is an antimicrotubule agent 
that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by 
preventing depolymerisation 
Incidence in Austria: 3,500 NSCLC 
EMA/FDA licensingfor this indication: EMA: 01/2015 CHMP adopted a new indication: 
Abraxane® in combination with carboplatin for the first-line treatment of non-small cell lung cancer in 
adult patients who are not candidates for potentially curative surgery and/or radiation therapy 
FDA: 10/2012: Locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) as first-line 
treatment in combination with carboplatin in patients who are not candidates for curative surgery or 
radiation therapy 
Phase III results: 

Socinski et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based 
paclitaxel plus carboplatin as first-line therapy in patients with advanced non–small-cell lung 
cancer: final results of a phase III trial. J Clin Oncol (2012) 30:2055-2062 
 
 
Background  
This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus 
carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non–small-cell 
lung cancer (NSCLC). 
 
Methods  
In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 
mg/m2 nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 
once every 3 weeks (nab-PC) or 200 mg/m2 sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks 
(sb-PC). The primary end point was objective overall response rate (ORR). 
 
Results 
On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-
PC (33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with 
squamous histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P = .001). nab-
PC was as effective as sb-PC in patients with nonsquamous histology (ORR, 26% v 25%; P = .808). 
There was an approximately 10% improvement in progression-free survival (median, 6.3 v 5.8 months; 
hazard ratio [HR], 0.902; 95% CI, 0.767 to 1.060; P = .214) and overall survival (OS; median, 12.1 v 
11.2 months; HR, 0.922; 95% CI, 0.797 to 1.066; P = .271) in the nab-PC arm versus the sb-PC arm, 
respectively. Patients ≥ 70 years old and those enrolled in North America showed a significantly 
increased OS with nab-PC versus sb-PC. Significantly less grade ≥ 3 neuropathy, neutropenia, 
arthralgia, and myalgia occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred 
in the sb-PC arm. 
 
Conclusion  
The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious 
and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point. nab-PC 
produced less neuropathy than sb-PC. 
 
 
Socinski et al. Safety and efficacy analysis by histology of weekly nab-paclitaxel in 
combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung 
cancer. Annals of Oncology (2013); 24: 2390–2396; 
Background:  
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This analysis compared the efficacy and safety outcomes by histology of nab-paclitaxel (nab-P) plus 
carboplatin (C) versus solvent-based paclitaxel (sb-P) plus C in patients with advanced non-small-cell 
lung cancer (NSCLC) based on preplanned stratification factors specified in the phase III trial protocol.  
Patients and methods:  
Patients with untreated stage III/IV NSCLC received 100 mg/m2 nab-P weekly and C (area under the 
curve, AUC = 6) every 3 weeks (q3w) or 200 mg/m2 sb-P plus C (AUC = 6) q3w. Primary end point 
was objective overall response rate (ORR). 
Results: 
nab-P/C versus sb-P/C produced a significantly higher ORR (41% versus 24%; response rate ratio 
[RRR] 1.680; P < 0.001) in patients with squamous cell (SCC) NSCLC. For nab-P/C versus sb-P/C, 
ORRs were 26% versus 27% (RRR 0.966; P = 0.814) in patients with adenocarcinoma, 33% versus 
15% (RRR 2.167; P = 0.323) in patients with large cell carcinoma (LC), and 24% versus 15% (RRR 
1.593; P = 0.372) in patients with not otherwise specified histology. Median overall survival for nab-
P/C versus sb-P/C in patients with SCC was 10.7 versus 9.5 months (HR 0.890; P = 0.310), and 12.4 
versus 10.6 months (HR 1.208; P = 0.721) for patients with LC. nab-P/C produced significantly (P < 
0.05) less grade 3/4 neuropathy and arthralgia, whereas sb-P/C produced less thrombocytopenia and 
anemia. 
Conclusion(s):  
First-line nab-P/C demonstrated a favorable risk-benefit profile in patients with NSCLC regardless of 
histology. 
 
2.2 Nivolumab (Opdivo®, BMS-936558, MDX1106, ONO4538) 
for the second-line therapy of squamous cell/ NON-
squamous cell NSCLC 

Drug description: a human programmed death receptor-1 (PD-1) blocking antibody 
Incidence in Austria: 3,500 NSCLC 
EMA/FDA licensingfor this indication: -/FDA: 03/2015: approved for metastatic 
squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy 
Phase III results: - 
Other sources: FDA: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf, p 19ff 
 
 
 
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3. Breast cancer 
3.1 Palbociclib (Ibrance®, PD-0332991) for the treatment of 
post-menopausal women with hormone receptor positive, 
Her2 negative advanced breast cancer 
Drug description: orally available cyclin-dependent kinase (CDK) inhibitor (targets CDK4 and 
CDK6) 
Incidence in Austria: 5,400 breast cancer patients 
EMA/FDA licensingfor this indication: -/FDA: 02/2015: accelerated approval,  indicated 
in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-
positive, human epidermal growth factor receptor 2 (HER2) - negative advanced breast cancer as 
initial endocrine-based therapy for their metastatic disease 
Phase III results:-  
Other Sources:  
 
Finn et al.The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole 
versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, 
advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.Lancet Oncol. 
(2015) Jan;16(1):25-35 
Background  
Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 
and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast 
cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of 
palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen 
receptor-positive, HER2-negative breast cancer. 
 
