Clinical Spotlight in Cancer Cachexia · 2018-06-01 · Lipid metabolism . Glucidic metabolism ↑ CRH and somatostatine ↓ Gh → anorexia ↓ IGF -1 Proteolysis . Nausea and vomiting

Clinical Spotlight in Cancer Cachexia

Abstract 1483O_PR

2014 European Oncology Congress in Madrid

Reference Slide Deck

www.primeoncolgy.org

Cachexia

• Often associated with cancer, cardiovascular disease, and chronic infection

“Multi-factorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass)

that cannot be fully reversed by conventional nutritional support

and leads to progressive functional impairment”

Fearon K, et al. Lancet Oncol. 2011;12(5):489-495.

– Pancreatic 83% – Stomach 83%-87% – Non-small cell lung 61% – Small cell lung 57%

– Prostate 56% – Colon 54% – Breast 36% – Non-Hodgkin 36%

Incidence of Cancer-Related Anorexia / Cachexia

• Affects the majority of patients with cancer; up to 80% in terminal stage

• Highest incidence is seen in patients with solid tumors

• Development of anorexia / cachexia is a poor prognostic factor associated with decreased survival

• Largest amount of weight loss occurs in lung cancer and cancers of the upper gastrointestinal tract

Dewys WD, et al. Am J Med. 1980;69(4):491-497.

Cancer Lymphocytes

Monocytes / