Dr. Saskia Carton; Imelda Ziekenhuis, Bonheiden

Dr. Veerle Casneuf; OLV Ziekenhuis Aalst-Asse-Ninove

Dr. Joëlle Collignon; Centre Hospitalier Universitaire de Liège, Liège

Prof. Dr. Karen Geboes; UZ Ghent, Ghent

Prof. Dr. Alain Hendlisz; Institut Jules Bordet, Brussels

Dr. Laura Mans; Hôpital Erasme, Brussels

Dr. Donatienne Taylor; CHU UCL Namur; site Sainte Elisabeth, Namur

Prof. Dr. Marc Peeters; UZA, Antwerp

Dr. Isabelle Sinapi; Grand Hôpital de Charleroi, Charleroi

Prof. Dr. Eric Van Cutsem; University Hospital Leuven, Leuven

Dr. Pieter Vandecandelaere; AZ Delta, Roeselare

Prof. Dr. Marc Van Den Eynde; Cliniques Universitaires Saint-Luc, Brussels

Prof. Dr. Jean-Luc Van Laethem; Hôpital Erasme, Brussels

a Belgian expert consensus

Practical guidance for the treatment of patients with

gastric or gastro-esophageal junction cancer

March 2020

DR. SASKIA CARTONImelda Ziekenhuis, Bonheiden

DR. VEERLE CASNEUFOLV Ziekenhuis Aalst-Asse-Ninove

DR. JOËLLE COLLIGNONCentre Hospitalier Universitaire

de Liège, Liège

PROF. DR. KAREN GEBOESUZ Ghent, Ghent

PROF. DR. ALAIN HENDLISZInstitut Jules Bordet, Brussels

DR. ISABELLE SINAPIGrand Hôpital de Charleroi, Charleroi

PROF. DR. ERIC VAN CUTSEMUniversity Hospital Leuven, Leuven

DR. PIETER VANDECANDELAEREAZ Delta, Roeselare

PROF. DR. MARC VAN DEN EYNDECliniques Universitaires

Saint-Luc, Brussels

PROF. DR. JEAN-LUC VAN LAETHEMHôpital Erasme, Brussels

1

DR. LAURA MANSHôpital Erasme, Brussels

DR. DONATIENNE TAYLORCHU UCL Namur,

site Sainte Elisabeth, Namur

PROF. DR. MARC PEETERS

UZA, Antwerp

INTRODUCTIONCurrently there are no specific Belgian guidelines for the treat-

ment of patients with advanced gastric or gastro-esophageal

junction (GEJ) cancer. Therefore, the clinical practice guide-

lines for the diagnosis, treatment and follow-up of gastric can-

cer formulated by the European Society for Medical Oncology

(ESMO) make up the guidebook for most centers in Belgium.1,2

However, at some points, these guidelines leave room for dis-

cussion and interpretation. Moreover, substantial heterogene-

ity exists into how gastric cancer patients are treated in Bel-

gium. In an attempt to provide answers to some of the

recurrent clinical questions encountered in daily practice, Eli

Lilly assembled an advisory board of gastric cancer specialists

coming from both the Northern and Southern part of the

country. The scope of these advisory board meetings was to

come up with practical guidance on the peri-operative man-

agement of patients with resectable gastric/GEJ cancer and

to provide recommendations on the optimal treatment ap-

proach for patients with unresectable gastric/GEJ cancer, tak-

ing into account the specific Belgian reimbursement criteria.

STAGING AND RISK ASSESSMENTAll patients who are diagnosed with gastric or gastro-esoph-

ageal junction (GEJ) cancer should be discussed during a

multidisciplinary tumor board (MDT). The core membership

of the multidisciplinary team should consist of surgeons, gas-

tro-intestinal or medical oncologists, radiation oncologists,

radiologists and pathologists. Prior to any decision with re-

spect to the treatment plan, adequate tumor staging is essen-

tial, and patients should undergo a thorough functional eval-

uation. This should include at least a physical examination, an

evaluation of the blood count, liver and renal function tests,

an endoscopy (plus echo-endoscopy), and contrast-enhanced

computed tomography (CT) imaging of the thorax and the

abdomen. In case of doubt, a dedicated MRI for the detection

of liver and/or peritoneal metastases and a laparoscopy with

or without peritoneal washing may be indicated.1

PERI-OPERATIVE TREATMENT FOR PATIENTS WITH RESECTABLE CANCERSurgical resection of gastric cancer, specifically at early stages,

