sorafenib side effects and dose adjustment · the gi symptoms seen during nexavar therapy may be...

$: Sorafenib Side effects and dose adjustment · The GI symptoms seen during NEXAVAR therapy may be different from patient to patient. \爀屮Some find that they experience their \൳ymptoms$
SORAMIC 1

Sorafenib - Side effects and dose adjustment -

Adverse events: prevention and management as key

• Patients should be informed to:– Take preventive measures, where

possible 1

– Be aware and report AEs as soon as possible 2,3

• Patients alerted to possible AEs before beginning treatment:– May be more accepting of these

symptoms 3

– Are more likely to stay on treatment 1-5

SORAMIC 2

1. Porta C, et al. Clin Exp Med. 2007;7:127-134. 2. Wood L. Commun Oncol. 2006;3:558-562. 3. Robert C, et al. Lancet Oncol. 2005;6:491-500. 4. Autier J, et al. Arch Dermatol. 2008;144(7):886-892. 5. Lacouture M, et al. The Oncologist. 2008;doi: 10.1634/theoncologists.2008-0131.

Adverse events: prevention and management as key

Early intervention and symptomatic treatment may:

– Improve quality of life (QOL) 1

– Facilitate adherence to therapy, optimizing potential benefits of therapy 1-5

SORAMIC 3

For non‐life‐threatening manageable events,

The “take‐home” message is:• Symptoms can usually be alleviated with symptomatic treatment or

dose modifications, and

sorafenib treatment can continue 1‐5

1. Autier J, et al. Arch Dermatol. 2008;144(7):886-892. 2. Wood L. Commun Oncol. 2006;3:558-562. 3. Robert C, et al. Lancet Oncol 2005;6:491-500. 4. Porta C, et al. Clin Exp Med 2007;7:127-134. 5. Lacouture M., et al. The Oncologist. 2008;doi: 10.1634/theoncologists.2008-0131.

AE usually occur early and are of short duration

SORAMIC 4

5

Possible side effects

SORAMIC

6

SHARP: Tolerability

Llovet JM, et al. NEJM 2008; 359(4): 378-90SORAMIC

7

Sorafenib (n=149)

Placebo (n=75)

Therapy-related AE %Grade

All 3/4 All 3/4HFSR 45 11 3 0Diarrhea 26 6 5 0Alopecia 25 - 1 -Fatigue 20 3 8 1Rash 20 1 7 0Hypertension 19 2 1 0Anorexia 13 0 3 0Nausea 11 1 11 1

“Asian-Pacific-SHARP”: Tolerability

Cheng AL, et al. Lancet Oncol 2009; 10(1): 25-34SORAMIC

System Organ Class Very Common

≥1/10

Common≥1/100, <1/10

Uncommon≥1/1,000, <1/100

Blood and Lymphatic System Disorders

Lymphopenia LeucopeniaNeutropeniaAnemiaThrombocytopenia

Immune System Disorders

Hypersensitivity reactions (incl. skin reactions and urticaria)

Endocrine Disorders Hypothyroidism

Metabolism and Nutrition Disorders

Hypophosphatemia Anorexia Hyponatriemia, dehydration

Ear and Labyrinth Disorders

Tinnitus

Cardiac Disorders Myocardial ischemia and infarction*, congestive heart failure*

Vascular Disorders Hemorraghe (incl. gastrointestinal*, respiratory tract* and cerebral hemorraghe*), hypertension

Respiratory, Thoracic and Mediastinal Disorders

Hoarseness Rhinorrhoea

8

Side Effects: Protocol Overview

* may have a life-threatening or fatal outcome

SORAMIC

System Organ Class Very Common

≥1/10

Common≥1/100, <1/10

Uncommon≥1/1,000, <1/100

Gastrointestinal Disorders

Diarrhea, nausea, vomiting Constipation, stomatitis (including dry mouth and glossodynia), dyspepsia,

dysphagia

Gastro esophageal reflux disease, pancreatitis, gastritis, gastrointestinal perforations*

