possible today or tomorrow ?major problem = malnutrition...in 11/13: stabilization or improvementof...

Drugs to treat and relieve patients with cancer cachexia

J. Arends, Freiburg, Germany

ESMO Preceptorship Supportive and Palliative Care, Lugano 16-17 April 2018

Drugs in Cachexia_ESMO Lugano 2018-04-17 1

Disclosures

1. Employee or executive position -

2. Consultancy -

3. Shares -

4. Honoraria for presentations -

5. Support for scientific studies -

6. Expert opinion - Helsinn Healthcare SA, Chugai Pharma Europe Ltd.

7. Other financial relations -

Jann Arends

Klinik für Innere Medizin I

Direktor: Prof. Dr. J. Duyster

Universitätsklinikum Freiburg

Germany

Drugs to treat and relieve patients with cancer cachexia- old drugs used for cachectic cancer patients

- new cachexia mechanism-based compounds

Major problem = malnutritionpossible today or tomorrow ?

Pharmacologic Topics

> Appetite stimulation

> Modulation of GI tract

> Anti-inflammatory agents

> Anticatabolic / anabolic agents

Antiemetics

Prokinetic agents, MCP, Domperidon

Inhibitors of GI motility, e.g. lopramide

Proton pump inibitors

Parasympathicomimetics

Anti-infective agents

Etc.

GI supportive agents





Corticosteroids

Progestins

Cannabinoids

(Ghrelin)

(Melanocortin 4 receptor antagonists)

Cyproheptadine

Branched-chain amino acids

Herbal medicine, bitters

Appetite stimulation

effectivity typical dose/day

Hydrocortisone 1

Prednisolone, methylprednisolone 5 20 mg

Dexamethasone 20 4 mg

Systematic review: 6 RCT (n=647; duration 4d to 8w):

� Stimulation of appetite, anti-emetic, increase well-being

� Effects disappear after 4 weeks !

Side-effects: myopathy

osteoporosis

immune suppression

edema

insulin resistance

GI ulcers

Corticosteroids

Yavuszen T et al. J Clin Oncol 2005

typical dose per day

Megestrolacetate 160-1600 mg

Medroxyprogesterone acetate 300-1200 mg

Stimulation of appetite

Increase in body weight, but no increase in LBM

Improve QoL

Side-effects: thromboembolism (5%)

impotence in males

vaginal spotting or bleeding

hypertension, hyperglycemia

edema

adrenal insufficiency

Not approved for cancer anorexia

Progestins

Marijuana stimulates appetite (mainly smoking)

- Marijuana extracts

- Delta-9-tetrahydrocannabinol = THC / Dronabinol

Stimulation of appetite with 5-20 mg

Effects on mood, nausea, pain

Use regulated by narcotics law

Side-effects: dizziness

slurred speech

Cannabinoids

RCT: n=164 cancer cachexia, 6 weeks:

cannabis extract (5 mg THC)

vs THC (5 mg)

vs placebo: app ∅, QoL ∅

Strasser F et al. J Clin Oncol 2009

Cannabinoids

Unfortunately: no dose escalation was allowed

RCT: n=21 cancer patients with sensory alterations, 18 days:

dronabinol (5 mg THC)

vs placebo: taste +, appetite +

energy intake +, protein intake +

Brisbois TD et al. Ann Oncol 2011

A trial in individual patients may be justified!

Cannabinoids





Steroids and cannabinoids

Non-steroidal anti-inflammatory drugs (NSAID)

N-3 fatty acids

Anti-cytokines: ruxolitinib

(anti-IL 6, anti-IL 1, anti-TNF, pentoxifyllin, thalidomide)

Anti-cancer treatment

Anti-infective agents, e.g. clarithromycin

Melatonin

Antioxidants

Anti-inflammatory agents

Lundholm K et al. Cancer Res 1994

NSAID

Systematic review: 13 studies (6 controlled studies)

� studies are small

� suboptimal design

� many studies without comparator

� in 11/13: stabilization or improvement of WT or LBM

� „NSAIDs may improve weight in cancer patients..“

� „Evidence is too frail to recommend..“

NSAID in cancer cachexia

Solheim T et al. Acta Oncol 2012

Not approved for cancer anorexia

N-6

PUFA

Prostanoids

2 and 4 series

N-3

PUFAProstanoids

3 and 5 series

pro-inflammatory

anti- / less inflammatory

Arachidonic acid

Eicosapentaenoic acid

Side effects: dyspepsia, nausea, fishy taste

prolonged bleeding time (??)