is potentially curative. However, the majority of patients will

eventually relapse after surgery. In an attempt to mitigate this

relapse risk, peri-operative chemotherapy has become stand-

ard of care for patients with resectable gastric cancer, includ-

ing GEJ tumors (for GEJ tumors also pre-operative chemora-

diotherapy).3-6 According to the expert panel, peri-operative

therapy is recommended in patients with ≥stage IB disease.1

For patients with resectable gastric cancer, the recommend-

ed peri-operative regimen consists of FLOT (4 pre- and 4 post-

operative 2-week cycles of 50 mg/m² docetaxel, 85 mg/m²

oxaliplatin, 200 mg/m² leucovorin and 2600 mg/m² 5-FU as

24-hour infusion on day 1), or a similar taxane-based triplet.7-9

For patients with resectable GEJ cancer, CROSS-trial based

chemoradiotherapy (carboplatin [doses titrated to achieve an

area under the curve of 2 mg/ml/min] + paclitaxel [50 mg/m2]

for 5 weeks and concurrent radiotherapy [41.4 Gy in 23 frac-

tions, 5 days per week]), is a feasible alternative for FLOT.5,6 In

the absence of a randomized head to head comparison of

CROSS and FLOT in this setting, it is impossible to make a firm

recommendation for one or the other. However, the expert

panel expressed a preference for CROSS-trial based chemora-

diotherapy in patients with esophageal extension (Siewert

type I and II), while FLOT is preferred in patients without eso-

phageal extension (Siewert type III or lower).

While FLOT should be considered as the standard of care, a

less intensive oxaliplatin/5-FU based peri-operative treatment

schedule (e.g. FOLFOX, FLO) can be considered in frail pa-

tients. In this respect, the expert panel underscores the im-

portance of assessing the frailty of patients in the light of the

entire treatment sequence (i.e. consider both the peri-opera-

tive chemotherapy as the type of surgery).

On a final note, it needs to be stressed that there is no longer

a place for the use of anthracyclines (i.e. epirubicin, adriamy-

1 2

Practical guidance for the treatment of patients with gastric

or gastro-esophageal junction cancer:

a Belgian expert consensus

cin) in the peri-operative treatment of patients with gastric/

GEJ cancer.

INOPERABLE OR METASTATIC GASTRIC/GEJ CANCERFIRST LINE TREATMENTFor all patients with palliative therapy intention (stage IV) a

quality controlled HER2 testing is mandatory before the start

of therapy. HER2 positivity is defined as HER2+++ on immu-

nohistochemistry or HER2++ followed by a positive FISH test.

However, in Belgium only positive FISH testing is accepted

for the reimbursement of trastuzumab. According to the Bel-

gian pathology guidelines, HER2-positivity is defined as hav-

ing a HER2/CEP17 ratio of 2 or more with the HER2 in-situ

hybridization test.10 For patients with a HER2-positive tumor,

platinum + fluoropyrimidine (5-FU or capecitabine) chemo-

therapy in combination with trastuzumab is the recom-

mended first-line treatment.11

The standard of care for patients with HER2-negative tumors

consists of doublet chemotherapy, including a platinum de-

rivative and a fluoropyrimidine (5-FU or capecitabine). For

patients in whom a rapid tumor response is needed, a tax-

ane-based triplet regimen (e.g. DCF, FLOT, or other tax-

ane-based triplets) can be considered in first line. However,

the expert panel underscores that this applies to only a mi-

nority of selected symptomatic patients, mainly due to the

significant increase in toxicity associated with taxane-based

triplets, accompanied however by a small increase in efficacy

and quality of life.12 Additionally, this also impacts their eligi-

bility for future treatment options. Given the toxicity associ-

ated with triplet chemotherapy, the expert panel recom-

mends to discontinue the taxane as soon as clinically possible

and to closely monitor the patient for side effects.

SECOND LINE TREATMENTRamucirumab in combination with paclitaxel is the standard

of care in the second line treatment of patients with meta-

static gastric/GEJ cancer. In case of paclitaxel-related toxicity,

de-escalation of the therapy to ramucirumab monotherapy

can be considered.13,14

For patients who received a taxane-based regimen in first

line (or in the peri-operative setting) and for patients with a

contra-indication to taxanes, ramucirumab monotherapy or

irinotecan-based chemotherapy (e.g. FOLFIRI) can be used in

second line. Of note, the use of ramucirumab monotherapy

in this setting is supported by results of a global dou-

ble-blinded randomized phase III trial.14 Irinotecan-based

treatments or taxane monotherapy are also validated op-

tions in second line and can be considered in case of a con-

tra-indication for ramucirumab.15-18

Of note, in patients where the taxane was de-escalated in

the maintenance phase of a first-line treatment, a taxane can

be re-introduced in a further treatment line. In case of de-es-

calation of the taxane in first-line due to side effect, re-intro-

duction should be discussed with the patient (and should

only be considered in case of resolution of the side effects).

