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
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 2
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
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 3
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
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 4
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
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 5
�
Anamorelin: Romana trials
Temel J et al. Lancet Oncol 2016
�
Anamorelin: Romana trials
Temel J et al. Lancet Oncol 2016
�
Anamorelin: Romana trials
Temel J et al. Lancet Oncol 2016
not
signif.
Anamorelin: Romana trials
Temel J et al. Lancet Oncol 2016
- 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
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 6
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
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 7
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