Long chain fatty acids

cyclooxygenase

COX

Cochrane systematic review

on 5 RCT: insufficient data

but: poor compliance

only short trials

Systematic review Colomer et al.

on 17 clinical trials: >1.5 g/d fish oil

➜ appetite +, weight +, QoL +

but: not based on RCTs

Dewey A et al. Cochrane Database Syst Rev 2007

Colomer R et al. Br J Nutr 2007

N-3 long chain fatty acids

Hurwitz HI et al. J Clin Oncol 2015

Ruxolitinib in pancreatic cancer

RCT, N=127

Capecitabine +/- ruxolitinib 2x15 mg

All patients Patients with SIRS





Anabolic androgenic steroids

(SARMs)

Insulin and insulin sensitivity modulators

Growth hormone, secretagogues, IGF-1

(amino acids and metabolites, e.g. HMB, creatine)

Proteasome inhibitors

ß-adrenergic receptor modulators

Hydrazine sulfate

Adenosine triphosphate (ATP)

(anti-myostatin, selumetinib, IL 15)

Anticatabolic and anabolic agents

Nandrolone RCT (n=37) 4 w WT (+)

Fluoxymesterone RCT (n=475) 4 w app +, WT (+)

Oxandrolone RCT (n=155) 12 w LBM +

�� less effective than corticosteroids and progestins

�� depression, thromboembolism, hypertension etc.

Anabolic androgenic steroids/SARMs

Chlebowski RT et al. Cancer 1986Loprinzi CL et al. J Clin Oncol 1999

Dobs AS et al. Lancet Oncology 2013

Selective androgen response modifiers (SARMs)

Enobosarm Phase 2b trial N=100, 113 days: LBM +

Phase 3 trial NSCLC NCT 01355484

Steroids, cannabinoids

Cyproheptadine

Branched-chain amino acids

Herbal medicine, bitters

Melanocortin 4 receptor antagonists

Ghrelin and analogues

Appetite stimulation

Anamorelin, oral ghrelin analogue = GH secretagogue receptor agonist

2012: RCT 12 w: WT +, grip strength +

2013: RCT 3 d: WT +

2014: RCT 12 w: WT +, LBM +, grip strength ∅

Ghrelin and Analogues

Garcia J et al. Supp Care Cancer 2012

Garcia J et al. Supp Care Can cer 2013

Temel J et al. ESMO 2014-09-25

Ghrelin, peptide hormone of gastric mucosa (28 AA)

2004: RCT (n=7) 3 h: food intake +

2008: RCT (n=21) 1 h: app ∅

2010: RCT (n=15) 10 d: app +, food +, WT-loss –

2010: RCT (n=31) 8 w: fat loss -

Neary NM et al. J Clin Endocrinol Metab 2004

Holst B et al. Br J Cancer 2008

Adachi S et al. Gastroenterol 2010

Lundholm K et al. Cancer 2010

Temel J et al. Lancet Oncol 2016

2 RCT, N=484 and 495, 93 sites, 19 countries

Lung cancer stage III or IV

BMI<20 or weight loss>5% in 6 months

Anamorelin 100 mg for 12 weeks

� Body weight

lean body mass

muscle function: hand grip strength

subjective anorexia: FAACT scale

Anamorelin: Romana trialsTitel





�

Anamorelin: Romana trials


�



�



not

signif.