Finally, due to the high prevalence of cross-resistance be-

tween taxanes, it is not advised to use paclitaxel for those

patients found with tumor progressive under docetaxel in

first-line therapy.19

THIRD LINE AND BEYONDRecently, a randomized controlled trial demonstrated a sur-

vival benefit of trifluridine/tipiracil over placebo in patients

with chemorefractory gastric cancer (third line and be-

yond).20 These results formed the rationale for the EMA ap-

proval of trifluridine/tipiracil in this setting, but this option is

currently not yet reimbursed in Belgium. For the time being,

irinotecan-based therapy (e.g. FOLFIRI) represents a feasible

treatment alternative. In addition to this, participation in a

clinical trial should always be considered.

FUTURE PERSPECTIVESRecently, clinical studies have identified effective treatments

for patients with MicroSatellite Instability (MSI)-high tumors

(immune checkpoint inhibitors) and for patients with tumors

harboring NTRK gene fusions (larotrectinib). However, as

these treatments are not (yet) reimbursed in Belgium and

given the fact that the exact position of these treatment op-

tions in the gastric/GEJ cancer treatment paradigm remains

to be elucidated, these options will not be discussed in this

article.

OLIGOMETASTATIC DISEASEIn recent years, oligometastatic disease has become a

much-debated topic in many cancer types, including gastric

cancer. Nevertheless, oligometastatic disease is a rare finding

in gastric cancer patients and, as a result, it is difficult to

make firm recommendations with respect to the manage-

ment of these patients. As for all other patients with gastric

cancer, oligometastatic patients need to be discussed in a

multidisciplinary team. For some patients, metastasis-direct-

ed therapies such as surgery or radiotherapy can be consid-

ered.

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REFERENCES1. Smyth E, et al. Ann Oncol 2016;27(Suppl 5):v38-49.

2. Muro K, et al. Ann Oncol 2019 ;30(1) :19-33.

3. Cunningham D, et al. N Engl J med 2006;355(1):11-20.

4. Ychou M, et al. J Clin Oncol 2011;29(13):1715-21.

5. Van Hagen P, et al. N Engl J med 2012;366(22):2074-84.

6. Shapiro J, et al. Lancet Oncol 2015;16(9):1090-8.

7. Al-Batran S, et al. Lancet Oncol 2016;17(12):1697-708.

8. Al-Batran S, et al. Lancet 2019;393(10184):1984-57.

9. Van Cutsem E, et al. Ann Oncol 2015;26(1):149-56.

10. Jouret-Mourin A, et al. Belg J Med Oncol 2011;5:14-22.

11. Bang Y, et al. Lancet 2010;376:687-97.

12. Okines A, et al. Ann Oncol 2009;20:1529-34.

13. Wilke H, et al. Lancet Oncol 2014;15:1224-35.

14. Fuchs CS, et al. Br J Cancer 2016;115:974-82.

15. Ford H, et al. J Clin Oncol 2014;15(1):78-86.

16. Kang J, et al. J Clin Oncol 2012;30(24):3035.

17. Thuss-Patience P, et al. Eur J Cancer 2011;47(15):2306-14.

18. Hironaka S, et al.. J Clin Oncol 2013;31(35):4438-44.

19. Shimura T, et al. Onkologie 2012;35(4):176-83.

20. Shitara K, et al. Lancet Oncol 2018;19(11):1437-48.

21. Shitara K, et al. Presented at ESMO 2019 ; Abstract LBA44.

22. https://www.ema.europa.eu/en/medicines/human/EPAR/vitrakvi

4

KEY MESSAGES FOR CLINICAL PRACTICE

• All patients with gastric or gastro-esophageal junction (GEJ) cancer should be discussed during a MDT.

• Neoadjuvant or peri-operative therapy is recommended in patients with ≥stage IB disease

• For patients with resectable gastric cancer, the recommended peri-operative regimen consists of FLOT.

• For patients with resectable GEJ cancer, chemoradiotherapy according to the CROSS regimen is a feasible alternative for FLOT.

• A less intensive oxaliplatin/5-FU based peri-operative treatment schedule can be considered in frail patients.

• For all patients with palliative therapy intention (stage IV) a quality controlled HER2 testing is mandatory before the start of therapy.

• For patients with a HER2-positive tumor, platinum + fluoropyrimidine (5-FU or capecitabine) chemotherapy in combination with trastuzumab is the recommended first-line treatment.

• The standard of care for patients with HER2-negative tumors consists of doublet chemotherapy, including a platinum derivative and fluoropyrimidine (5-FU or capecitabine).

• For a minority of selected, symptomatic patients in whom a rapid tumor response is needed, a taxane-based triplet regimen (e.g. DCF, FLOT) can be considered in first line.