Hepatobiliary Disorders Increase in bilirubin and jaundice, cholecystitis,

cholangitis

Skin and Subcutaneous Tissue Disorders

Rash, alopecia, hand foot syndrome**, erythema, pruritus

Dry skin, dermatitis exfoliative, acne, skin

desquamation

Eczema, erythema multiforme, minor keratocanthoma

(squamous cell cancer of the skin)

Musculoskeletal, Connective Tissue and

Bone Disorders

Arthalgia, myalgia

Reproductive System and Breast Disorders

Erectile dysfunction Gynaecomastia

General conditions and Administration Site

Conditions

Fatigue, pain (including mouth, abdominal, bone, tumour pain and

headache)

Asthenia, fever, influenza like illness

Investigations Increased amylase, increased lipase Weight decrease, transient increase in

transaminases

Transient increase in blood alkaline phosphatase, INR

abnormal, prothrombin level abnormal

9

Side Effects: Protocol Overview

* may have a life-threatening or fatal outcome** hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA

SORAMIC

CTCAE v4.0 (May 2009) -

general criteria -

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

CTCAE v4.0

Mild; asympto-

maticor mild symptoms;clinical or diagnosticobservations only;intervention notindicated.

Moderate; minimal,local or noninvasiveinterventionindicated; limitingage-

appropriateinstrumental ADL.

Severe or medicallysignificant but notimmediately lifethreatening;Hospitali-

zation orprolongation ofHospitali-

zationindicated; disabling;limiting self careADL.

Life-

threatening conse-

quences; urgent intervention indicated

Death related to AE

10

CTCAE v4.0 Grade 2 Grade 3

Specific limit to function

limitingage-appropriateinstrumental ADL

limiting self careADL

Definition of ADL Instrumental ADL refer topreparing meals,shopping for groceries orclothes, using thetelephone, managingmoney, etc.

Self care ADL refer tobathing, dressing andundressing, feeding self,using the toilet, takingmedications, and notbedridden.

11

CTCAE v4.0 (May 2009) -

general criteria /

activities of daily life ADL -

12

Dosing

SORAMIC

Dose Level 1 400mg bid (twice a day)

Dose Level -1 400mg qd (every day)

Dose Level -2 400mg qod (every other day)

Dose Level 1b (re-escalation) * (400mg –

0 –

200mg ) qd (every day)

13

Dose Levels

*Dose level 1b:

not to be used in the first 20 patients of the palliative arm (+

RE/SIRT); introduction after approval by the DSMB

SORAMIC

14

Primary interventional treatment(RFA /RE)

Primary interventional treatment(RFA /RE)

Dose level 1: 400mg bidDose level 1: 400mg bid

START Sorafenib:Dose level -1: 400mg qd

START Sorafenib:Dose level -1: 400mg qd

Day 0

Day 10

Day 3

Dose Escalation

SORAMIC

15

Dose-Adjustment

SORAMIC

16

• 1st reduction to -1: 400mg qd

• 2nd reduction to -2: 400mg qod

CAVE: Withdrawal criteria !

• After toxicity resolution: step-wise re-escalation

• Documentation according to CTCAE 4.0

Dose De-escalation: General Comments

SORAMIC

17

Dose Re-escalation - Overview

SORAMIC

18

Diarrhea

SORAMIC

Common GI Symptoms: Description

•

Can occur at any time during the course of treatment and include:–

Diarrhea: usually presents as loose/more frequent stools rather than watery diarrhea (diarrhea = an increase of more than 7 stools/day)

–

Nausea–

Vomiting

–

Abdominal cramps and bloating•

GI symptoms are usually Grade 1 or 2

19NEXAVAR® (sorafenib tablets) [package insert]. Wayne, NJ: Bayer Healthcare; 2008. 2. NEXAVAR®

(sorafenib tablets) [summary of product characteristics]. Bayer Healthcare; 2008.

HCC (n = 297)All Grades (%) Grades ¾

(%)

Diarrhea 55 10/<1Nausea 242 1/0Vomiting 152 2/0

Vorführender

Präsentationsnotizen

The GI symptoms seen during NEXAVAR therapy may be different from patient to patient. Some find that they experience their symptoms just in the evening; others may experience them 1 or 2 days every cycle.