- Adequate energy and protein supply

- Physical training

- Pain treatment

- Psycho-oncological care

- Treatment of GI defects

… nutrition + exercise interventionmay not be enough for clinical benefitneeded is a multi-modal approach: Steroids and cannabinoids

Non-steroidal anti-inflammatory drugs (NSAID)

N-3 fatty acids

Anti-cytokines: ruxolitinib

Antibiotics, e.g. clarithromycin

Melatonin

Antioxidants

Anti-inflammatory agents

Pentoxifyllin: suppresses TNF synthesis; 1 RCT neg in cachexia

Thalidomide: inhibits TNF synthesis; 4 pos trials

Cochrane SR inconclusive

anti-TNF: infliximab RCT neg in n=89 pancreatic cancer

etanercept: RCT neg in 63 cachectic patients

anti-IL 6

anti-IL 1





Interleukin 6 antibodies

BMS 945429

Preclinical

phase I and II trails (NSCLC) � symptoms -, fatigue-, LBM+

Bayliss et al. Exp Opin Biol Ther

2011

Tocilizumab

Case report (NSCLC) � WT +, Hgb +, ALB +, CRP -

Ando K et al. J Clin Oncol 2013

Interleukin 1 antibody MABp1

At this time Phase 3 RCT in preparation

MABp1b

NCT 02138422: RCT, n=333 patients with advanced CRC

MABp1 iv q2 weeks X 4

Outcome: LBM stable + 2/3 symptoms stable

� 33 vs 19 % (p<0.005)

Hickish T et al. Lancet Ocol 2017

Anabolic androgenic steroids

(SARMs)

Insulin and insulin sensitivity modulators

Growth hormone, secretagogues, IGF-1

(amino acids and metabolites, e.g. HMB, creatine)

Proteasome inhibitors

ß-adrenergic receptor modulators

Hydrazine sulfate

Adenosine triphosphate (ATP)

(anti-myostatin, selumetinib, IL 15)

Anticatabolic and anabolic agents Anabolic androgenicsteroids / SARMs

Nandrolone

Testosterone

Enobosarm

Enobosarm: Change in LBM

Dobs et al., Lancet Oncology 2013

Dobs L et al. Lancet Oncology 2013

Enobosarm: Stair climb time and power





ENOBOSARM vs PLACEBO

p (original data) p (responder analysis)(LBM: no loss, function:

+10%)

POWER1 POWER2 POWER1 POWER2

LBM 0.003 0.0227 0.036 0.113

SCP 0.036 0.7923 0.315 0.289

HGS n.s. n.s. n.s. n.s.

Enobosarm: effectivity according to responder analysis

� �

Myostatin �� Activin Receptor Type IIB

Muscle

Myostatin

Activin A

Rezeptor IIB

blocks muscle protein synthesis

Stamulumab Wyeth muscle dystrophy; discontinued

Landogrozumab Ei Lilly cachexia, data under review

Trevogrozumab Sanofi sarcopenia

Domagrozumab Pfizer muscle dystrophies

Bimagrumab Novartis sarcopenia

Myostatin antibodies Myostatin antibodies

Bimagrumab

N=40 adults, >65 years, with sarcopenia

Bimagrumab 30 mg/kg iv once

Observation 16 weeks:

� muscle mass improved

� muscle strength improved

� mobility improved

� slow walking speed improved

Rooks D et al. J Am Geriatr Soc 2017

� To improve appetite relieve psychological distress and chronic pain

� Optimize gastrointestinal function and relieve nausea

� To stimulate appetite, corticosteroids and progestins are best established;

both have unwanted side-effects that need to be considered

� Anticancer treatment may improve metabolism and decrease inflammation

� Anti-inflammatory agents, like NSAIDs and N-3 fatty acids may be used to

counteract chronic inflammatory states in cancer patients

� Hunger-inducing agents like anamorelin and MC4R antagonists as well as

anabolic-androgenic agents, anti-myostatin, anti-IL6 and anti-IL1

antibodies and other agents are being investigated as potential anticachectic agents

� All anticachectic agents should be accompanied by exercise training

Conclusion

possible today or tomorrow ?major problem = malnutrition...in 11/13: stabilization or improvementof...

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