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Semlitsch, T.

Horvath, K.

HASH(0x558738db7808)

Grössmann, N.

Wild, C.

Horizon Scanning in Oncology    
 
Ergänzende Informationen zu den Arzneistoffen für Priorisierung XXVI – HSS Onkologie Seite 1 von 6 
 
 
 
 
 
Horizon Scanning in Oncology 
26
th
 Prioritization –  1st quarter 2016 
 
General Information, efficacy and 
safety data 
 
 
 
 
 
 
Nicole Grössmann 
Claudia Wild 
 
 
 
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. 
 
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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 26
th
 prioritisation (March 2016), 12 drugs were filtered out of 224 identified and were sent to 
prioritisation. Of these, 2 drugs were ranked as ‘highly relevant’ by the expert panel, 9 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 prioritised drugs are provided in the following 
table. 
 
No Filtered Drugs – 26th prioritisation 1st quarter 2016 
Overall 
category 
1. 
Nab-paclitaxel (Abraxane
®
) versus solvent-based paclitaxel in neoadjuvant 
chemotherapy for early breast cancer 
Relevant 
2. 
Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive 
breast cancer 
Relevant 
3. 
Fulvestrant plus palbociclib (Ibrance
®
) versus fulvestrant plus placebo for treatment of 
hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on 
previous endocrine therapy 
Relevant 
4. 
Taxanes versus S-1 (Teysuno
®
) as the first-line chemotherapy for metastatic breast 
cancer 
Not relevant 
5. Cediranib in patients with relapsed platinum-sensitive ovarian cancer Relevant 
6. 
Standard first-line chemotherapy with or without nintedanib (Vargatef
®
) for advanced 
ovarian cancer 
Relevant 
7. 
Afatinib (Giotrif
TM
) beyond progression in patients with non-small-cell lung cancer 
(NSCLC) following chemotherapy, erlotinib/gefitinib and afatinib 
Highly 
relevant 
8. 
Apatinib in patients with chemotherapy-refractory advanced or metastatic 
adenocarcinoma of the stomach or gastroesophageal junction 
Relevant 
9. 
Everolimus (Afinitor
®
) for the treatment of advanced, non-functional neuroendocrine 
tumours of the lung or gastrointestinal tract 
Relevant 
10. 
Eribulin (Halaven
®
) versus dacarbazine in patients with leiomyosarcoma and adipocytic 
sarcoma 
Relevant 
11. 
Bendamustine (Levact
®
, Treanda
®
) plus rituximab versus fludarabine plus rituximab for 
patients with relapsed indolent and mantle-cell lymphomas 
Relevant 
12. 
Obinutuzumab (Gazyvaro
®
, Gazyva
®
) plus bendamustine versus bendamustine in 
relapsed/refractory indolent non-hodgkin lymphoma 
Highly 
relevant 
 
Horizon Scanning in Oncology    
 
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1 Lung cancer 
1.1 Afatinib (GiotrifTM) beyond progression in patients with non-
small-cell lung cancer following chemotherapy, 
erlotinib/gefitinib and afatinib 
Overview 
Drug Description kinase inhibitor  ErbB-family blocker 
Patient Indication 
in patients who acquired resistance to erlotinib/gefitinib and progressed on 
afatinib after initial benefit 
Incidence in 
Austria 
4,573 newly diagnosed per year (2012), 30.5/100,000/year 
Ongoing Phase III - 
Approval 
status for 
this 
indication 
EMA - 
FDA - 
Approval 
status for 
other 
indications 
EMA 
09/2013: approved for the treatment of non-small-cell lung cancer 
(NSCLC) with epidermal-growth-factor-receptor (EGFR) mutation(s) 
 
02/2016: The CHMP adopted a new indication as follows: 
Giotrif
TM
 as monotherapy is indicated for the treatment of locally advanced 
or metastatic NSCLC of squamous histology progressing on or after 
platinum-based chemotherapy. 
FDA 
07/2013: approved for the first-line treatment of patients with metastatic 
non-small cell lung cancer (NSCLC) whose tumours have epidermal 
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) 
substitution mutations as detected by an FDA-approved test 
Costs  
Giotrif
TM
 film-coated tablets 40mg for 30 days: € 2,176.13 
Paclitaxel 600mg: € 1,195.40 
 
Patients received Giotrif
TM
 – 40mg/day and Paclitaxel 80mg/m
2
/week.
  
For 1 month of therapy, assuming a body surface of 1.70 m
2
 costs of about 
€ 3,260 would occur. 
 
Phase III results  
Ann Oncol (2016), Issue 27: 417–423 (Schuler et al.): “Afatinib beyond progression in patients with 
non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III 
randomized LUX-Lung 5 trial” 
 
Background 
Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after 
treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued 
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irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching 
to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy.  
 
Methods 
Patients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had 
progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib 
(50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m2/week) or 
investigator’s choice of single-agent chemotherapy. The primary end point was progression-free 
survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety 
and patient-reported outcomes. 
 
Results 
Two hundred and two patients with progressive disease following clinical benefit from afatinib were 
randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 
5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) 
significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health 
status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The 
median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent 
chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients 
receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-
related adverse events were consistent with those previously reported with each agent.  
 
Conclusion 
Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients 
who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 
5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, 
versus switching to single-agent chemotherapy. 
 