2020SORAMIC

Side Effects: Diarrhea

Toxicity Grade 1 2 3 4 5

Clinical presentation Increase of

<4 stools/d over baseline;mild increase in ostomy output compared to baseline

Increase of 4-6 stools/d over baseline; moderate increase in ostomy output compared to baseline;

Increase of >7 stools/day over baseline; incontinence; Hospitalisation indicated; severe increase in ostomy output compared to baseline; limiting self care ADL

Life-threatening consequences (e.g., hemodynamic collapse), ugent intervention indicated

Death

Diarrhea

CTCAE v4.0

General GI Symptoms: Diarrhea Management

•

Advise patients to:–

Maintain hydration with plenty of fluids containing water, salts, and sugar1,2

–

Avoid fluids with meals OR when taking a bulk-forming laxative1,2

–

Avoid foods that can aggravate the diarrhea (spicy, fatty, dairy

products, caffeine)1,2

–

Eat plain, simple foods, such as bananas, potatoes, rice1

–

Avoid stool softeners 2

•

Diarrhea may be managed with:–

Increased intake of high-fiber diet–

Anti-diarrhea medications (loperamide 2mg after each loose bowel movement, racecadotril 100mg bid

or diphenoxylate), when indicated 1,2

–

Cholestyramine (cholesterol-lowering agent that decreases motility/increases reabsorption); not to be taken 1-2 hours before or after scheduled dose of sorafenib 2

•

Dose modification/interruption

(per protocol) may be initiated, if necessary1,2

211. Wood L. Comm Oncol. 2006;3:558-562. 2. Bhojani N, et al. Eur Urol. 2007; doi: 10.1016/j.euroro.2007.

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

22

Dose De-escalation: Non-Haematologic (I)

Grade 1 / 2

Grade 3

Continue at same dose levelSupportive treatment

Withhold until toxicity is <

°1

In case of 2nd °3 toxicity


°1, resume at dose level -1

If no toxicity > °1, re-escalation possible

If toxicity > °1, de-escalation to -2

SORAMIC

or discontinuation

Treatment at this level for 28 days

then resume at same dose level

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

23

Dose De-escalation: Non- Haematologic (II)

Grade 4 Withhold until toxicity is <


Discontinuation at discretion of investigatorDiscussion with study sponsor

SORAMIC

If toxicity > °1, de-escalation to -2 or discontinuation

24

HFSR Hand-Foot-Skin-Reaction

SORAMIC

HFSR: Typical Presentation

•

Painful, red, swollen, symmetrical, bilateral areas on palms/soles–

Also found on lateral sides of fingers and around the nail

•

Thickening of skin (hyperkeratosis)

•

Dry and/or cracked skin

•

Callus-like blisters

•

Preceded or accompanied by prickling, tingling or “creeping” sensation

25Porta et al. Clin Exp Med 2007, 7:127-134

HFSR: Onset and Course

•

Onset usually within first 6 weeks of treatment with a Tyrosine Kinase Inhibitor (TKI)–

Symptoms can begin as early as 1 to 2 weeks–

Intensity of symptoms frequently decreases over time

•

Preventative measures before treatment may minimize incidence and severity (reduce occurence of Grade 3 events)

•

If HFSR does occur–

It must be recognized and treated promptly–

Early symptoms may quickly resolve with adequate symptomatic treatment might prevent progression to higher grade

•

Temporary treatment discontinuation often results in symptomatic improvement

–

Symptoms may be less severe when re-challenged at a dose reduction26

HFSR: Prevention and Management

•

Patients should be informed that…–

They might have dermatological side effects–

They should take preventive measures–

They should monitor and report to their health care professionals

•

Patients who are alerted before beginning treatment…–

May be more accepting of these symptoms–

May be more likely to stay on treatment

•

Early intervention…–

Improves quality of life and treatment compliance–

Maximizes benefits of treatment

•

The “take-home”

message…–

Dermatologic symptoms can usually be alleviated with symptomatic treatment or dose modifications, and Nexavar treatment can continue

27

Toxicity Grade 1 2 3 4 5Clinical presentation

Minimal skin changes or dermatitis (e.g.,erythema, edema, or hyperkeratosis)without pain

Skin changes (e.g.,peeling, blisters,bleeding, edema, or hyperkeratosis) with pain; limitinginstrumental ADL

Severe skinchanges(e.g. peeling,blisters, bleeding,edema, or hyper-keratosis) with pain;limiting self care ADL

- -

28

Side Effects: Hand-Foot- Skin Reaction

Hand-Foot-Skin

reaction

SORAMIC

CTCAE v4.0

HFSR Protocol-defined Grading: Grade 1

29

Grade 1:“Minimal skin changes or dermatitis (e.g.,erythema, edema, or hyperkeratosis) without pain

“

Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet, and/or discomfort, which does not disrupt normal activities.