• Ramucirumab in combination with paclitaxel is the standard of care in the second line treatment of patients with metastatic gastric/GEJ cancer.

• For patients who received a taxane-based regimen in first line (or in the peri-operative setting) and for patients with a contra-indication to taxanes, ramucirumab monotherapy or irinotecan-based chemotherapy (e.g. FOLFIRI) can be used in second line.

• Trifluridine/tipiracil will likely become a standard option in third line in addition to an irinotecan-based regimen. Until trifluridine/tipiracil is reimbursed irinotecan-based therapy (e.g. FOLFIRI) represents a feasible alternative.

• Oligometastatic disease is a very rare finding in gastric cancer, but for some of these patients, metastasis-directed therapies can be considered (after MOC discussion).

PROF. VERSLYPE

PROF. BORBATH

PROF. BORBATH

BASED ON SIGNIFICANT SURVIVAL AND QUALITY OF LIFE IMPROVEMENTSOVER PLACEBO IN THE REACH STUDY PROGRAM

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Until recently, sorafenib was the undisputed standard of care in the

fi rst line treatment of patients with inoperable, or metastatic HCC.

A recent phase III study demonstrated non-inferiority of lenvatinib to

sorafenib in this setting, offering an alternative for sorafenib in the

frontline setting. Lenvatinib only recently obtained reimbursement

in Belgium, so the experience with this agent in Belgium is still

limited. The treatment options in second line are limited and are

even further restricted by the Belgian reimbursement criteria. In

fact, cabozantinib is not reimbursed at all, while regorafenib is not

eligible for reimbursement in the subset of patients with intolerance

to fi rst line sorafenib (excluding approximately 20% of patients).

Recently, ramucirumab was added to the treatment arsenal for

advanced HCC patients in whom sorafenib failed.

The reimbursement of ramucirumab in this setting is based on

the results of REACH and REACH-2, demonstrating a clinically

meaningful and statistically signifi cant improvement in the OS with

ramucirumab over placebo in patients with an elevated α-feto-

protein level. Of note, I think that Eli Lilly needs to be acknowledged

for the fact that they continued the development of ramucirumab

in this setting after the REACH trial failed to demonstrate an OS

benefi t in the overall study population. Instead of terminating the

clinical program they pushed further and set up an additional trial

to validate the OS signal observed in the subgroup of patients

with an α-fetoprotein level of 400ng/mL. Also the safety profi le of

ramucirumab proved to be manageable in these trials and in my

experience this safety profi le also compared favorable to the alter-

native options in second line (e.g. in contrast to regorafenib and

cabozantinib no hand-foot syndrome with ramucirumab).

In summary, ramucirumab offers a safe and effective treatment

option for patients with advanced HCC who fail on frontline sorafenib

and who have an α-fetoprotein level of at least 400 ng/mL. It would

be very interesting to have a head to head comparison between

ramucirumab and either regorafenib or cabozantinib, but unfortuna-

tely the chance that such a study will ever be set up is very small.

Earlier this year results of the phase III IMbrave trial demonstrated

superior outcomes with a combination of atezolizumab and bevaci-

zumab over sorafenib in the fi rst-line treatment of advanced HCC

patients.16 As such, this combination has the potential to further

re-shape the treatment paradigm for advanced HCC in the future

(no EMA approval in this setting to date).

REFERENCES1. Llovet J, et al. Nat Rev Clin Oncol 2018;15:599-616.

2. Llovet J, et al. N Engl J Med 2008;359:378-90.

3. Cheng A, et al. Lancet Oncol 2009;10:25-34.

4. Kudo M, et al. Lancet 2018;391:1163-73.

5. Bruix J, et al. Lancet Oncol 2017;389:54-66.

6. Abou-Alfa G, et al. N Engl J Med 2018;379:54-63.

7. Zhu AX, et al. Nat Rev Clin Oncol 2011;8: 292-301.

8. Spratlin, JL, et al. J Clin Oncol 2010; 28: 780-87.

9. Smyth E, et al. Ann Oncol 2016;27(Suppl_5): v38-v49.

10. Zhu A, et al. Lancet 2015;16:859-70.

11. Tangkijvanich P, et al. 2000; 31: 302-08.

12. Nakazawa T, et al. Eur J Gastroenterol Hepatol 2013;25:683-89.

13. Zhu A, et al. Lancet Oncol 2019;20:282-96.

14. Yount S et al. J Pain Symptom Manage 2002; 24(1):32-44.

15. Zhu A, et al. Presented at ESMO 2018; Abstract 622PD.

16. Cheng A, et al. Presented at ESMO ASIA 2019; Abstract LBA3.

RESPONSIBLE PUBLISHER: ARIEZ INTERNATIONAL BV. THIS PUBLICATION WAS SPONSORED BY ELI LILLY.