2 Lymphoma 
2.1 Obinutuzumab (Gazyvaro®, Gazyva®) plus bendamustine 
versus bendamustine in relapsed/refractory indolent non-
hodgkin lymphoma 
Overview 
Drug Description 
A type II, glycoengineered, humanized anti-CD20 monoclonal antibody for 
iv administration 
Patient Indication 
after first-line treatment of patients with follicular lymphoma in combination 
with bendamustine 
Incidence in 
Austria 
1,265 newly diagnosed per year (2012), 9.0/100,000/year 
Ongoing Phase III - 
Approval 
status for 
this 
indication 
EMA  
FDA 
On February 26, 2016, the U. S. Food and Drug Administration approved 
obinutuzumab for use in combination with bendamustine followed by 
obinutuzumab monotherapy for the treatment of patients with follicular 
lymphoma (FL) who relapsed after, or are refractory to, a rituximab-
containing regimen. 
Approval 
status for 
EMA Approved since 03/2010:  
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other 
indications 
chronic lymphocytic leukaemia  in patients for whom treatment with 
fludarabine is not appropriate. 
non-Hodgkin’s lymphoma in patients whose cancer got worse during or 
following treatment containing rituximab. 
multiple myeloma in combination with prednisone in patients older than 65 
years who are not eligible for stem-cell transplantation and cannot be 
treated with thalidomide or bortezomib. 
FDA 
11/2013: Obinutuzumab in combination with chlorambucil, for the 
treatment of patients with previously untreated chronic lymphocytic 
leukemia. 
Costs  
Gazyvaro
®
 concentrate for solution for injection 1,000mg: € 3,668.20 
 
The recommended dose of Gazyvaro
®
 is 1,000mg administered as an 
intravenous infusion on days 1, 8, and 15 (28-days) cycle 1  € 11,004.60 
cycles 2-6: in each cycle 1,000 mg on day 1  € 3,668.20 
 
Abstract 
ASH 2015 Annual Meeting (Pott et al.): 
Background 
Minimal residual disease (MRD) response after first-line treatment of follicular lymphoma (FL) is likely 
to predict clinical course. The prognostic relevance of MRD in relapsed/refractory (r/r) FL remains 
unclear. We report MRD assessment with respect to clinical outcomes in r/r FL pts in GADOLIN 
(NCT01059630). GADOLIN is an open-label, multicenter, randomized phase III study of pts with r/r 
indolent NHL (refractory to rituximab) to investigate the efficacy and safety of obinutuzumab (G) plus 
bendamustine (B) followed by G maintenance vs B alone. A significant improvement in PFS in the G-B 
arm was reported (Sehn L, et al. ASCO 2015). 
 
Methods 
MRD was analyzed by t(14;18) and/or Ig variable domain allele-specific RQ-PCR in pts with a clonal 
marker detectable at diagnosis in peripheral blood (PB) or bone marrow (BM) by consensus PCR. 
(Assessment of Ig rearrangements allows detection of a lymphoma marker in pts with a t(14;18) 
breakpoint not detected by generic PCR and avoids false positive signals, as a low level of the 
translocation can be detected in some healthy individuals.) Assays were designed with a sensitivity of 
10-5 and accepted for MRD assessment when a sensitivity of ≤10-4 was reached. Results were 
evaluated according to ESG-MRD criteria. MRD status was analyzed at interim staging (C4, D1) and 
after end of induction (EOI), and defined as negative (-ve) if RQ-PCR and subsequent nested PCR 
produced a -ve result, i.e. achieving an MRD response. PFS was measured from the EOI date. 
 
Results 
321 of 396 randomized pts were diagnosed with FL. Baseline samples (PB and/or BM) were available 
for 285 of the 304 FL pts who had completed induction at the clinical cut-off date (1 Sep 2014; FL-ITT 
population). A clonal marker was detected in 183 (64%) of these pts; 128/183 (70%) had a RQ-PCR 
assay fulfilling the sensitivity criteria. EOI samples were available for 93 pts (biomarker-evaluable 
population) and 64 had a PB sample at mid-induction to assess MRD-response kinetics. The 
distribution of age, stage, and FLIPI in the biomarker-evaluable population was similar to the non-
evaluable population of the B arm, while there was an enrichment of younger age, advanced-stage 
disease, and high risk FLIPI in the biomarker-evaluable population of the G-B arm. 
MRD response was analyzed in 93 pts at EOI and was significantly higher in pts receiving G-B 
induction, with 42/51 (82%) achieving MRD -ve status compared with 18/42 pts (43%) in the B arm 
(p<0.0001, Chi-Squared). At mid-induction, 30/39 (77%) pts in the G-B arm achieved early MRD -ve 
status vs 10/25 (40%) in the B arm (p=0.0029; Table). MRD response was associated with clinical CR; 
2/33 (6%) MRD positive (+ve) pts vs 17/60 (28%) MRD -ve pts achieved a CR. Moreover, 39/63 pts 
with partial remission were MRD -ve. 
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Pts in the G-B arm who were MRD -ve at EOI had an improved PFS at 24 mo post-EOI (74%; median 
PFS not reached) compared with the B arm (21%; median PFS, 7.6 mo). PFS for MRD non-
responders was comparably poor in both treatment arms; all pts progressed before 24 mo with a post-
EOI median PFS of 5.4 mo (G-B) and 3.0 mo (B; Figure). 
 
Discussion 
Our results suggest that G significantly contributes to the depth of response to B vs B alone during 
induction treatment and support the notion that MRD status at EOI treatment is a sensitive marker of 
efficacy in the setting of r/r FL. MRD response identifies a prognostically favorable group of pts that 
appear to benefit from treatment with G-B at relapse. The improved PFS outcome suggests that these 
pts also benefit from G maintenance. Pts without an MRD response had a very poor prognosis, 
irrespective of treatment arm. Future analyses will assess MRD kinetics during maintenance and 
follow-up. 
 


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