30

Grade 2: Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL


31

Grade 3: “Severe skin changes (e.g. peeling, blisters, bleeding, edema, or

hyper-

keratosis) with pain; limiting self care ADL”Moist desquamation, ulceration, blistering or severe pain of the

hands

and/or feet, and/or severe discomfort that limits self care ADL.


HFSR Prevention and Management:

Calluses•Before sorafenib therapy:

–

Check condition of hands and feet–

Suggest a manicure/ pedicure, when indicated

–

Recommend pumice stone use for callus or ‘rough spot’

removal

32

During sorafenib therapy: Reduce-

Pressure points-

Items that rub, pinch, or create friction

Wood L. Comm Oncol. 2006;3:558-562. Robert C, et al. Lancet Oncol. 2005;6:491-500.

33

Apply non

urea-based

creams liberally– Cetaphil®– Aveeno®

– Udderly Smooth®

– Gold Bond®

– Norwegian Formula®

– Eucerin®

Alpha Hydroxy Acids

(AHA)– ~5% to 8% provide gentle

chemical exfoliation– Apply liberally two

times each day

Apply urea-based creams sparingly and only to affected areas

Avoid products with >10% urea, as these may increase irritation

Avoid systemic steroids



34

Protect tender areas

Use socks/gloves to cover moisturizing creams

Wear well-padded footwear

Use insole cushions or inserts (eg, silicon, gel)

Soak feet in tepid water and Epsom salts



Cushions

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

35

Dose De-escalation: HFSR (I)

Grade 1

Grade 2

Supportive measures & continue at same dose level

Supportive measures and decrease to level -1 (28 days)

If toxicity <

°1

Re-escalate

If no

toxicity > °1, resume at level -1 (28 days)

Hand-Foot-Skin

reaction

Interrupt for 7 days

If no

toxicity > °1, re-escalation possible

If toxicity > °1

If toxicity <

°1

SORAMIC

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

36

Dose De-escalation: HFSR (II)

Grade 2 2nd occurence

If no


Hand-Foot-Skin

reaction


If no

toxicity > °1, re-escalation possible Maximum level at which toxicity was not exceeding °1

3rd occurence

4th occurence

If no

toxicity > °1, resume at level -1 indefinitely




400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

37

Dose De-escalation: HFSR (III)

Grade 3 1st occurence

If no


Hand-Foot-Skin

reaction

Interrupt for 7 days / until tox. < °1

If no


2nd occurence

3rd occurence

Decrease indefinitely to level with toxicity <

°1

Interrupt for 7 days / until tox. <

°1

Interrupt for 7 days / until tox. < °1


38

Arterial Hypertension

SORAMIC

SORAMIC 39

• A disorder characterised by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mmHg

• Hypertension most commonly presents early

• Monitor blood pressure weekly during the first 6 weeks

• Thereafter, blood pressure check as needed

Hypertension

SORAMIC 40

Toxicity Grade 1 2 3 4 5

Clinical presentation

Pre-

hypertension (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg)

Stage 1 hypertension (systolic BP 140-159 mmHg or diastolic BP 90-99 mmHg); medical intervention indicated; recurrent or persistent (≥

24 hrs); symptomatic increase by > 20 mmHg (diastolic) or to > 140/90 mmm Hg if previously WNL; monotherapy indicated

Stage 2 hypertension (systolic BP ≥

160 mmHg or diastolic BP ≥

100 mm Hg) medical intervention indicated, more than one drug or more intensive therapy than previously used indicated

Life-

threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated

Death

CTCAE v4.0

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

41

Dose De-escalation: Hypertension (I)