 
 
Methods  
In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen 
receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for 
their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that 
accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-
positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to 
have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In 
both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation 
system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg 
daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 
weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed 
progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an 
unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was 
amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing 
but closed to accrual; these are the results of the final analysis of progression-free survival. 
 
Results 
Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus 
letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival 
(median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 
months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the 
palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 
10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib 
plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median 
progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not 
estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in 
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cohort 2 (n=99), median progression-free survival was 11.1 months (7.1-16.4) for the letrozole group 
and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303-0.853; one-
sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus 
letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus 
none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than 
one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), 
back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related 
infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and 
two (2%) in the letrozole group discontinued the study because of adverse events. 
 
Conclusion  
The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free 
survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A 
phase 3 trial is currently underway. 


HASH(0x558738ef89b8)

Fischer, S.

Kisser, A.

HASH(0x558738e7ea38)

Rothschedl, E

Nachtnebel, A

HASH(0x558738c5daa0)

Horizon Scanning in Oncology    
 
Ergänzende Informationen zu den Arzneistoffen für Priorisierung XXIV – HSS Onkologie Seite 1 von 5 
 
 
 
 
 
Horizon Scanning in Oncology 
24
th
 Prioritization –  3 rd  quarter 2015 
 
General Information, efficacy and 
safety data 
 
 
 
 
 
 
Eleen Rothschedl 
Anna Nachtnebel 
 
 
 
Please note: 
Within this document you find general information about the drug of interest and the indication it is 
intended to be used for. Further we have included full text publications and conference abstracts of 
phase III trials, assessing the safety and efficacy of the drugs of interest. 
At the very end of each chapter we have provided a table containing the prioritization criteria and a 
drop-down field to apply the provided criteria. 
 
 
 
 
 
Ergänzende Informationen zu den Arzneistoffen für Priorisierung XXIV – HSS Onkologie Seite 2 von 5 
Introduction 
As part of the project „Horizon Scanning in Oncology“ (further information can be found here: 
http://hta.lbg.ac.at/page/horizon-scanning-in-der-onkologie), 9 information sources are scanned 
frequently to identify emerging anticancer drugs. 
Every 3 months, these anticancer therapies are filtered (i.e. in most cases defined as availability of 
phase III results; for orphan drugs also phase II) to identify drugs at/around the same time as the 
accompanying drug licensing decisions of the EMA.  
An expert panel consisting of oncologists and pharmacists then applies 5 prioritisation criteria to 
elicit those anti-cancer therapies which might be associated with either a considerable impact on 
financial resources or a substantial health benefit.  
For the 24th prioritisation (September 2015), 7 were filtered out of 191 identified drugs and were 
sent to prioritisation. Of these, 2 drugs were ranked as ‘highly relevant’ by the expert panel, 4 as 
‘relevant’ and 1 as ‘not relevant’. For ‘highly relevant’ drugs, further information including, for 
example, abstracts of phase III studies and licensing status is contained in this document. 
The summary judgements of the expert panel for all drugs are provided in the following table. 
 
 
No.  
 
Filtered Drugs – 23
rd
 prioritisation 2
nd
 quarter 2015 
 
Overall category 
1. Afatinib (Giotrif®, Gilotrif®, BIBW 2992) as second-line 
treatment of patients with advanced squamous cell carcinoma of 
the lung 
Relevant 
2. Necitumumab (IMC-11F8, LY3012211) as first-line therapy in 
patients with stage IV squamous NSCLC 
Relevant 
3. Standard chemotherapy with or without bevacizumab (Avastin®) 
for women with newly diagnosed ovarian cancer 
Highly relevant 
4. Docetaxel (Taxotere®, Docefim®) in metastatic hormone-
sensitive prostate cancer 
Relevant 
5. Everolimus (Afinitor®, RAD-001) as first-line treatment for 
patients with HER2-positive advanced breast cancer 
Highly relevant 
6. Oxaliplatin (Eloxatin®) added to fluorouracil-based preoperative 
chemoradiotherapy and postoperative chemotherapy of locally 
advanced rectal cancer 
Not relevant 
7. Vosaroxin (QinprezoTM, AG-7352, SPC-595, SNS 595, 
Voreloxin) in patients with first relapsed or refractory acute 
myeloid leukaemia 
Relevant 
 
 
Horizon Scanning in Oncology    
 
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1 Ovarian Cancer  
1.1 Standard chemotherapy with or without bevacizumab 
(Avastin®) for women with newly diagnosed ovarian cancer 
Overview 
Drug Description 
 
a recombinant monoclonal antibody that binds to vascular endothelial 
growth factor  (VEGF) and inhibits the binding to its receptors (VEGFR-1 
and VEGFR-2) 
 
Incidence in 
Austria 
9.0 per 100,000 women per year, 683 newly diagnosed women per year 
Approval 
status for 
this 
indication 
EMA 
- in combination with carboplatin and paclitaxel is indicated for the 
front-line treatment of adult patients with advanced (International 
Federation of Gynecology and Obstetrics (FIGO) stages III B, III C 
and IV) epithelial ovarian, fallopian tube, or primary peritoneal 
cancer since July 2014 
FDA - 
Phase III results: 
The Lancet (2015) Vol.16, Issue: 8 Pages 928-936 (Oza et al.) Standard chemotherapy with or 
without bevacizumab for women with newly diagnosed ovarian cancer (ICON 7): overall survival 
results of a phase 3 randomised trial. 
Background  
The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer 
with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high 
risk of disease progression. We report the final overall survival results of the trial. 
 