COPYRIGHT

© Copyright 2020 Ariez International B.V., Zaandam, The Netherlands. All rights reserved. No part of this publication may be reproduced, stored in any retrieval system, or transmitted in

any form by any means, including photocopying or other electronic and mechanical methods, without the prior written permission of the publisher.

PROF. IVAN BORBATH,

CLINIQUES UNIVERSITAIRES ST LUC, BRUSSELS

AN EXPERT OPINION

RAMUCIRUMAB: A NEW, SECOND LINETREATMENT OPTION FOR AFP-HIGH PATIENTS WITH

ADVANCED HEPATOCELLULAR CARCINOMA

Patients with advanced HCC in whom fi rst line treatment

with sorafenib failed have very limited second line treatment

options. For the moment, regorafenib is the only agent that is

reimbursed in this setting in Belgium, but this reimbursement

does not cover patients with sorafenib intolerance. The phase

III REACH program adequately addressed the medical need

in the second line treatment of advanced hepatocellular carci-

noma (HCC) by demonstrating a signifi cant OS improvement

with the anti-VEGF agent ramucirumab over placebo in patients

with an α-fetoprotein (AFP) level of at least 400ng/mL (median

OS 8.1 vs. 5.0 months ;HR[95%CI]: 0.694[0.571-0.842]; p=

0.0002). In addition, ramucirumab also proved to be associated

with a consistent benefi t in the time to a deterioration (TtD)

in the quality of life of patients. These convincing data formed

the rationale for the EMA approval of ramucirumab in the

treatment of advanced HCC patients with an AFP level of at

least 400 ng/mL who failed fi rst line treatment with sorafenib

(both intolerant and progressive). In this edition of “opinions in

oncology”, the main results obtained with ramucirumab in ad-

vanced HCC will be discussed after which Prof. Ivan Borbath

(Departments of gastro-enterology and medical oncology,

Cliniques Universitaires St Luc, Brussels) and Prof. Chris

Verslype (Digestive oncology, University Hospitals Leuven,

Leuven) will share their views on these data.