Grade 1asymptomatic

transientConsider increased BP-monitoring

Hypertension

Grade 2asymptomatic

diastolicBP > 110mmHg: antihypertensive therapy, continue sorafenib

SORAMIC

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

42

Dose De-escalation: Hypertension (I)

Grade 2Symptomatic

Persistentor BP = 110mmHG

Grade 3

Withhold until symptoms resolve + diastolic BP < 100mmHG

When achieved, resume at dose level -1

If diastolic BP > 100mmHG: de-escalation to level -2

Hypertension

Grade 4 Discontinuation

SORAMIC

No re-esalation planned !

Management of arterial hypertension

•

Control elevated blood pressure before starting Nexavar therapy

•

Standard oral antihypertensive agents may be used

•

Permanent discontinuation of Nexavar should be considered in cases of severe or persistent hypertension (despite adequate antihypertensive therapy)

•

Advise patients

–

that their blood pressure needs to be monitored regularly

–

Seek medical advice if symptoms of hypertension appear, such as headache or blurred vision

SORAMIC 43Wood L. Comm Oncol. 2006;3:558-562. Bhojani N, et al. Eur Urol. 2007; doi: 10.1016/j.euroro.2007.

Management of arterial hypertension

•

Standard antihypertensives may be used

–

However, as sorafenib is cleared hepatically, appropriate antihypertensives without hepatic clearance may be a reasonable first choice

–

Country-specific hypertension management guidelines should be consulted

–

If possible, avoid diuretics as patients may use fluids with increased stool frequency as well

–

Unselective beta-blockers may additionally help control complications of portal hypertension

SORAMiC 44

45

Hematologic side effects

SORAMIC

Hematologic side effects

SORAMIC 46

Toxicity Grade 1 2 3 4 5Leukocytes <LLN -

3000/mm3

<LLN –

3.0 x 109/L

<3000-

2000/mm3

<3.0 –

2.0 x 109/L

<2000-

1000/mm3

<2.0 –

1.0 x 109/L

<1000/mm3

<1.0 x 109/LDeath

Neutrophils <LLN -

1500/mm3

<LLN –

1.5 x 109/L

<1500-

1000/mm3

<1.5 –

1.0 x 109/L

<1000-

500/mm3

<1.0 –

0.5 x 109/L

<500/mm3

<0.5 x 109/L

Patelets <LLN –

75,000/mm3

<LLN –

75.0 x 109/L

<75,000-

50,000/mm3

<75.0 –

50.0 x 109/L

<50,000 –

25,000/mm3

<50.0 -

25.0 x 109/L

<25,000/mm3

<25.0 x 109/L

Hb Hgb < LLN –

6.2 mmol/l

Hgb < 6.2 –

4.9 mmol/l

Hgb < 4.9 –

4.0, transfusion indicated

Life-

threatening

consequences; urgent

intervention indicated

death

CTCAE v4.0

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

47

Dose De-escalation: Haematologic (I)

Grade 1 / 2

Grade 3

Continue at same dose level

In case of 2nd °3 toxicity



If no


47

Haematopoetic reactions

SORAMIC


Treatment at this level for 28 days


°1 then resume at same dose level

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

48

Dose De-escalation: Haematologic (II)

Grade 4 Withhold until toxicity is <


Discontinuation at the investigator‘s discretion Discussion with study sponsor

48

Haematopoetic reactions

SORAMIC


49

Fatigue

SORAMIC

Fatigue: grading of severity

SORAMIC 50

Toxicity Grade 1 2 3 4 5Clinical presentation:

Fatigue relieved by rest

Fatigue not relieved by rest; limiting instrumental ADL

Fatigue not relieved by rest, limiting self care ADL

- -

Characterized by a state of general weakness with a pronounced inability to summon sufficient energy to accomplish daily activities

CTCAE v4.0

http://www.feierabend.de/images/channel/web/2/8/g.480028.jpg

Fatigue: Management

•

Fatigue related to other diseases should be excluded:

–

Hypothyroidism

–

Anemia

–

Depression (organic cause)

•

Symptoms of fatigue may be relieved by:1

–

Setting priorities so they can complete their most important tasks

–

Saving demanding activities for when they have the most energy

–

Avoiding long naps that will keep them awake at night

–

Distracting themselves with games, music, books, etc.