Methods  
ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 
countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly 
diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of 
Gynecology and Obstetrics [FIGO] stage I–IIa, grade 3 or clear cell histology) or more advanced 
disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, 
were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of 
intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m² of body surface area) or the same 
chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, 
given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. 
Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, 
interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary 
endpoint was progression-free survival; the study was also powered to detect a difference in overall 
survival. Analysis was by intention to treat. This trial is registered as an International Standard 
Randomised Controlled Trial, number ISRCTN91273375. 
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Results  
Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to 
receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the 
end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had 
died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed 
evidence of non-proportional hazards, so we used the difference in restricted mean survival time as 
the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted 
mean survival time 44·6 months [95% CI 43·2–45·9] in the standard chemotherapy group vs. 45·5 
months [44·2–46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a 
predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard 
chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall 
survival was noted between women who received bevacizumab plus chemotherapy and those who 
received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0–37·0] with 
standard chemotherapy vs. 39·3 months [37·0–41·7] with bevacizumab; log-rank p=0·03). However, in 
non-high-risk patients, the restricted mean survival time did not differ significantly between the two 
treatment groups (49·7 months [95% CI 48·3–51·1]) in the standard chemotherapy group vs. 48·4 
months [47·0–49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free 
survival showed no difference between treatment groups. During extended follow-up, one further 
treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 
2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated 
patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with 
standard chemotherapy) were reported. 
 
Conclusion 
Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study 
population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, 
which is concordant with the progression-free survival results from ICON7 and GOG-218, and 
provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian 
cancer. 
2 Breast Cancer 
2.1 Everolimus (Afinitor®, RAD-001) as first-line treatment for 
patients with HER2-positive advanced breast cancer 
Overview 
Drug Description an inhibitor of the mammalian target of rapamycin (mTOR) protein 
Incidence in 
Austria 
 
76.2 per 100,000 women per year; 5,423 newly diagnosed women per 
year 
Approval 
status for 
this 
indication 
EMA - 
FDA - 
Phase III results: 
The Lancet (2015) Vol.16, Issue: 7, Pages 816-829 (Hurvitz et al.) Combination of everolimus with 
trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast 
cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial 
 
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Background  
mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due 
to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed 
the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for 
patients with HER2-positive advanced breast cancer. 
 
Methods  
In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. 
Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast 
cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, who had not 
received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of 
randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors 
(RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment 
for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an 
interactive voice and web response system to receive either 10 mg everolimus once a day orally or 
placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent 
weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m² on 
days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of 
trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned 
treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that 
were identical in packaging, labelling, appearance, and administration schedule. The two primary 
objectives were investigator-assessed progression-free survival in the full study population and in the 
subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added 
during the course of the study, before unmasking based on new clinical and biological findings from 
other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this 
trial is closed and results of the final progression-free survival analyses are presented here. This trial is 
registered with ClinicalTrials.gov, number NCT00876395. 
 
Results  
Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive 
everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4–46·6). In the 
full population, median progression-free survival was 14·95 months (95% CI 14·55–17·91) with 
everolimus versus 14·49 months (12·29–17·08) with placebo (hazard ratio 0·89, 95% CI 0·73–1·08; 
p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with 
everolimus was 20·27 months (95% CI 14·95–24·08) versus 13·08 months (10·05–16·56) with 
placebo (hazard ratio 0·66, 95% CI 0·48–0·91; p=0·0049); however, the protocol-specified significance 
threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were 
stomatitis (314 [67%] of 472 patients in the everolimus group vs. 77 [32%] of 238 patients in the 
placebo group), diarrhoea (267 [57%] vs. 111 [47%] patients), and alopecia (221 [47%] vs. 125 [53%]). 
The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo 
group were neutropenia (117 [25%] vs. 35 [15%]), stomatitis (59 [13%] vs. three [1%]), anaemia (46 
[10%] vs. six [3%]) and diarrhoea (43 [9%] vs. 10 [4%]) On-treatment adverse event-related deaths 
were reported in 17 (4%) patients in the everolimus group and none in the placebo group. 
 
Conclusion 
Although progression-free survival was not significantly different between groups in the full analysis 
population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, 
HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for 
significance. The safety profile was generally consistent with what was previously reported in 
BOLERO-3. Proactive monitoring and early management of adverse events in patients given 
everolimus and chemotherapy is crucial. 
 
 


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