MINIMAL INFORMATION OF THE SPC 1. NAME OF THE MEDICINAL PRODUCT Cyramza 10 mg/ml concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml of concentrate for solution for infusion contains 10 mg ramucirumab. Each 10 ml vial contains 100 mg of ramucirumab. Each 50 ml vial contains 500 mg of ramucirumab. Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology. Excipient with known effect Each 10 ml vial contains approximately 17 mg sodium. Each 50 ml vial contains approximately 85 mg sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate). The concentrate is a clear to slightly opalescent and colourless to slightly yellow solution, pH 6.0. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Gastric cancer Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy (see section 5.1). Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate (see section 5.1). Colorectal cancer Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine. Non-small cell lung cancer Cyramza in combination with docetaxel is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with disease progression after platinum-based chemotherapy. Hepatocellular carcinoma Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have been previously treated with sorafenib. 4.2 Posology and method of administration Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology. Posology Gastric cancer and gastro-oesophageal junction (GEJ) adenocarcinoma Cyramza in combination with paclitaxel The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenous infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel infusion, patients should have a complete blood count and blood chemistry performed to evaluate hepatic function. Criteria to be met prior to each paclitaxel infusion are provided in Table 1. Table 1: Criteria to be met prior to each paclitaxel administration ,Neutrophils Day 1: ≥1.5 x 109/L Days 8 and 15: ≥1.0 x 109/L.Platelets Day 1: ≥100 x 109/L Days 8 and 15: ≥75 x 109/L.Bilirubin <1.5 x upper limit of normal value (ULN). Aspartate aminotransferase (AST) /Alanine aminotransferase (ALT) No liver metastases: ALT/AST ≤3 x ULN Liver metastases: ALT/AST ≤5 x ULN. Cyramza as a single agent The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks. Colorectal cancer The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered by intravenous infusion, prior to FOLFIRI administration. Prior to chemotherapy, patients should have a complete blood count. Criteria to be met prior to FOLFIRI are provided in Table 2. Table 2: Criteria to be met prior to FOLFIRI administration Neutrophils ≥1.5 x 109/L. Platelets ≥100 x 109/L. Chemotherapy-related gastro-intestinal toxicity ≤ Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]). Non-small cell lung cancer (NSCLC) The recommended dose of ramucirumab is 10 mg/kg on day 1 of a 21 day cycle, prior to docetaxel infusion. The recommended dose of docetaxel is 75 mg/m2 administered by intravenous infusion over approximately 60 minutes on day 1 of a 21 day cycle. For East Asian patients, a reduced docetaxel starting dose of 60 mg/m2 on day 1 of a 21 day cycle should be considered. See docetaxel prescribing information for specific dosing advice. Hepatocellular carcinoma (HCC) The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks. Alpha fetoprotein (AFP) testing in HCC Patients with HCC should be selected based on a serum AFP concentration of ≥ 400 ng/ml with a validated AFP test prior to ramucirumab treatment (see section 5.1). Duration of treatment It is recommended that treatment be continued until disease progression or until unacceptable toxicity has occurred. Premedication Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) prior to infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reaction premedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or 2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequent infusions, premedicate with the following or equivalent medicinal products: an intravenous histamine H1 antagonist (for example diphenhydramine hydrochloride), paracetamol and dexamethasone. See prescribing information for paclitaxel, for components of FOLFIRI and for docetaxel, as applicable, for premedication requirements and additional information. Posology adjustments for ramucirumab Infusion-related reactions The infusion rate of ramucirumab should be reduced by 50% for the duration of the infusion and all subsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should be immediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4). Hypertension The blood pressure of patients should be monitored prior to each ramucirumab administration and treated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the event of severe hypertension, until controlled with medical management. If there is medically significant hypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapy should be permanently discontinued (see section 4.4). Proteinuria Patients should be monitored for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level (see Table 3). A second dose reduction (see Table 3) is recommended if a urine protein level ≥2 g/24 hours reoccurs. Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome. Table 3: Ramucirumab dose reductions for proteinuria Initial ramucirumab dose: 8 mg/kg First dose reduction to: 6 mg/kg Second dose reduction to: 5 mg/kg Initial ramucirumab dose: 10 mg/kg First dose reduction to: 8 mg/kg Second dose reduction to: 6 mg/kg. Elective surgery or impaired wound healing Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing complications, until the wound is fully healed (see section 4.4). Permanent discontinuation Ramucirumab therapy should be permanently discontinued in the event of: Severe arterial thromboembolic events (see section 4.4). Gastrointestinal perforations (see section 4.4). Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding (see section 4.4). Spontaneous development of fistula (see section 4.4). Hepatic encephalopathy or hepatorenal syndrome (see section 4.4). Paclitaxel dose adjustments Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. For NCI CTCAE Grade 4 haematological toxicity or Grade 3 paclitaxel-related non-haematological toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. A second reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur. FOLFIRI dose adjustments Dose reductions for individual components of FOLFIRI may be made for specific toxicities. Dose modifications of each component of FOLFIRI should be made independently and are provided in Table 4. Table 5 provides details of dose delays or dose reductions of components of FOLFIRI at the next cycle based on maximum grade of specific adverse drug reactions. Table 4: FOLFIRI dose reductions FOLFIRI componenta Irinotecan Dose level Initial dose 180 mg/m2 -1 150 mg/m2 -2 120 mg/m2 -3 100 mg/m2 FOLFIRI componenta 5-FU bolus Dose level Initial dose 400 mg/m2 -1 200 mg/m2 -2 0 mg/m2 -3 0 mg/m2 FOLFIRI componenta 5-FU infusion Dose level Initial dose 2,400 mg/m2 over 46-48 hours -1 2,000 mg/m2 over 46-48 hours -2 1,600 mg/m2 over 46-48 hours -3 1,200 mg/m2 over 46-48 hours a 5-FU = 5-fluorouracil. Table 5: Dose modification of FOLFIRI components due to specific ADRs ADR Diarrhoe NCI CTCAE grade 2 Dose modification at day 1 of cycle subsequent to ADR If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level for 5-FU. For recurrent Grade 2 diarrhoea, reduce by 1 dose level for 5-FU and irinotecan. NCI CTCAE grade 3 Dose modification at day 1 of cycle subsequent to ADR If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level for 5-FU and irinotecan NCI CTCAE grade 4 Dose modification at day 1 of cycle subsequent to ADR If diarrhoea has recovered to Grade ≤1, reduce by 2 dose levels for 5-FU and irinotecan. If Grade 4 diarrhoea does not resolve to Grade ≤1, withhold 5-FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1. ADR Neutropenia or Thrombocytopenia NCI CTCAE grade 2 Dose modification at day 1 of cycle subsequent to ADR Haematological criteria in table 2 are met No dose modification. Haematological criteria in Table 2 are not met Reduce by 1 dose level for 5-FU and irinotecan NCI CTCAE grade 3 Dose modification at day 1 of cycle subsequent to ADR Haematological criteria in table 2 are met Reduce by 1 dose level for 5-FU and irinotecan. Haematological criteria in Table 2 are not met Delay 5-FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 1 level for 5-FU and irinotecan NCI CTCAE grade 4 Dose modification at day 1 of cycle subsequent to ADR Haematological criteria in table 2 are met Reduce by 2 dose levels for 5-FU and irinotecan. Haematological criteria in Table 2 are not met Delay 5-FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for 5-FU and irinotecan ADR Stomatitis/Mucositis NCI CTCAE grade 2 Dose modification at day 1 of cycle subsequent to ADR If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5-FU. For recurrent Grade 2 stomatitis, reduce by 2 dose levels for 5-FU. NCI CTCAE grade 3 Dose modification at day 1 of cycle subsequent to ADR If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5-FU. If Grade 3 mucositis/stomatitis does not resolve to Grade ≤1, delay 5-FU for a maximum of 28*days until resolution to Grade ≤1, then dose reduce by 2 dose levels for 5-FU. ADR Febrile neutropenia Dose modification at day 1 of cycle subsequent to ADR Haematological criteria in table 2 are met and fever resolved Reduce by 2 dose levels for 5-FU and irinotecan Haematological criteria in Table 2 are not met and fever resolved. Delay 5-FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for 5-FU and irinotecan. Consider use of colony-stimulating factor prior to next cycle.*The 28 day time period begins on day 1 of the cycle subsequent to the ADR. Docetaxel dose adjustments Docetaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or other Grade 3 or 4 non-haematological toxicities during docetaxel treatment should have treatment withheld until resolution of the toxicity. It is recommended to reduce the docetaxel dose by 10 mg/m2 for all following cycles. A second reduction of 15 mg/m2 is recommended if these toxicities persist or reoccur. In this case, East Asian patients with a starting dose of 60 mg/m² should have docetaxel treatment discontinued (see Posology). Special populations Elderly In the pivotal studies there is limited evidence that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions are recommended (see sections 4.4 and 5.1). Renal impairment There have been no formal studies with Cyramza in patients with renal impairment. Clinical data suggest that no dose adjustments are required in patients with mild, moderate or severe renal impairment (see sections 4.4 and 5.2). No dose reductions are recommended. Hepatic impairment There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical data suggest that no dose adjustments are required in patients with mild or moderate hepatic impairment. There are no data regarding ramucirumab administration in patients with severe hepatic impairment (see sections 4.4 and 5.2). No dose reductions are recommended. Paediatric population The safety and efficacy of Cyramza in children and adolescents (<18 years) has not been established. No data are available. There is no relevant use of ramucirumab in the paediatric population for the indications of advanced gastric cancer or gastro-oesophageal adenocarcinoma, adenocarcinoma of the colon and rectum, lung carcinoma, and hepatocellular carcinoma. Method of administration Cyramza is for intravenous use. After dilution, Cyramza is administered as an intravenous infusion over approximately 60 minutes. It should not be administered as an intravenous bolus or push. To achieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of 25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patient should be monitored during infusion for signs of infusion-related reactions (see section 4.4) and the availability of appropriate resuscitation equipment should be ensured. For instructions on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. For patients with NSCLC, ramucirumab is contraindicated where there is tumour cavitation or tumour involvement of major vessels (see section 4.4). 4.8 Undesirable effects Summary of the safety profile The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were: Gastrointestinal perforation (see section 4.4) Severe gastrointestinal haemorrhage (see section 4.4) Arterial thromboembolic events (see section 4.4) The most common adverse reactions observed in ramucirumab-treated patients are: neutropenia, fatigue/asthenia, leukopenia, epistaxis, diarrhoea and stomatitis. Tabulated list of adverse reactions Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens for the treatment of gastric cancer, mCRC and NSCLC. ADRs are listed below by MedDRA body system organ class. The following convention has been used for classification of frequency: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Table 6: ADRs reported in patients treated with ramucirumab as monotherapy in phase 3 clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml) System organ class (MedDRA) Blood and lymphatic system disorders Very common Thrombocytopeniaa Common Neutropeniaa System organ class (MedDRA) Metabolism and nutrition disorders Common Hypokalaemiaa,b Hyponatraemiaa