–

Staying as active as they can during the day

–

Exercising regularly: advise them to talk to their doctor before starting an exercise program

–

Avoiding caffeine after midday

•

No standard treatment exists for cancer-

or cancer treatment related fatigue

SORAMIC 51

National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/PDF/fatig ue.pdf.Accessed 11 December 2008.

52

Renal Failure

SORAMIC

SORAMIC 53

Renal Failure under therapy with sorafenib

• 252 cases of significant renal events were identified in the Serious Adverse Event (SAE) database (~ 40000 treated patients)

• 1. Pre-renal in 105 cases (41%)

- Most cases originated due to pre-renal renal dysfunction

- This suggests that Nexavar may have the potential to contribute to the development of renal failure through inducing diarrhea, vomiting and dehydration with subsequent volume depletion

• 2. renal in 11 cases (4%)

- Most of these cases were considered to have additional confounding factors in addition to Nexavar dosing

- HOWEVER it cannot be excluded that in rare instances Nexavar may have contributed to renal adverse events of primary renal origin

• 3. Post-renal in 7 cases (3%)

• 4. Unknown in 129 cases (51%)

SORAMIC 54

• It is estimated that by the end of 2007, approximately 40,000 patients had received Nexavar, including patients in clinical trials and marketed use

Renal failure

SORAMIC 55


eGFR or CrCl < LLN-60 ml/min/1.73 m2 or proteinuria 2+ present; urine protein/creati

nine > 0.5

eGFR or CrCl 59-30 ml/min/1.73 m2

eGFR or CrCl 29-15 ml/min/1.73m

2

eGFR or CrCl < 15 ml/min/1.73 m2; dialysis or renal transplant indicated

death

CTCAE v4.0

Characterized by gradual and usually permanent loss of kidney function resulting in renal failure

Renal failure – prevention and management

•

Monitoring of fluid balance and electrolytes in patients at risk

of

renal dysfunction is advised

•

In a clinical pharmacology study, the pharmacokinetics of Nexavar

were evaluated following administration of a single 400 mg dose to

subjects with normal renal function, and in subjects with mild

(creatinine clearance [CrCl] 50-80 ml/min), moderate (CrCl 30 to <

50 ml/min), or severe (CrCl< 30ml/min) renal impairment, not

requiring dialysis

•

There was no relationship observed between Nexavar exposure and

renal function

•

No dosage adjustment is necessary based on mild, moderate or

severe renal impairment not requiring dialysis.

•

Sorafenib has not been studied in patients undergoing dialysis.SORAMIC 56

57

Liver function impairment

SORAMIC

Liver function impairment

SORAMIC 58


Asterixis, mild encepha-

lopathy, limiting self care ADL

Moderate to severe encephalopath y, coma, life threatening consequences

death

CTCAE v4.0


ALAT/ASAT > ULN –

3.0 ULNAsymptomatic with ALT/AST > 3.0-5.0xULN; > 3 x ULN with the appearance of worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia

ALAT/ASAT > 5.0-20.0 x ULN; > 5 x ULN for > 2 weeks

ALAT/ASAT> 20 x ULN

Sorafenib in patients with impaired liver function

•

Patients in SHARP and AP Trial primarily had HCC with CPA liver disease (due to inclusion criteria)1,2

•

The US FDA3and EMEA4 approved Nexavar for HCC* without specifying the underlying cirrhosis status:–

US FDA3: Indication: unresectable HCC; Special Populations:

Hepatic impairment: No dose adjustment is

necessary in HCC patients with CPA and CPB hepatic impairment. Nexavar has not been studied in patients with Child-Pugh C (CPC) hepatic impairment.

–

EU SPC4:

Indication: treatment of HCC; Posology Adjustments: No dose adjustment is required in patients with CPA and CPB (mild to moderate) hepatic impairment. No data is available on patients with CPC.