Hypoalbuminaemiaa System organ class (MedDRA) Nervous system disorders Very common Headache Common Hepatic encephalopathyc System organ class (MedDRA) Vascular disorders Very common Hypertensiona,d Common Arterial thromboembolic eventsa System organ class (MedDRA) Respiratory, thoracic, and mediastinal disorders Common Epistaxis System organ class (MedDRA) Gastrointestinal disorders Very common Abdominal paina,e Diarrhoea Common Intestinal obstructiona Uncommon Gastrointestinal perforationa System organ class (MedDRA) Skin and subcutaneous tissue disorders Very common Rasha System organ class (MedDRA) Renal and urinary disorders Very common Proteinuriaa,f System organ class (MedDRA) General disorders and administration site disorders Very common Peripheral oedema Common Infusion-related reactionsa a Terms represent a group of events that describe a medical concept rather than a single event or preferred term. b Includes: hypokalaemia and blood potassium decreased. c Based on study REACH-2 and REACH (single-agent ramucirumab in HCC). Includes hepatic encephalopathy and hepatic coma. d Includes: blood pressure increased and hypertension. e Includes: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain. f Includes one case of nephrotic syndrome Table 7: ADRs reported in patients treated with ramucirumab in combination with chemotherapy in phase 3 clinical trials (RAINBOW, REVEL and RAISE) System organ class (MedDRA) Infections and infestations Common Sepsisa,b System organ class (MedDRA) Blood and lymphatic system disorders Very common Neutropeniaa Leukopeniaa,c Thrombocytopeniaa Common Febrile neutropeniad System organ class (MedDRA) Metabolism and nutrition disorders Common Hypoalbuminaemiaa Hyponatraemiaa System organ class (MedDRA) Vascular disorder Very common Hypertensiona,e System organ class (MedDRA) Respiratory, thoracic, and mediastinal disorders Common Epistaxis System organ class (MedDRA) Gastrointestinal disorders Very common Stomatitis Diarrhoea Common Gastrointestinal haemorrhage eventsa,f Gastrointestinal perforationa System organ class (MedDRA) Skin and subcutaneous tissue disorders Common Palmar-plantar erthyrodysaesthesia syndromeg System organ class (MedDRA) Renal and urinary disorders Very common Proteinuriaa,h System organ class (MedDRA) General disorders and administration site disorders Very common Fatiguea,i Mucosal inflammationd Peripheral oedema a Terms represent a group of events that describe a medical concept rather than a single event or preferred term. b Based on study RAINBOW (ramucirumab plus paclitaxel). c Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased. d Based on study REVEL (ramucirumab plus docetaxel). e Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy. f Based on study RAINBOW (ramucirumab plus paclitaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, MalloryWeiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage. g Based on study RAISE (ramucirumab plus FOLFIRI). h Includes cases of nephrotic syndrome. i Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel). Includes: fatigue and asthenia.

Clinically relevant reactions (including Grade ≥3) associated with antiangiogenic therapy observed in ramucirumab-treated patients across clinical studies were: gastrointestinal perforations, infusion-related reactions and proteinuria (see sections 4.2 and 4.4). Colorectal cancer Ramucirumab in combination with FOLFIRI In the RAISE study, in mCRC patients treated with ramucirumab plus FOLFIRI, the most frequent (≥1%) ADR that led to the discontinuation of ramucirumab was proteinuria (1.5%). The most frequent (≥1%) ADRs leading to discontinuation of one or more components of FOLFIRI were: neutropenia (12.5%), thrombocytopenia (4.2%), diarrhoea (2.3%) and stomatitis (2.3%). The most frequent component of FOLFIRI to be discontinued was the 5FU bolus. Adverse reactions from other sources ADRs of haemangioma and thrombotic microangiopathy were reported in ramucirumab clinical trials at a frequency of common (1.5%) and rare (0.03%), respectively, and through post-marketing reporting. ADRs of aneurysms and artery dissections have a frequency of ‘not known’. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Belgium : l’Agence fédérale des médicaments et des produits de santé, Division Vigilance, Boîte Postale 97, B- 1000 Bruxelles Madou (www.afmps.be ou adversedrugreactions@fagg-afmps.be) Luxembourg : Centre Régional de Pharmacovigilance de Nancy, Bâtiment de Biologie Moléculaire et de Biopathologie (BBB), CHR de Nancy – Hôpitaux de Brabois, Rue du Morvan, 54511 VANDOEUVRE LES NANCY CEDEX, tel. : (+33) 3 83 65 60 85/87, fax : (+33) 3 83 65 61 33, e-mail crpv@chru-nancy.fr or Direction de la Santé, Division de la Pharmacie et des Médicaments, Allée Marconi – Villa Louvigny, L- 2120 Luxembourg, tel. : (+352) 247-85592, fax : (+352) 247-95615, e-mail pharmacovigilance@ms.etat.lu. Link for the form: http://www.sante.public.lu/fr/politique-sante/ministere-sante/direction-sante/div-pharmacie-medicaments/index.html 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83 3528 BJ Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/14/957/001-003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 19 December 2014 Date of latest renewal: 26 September 2019 10. DATE OF REVISION OF THE TEXT 30th of September 2019 METHOD OF DELIVERY Medicine only available on medical prescription Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Public Price (€) Patient Price (€)CYRAMZA® 100 mg 400,40 0 CYRAMZA® 500 mg 2002,01 0REIMBURSED in Combo & Monotherapy

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