SORAMIC 59

HCP = healthcare professional1. Llovet JM, et al. N Engl J Med 2008;359:378–90. 2. Cheng A-L, et al. Lancet Oncol 2009;10:25–34; 3. US prescribing information. 4. EU summary of product characteristics. 5. Abou-Alfa GK, et al. J Clin Oncol 2008;26(May 20 Suppl.):217s (Abstract 4518). 6. Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293– 300. 7. Yau T, et al. Cancer 2009;114:428–36. 8. Furuse J, et al. Cancer Sci 2008;99:159–65. 9. Pinter M, et al. Oncologist 2009 [Epub]. 10. Zhu AX, Clark JW. Oncologist 2009 [Epub]

Recommendations

• Liver cirrhosis is the underlying chronic disease in most patients with HCC

• Liver function impairment and complications of portal hypertension can occur independently of the additional malignant disease and its treatment

• Prevention of complications of liver cirrhosis and its sequels should be aimed at

• Liver function needs to be monitored regularly in patients treated with sorafenib

• Progression to Child C or Child B (> 7 points) cirrhosis should lead to study exclusion

SORAMIC 60

61

Pulmonary side effects

SORAMIC

Dyspnea

SORAMIC 62


Shortness of breath with moderate exertion

Shortnes of breath with minimal exertion, limiting instrumental ADL

Shortness of breath at rest; limiting self care ADL

Life-threatening consequences; urgent intervention indicated

death

CTCAE v4.0

Characterized by an uncomfortable sensation of diffculty breathing

Interstitial lung disease

• ILD and TKI

- Gefitinib was associated with an increase in the frequency of ILD in Japanese patients

- the potential association of Nexavar with ILD was assessed in the overall pharmacovigilance program

- Case report: “Interstitial pneumonia probably associated with sorafenib treatment: An alert of an adverse event”

- interstitial pneumonia occurred in 4 among approximately 2000 Japanese patients treated with sorafenib

SORAMIC 63

Nakagawa et al.:Interstitial lung disease in gefitinib-treated Japanese patients with non-small cell lung cancer - a retrospective analysis.BMC Res Notes. 2009 Aug 5;2:157.Ide et al.: Interstitial pneumonia probably associated with sorafenib treatment: An alert of an adverse event. Lung Cancer. 2010 Feb;67(2):248-50

• 1. ILD

a group of lung diseases affecting the interstitium (alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues)

• 2. symptoms

- breathlessness during exercise

- dry cough

- signs of heart failure

• 3. causes

- inhaled substances (e.g. Asbestosis)

- drug induced (chemotherapeutics)

- Connective tissue disease (polymyositis)

- infectionSORAMIC 64

Interstitial lung disease

• Very rare differential diagnsosis in case of dyspnoeic patients treated with sorafenib

• Perform chest x-ray, pulmonary function tests, CT Thorax if necessary

• Rule out infectious causes, pleural effusions and other causes of dyspnoea

• Supplement oxgen if necessary

• Induce specific therapy, consider steroids

SORAMIC 65

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

66

Dose De-escalation: Non-Haematologic

(I)

Grade 1 / 2

Grade 3

Continue

at same

dose levelSupportive

treatment

Withhold

until

toxicity

is

<

°1

In case

of 2nd °3 toxicity

Withhold

until

toxicity

is

<

°1, resume

at dose level

-1

If

no toxicity

> °1, re-escalation

possible

If

toxicity

> °1, de-escalation

to -2

SORAMIC

or

discontinuation

Treatment at this

level

for

28 days

then

resume

at same

dose level

400mg qod

400mg qd

400mg bid

(400–0–200mg ) qd

67

Dose De-escalation: Non- Haematologic

(II)

Grade 4 Withhold

until

toxicity

is

<

°1, resume

at dose level

-1

Discontinuation

at discretion

of investigatorDiscussion

with

study

sponsor

SORAMIC

If

toxicity

> °1, de-escalation

to -2 or

discontinuation

Key messages

• Patients need to be informed about possible side-effects

• Prevention is better than treatment• Grading the severity of AE is crucial• Dose-adjustment!

– Hematologic – arterial hypertension – HFSR – others

• Please keep in- and exclusion criteria in mind

SORAMIC 68

sorafenib side effects and dose adjustment · the gi symptoms seen during nexavar therapy may be...

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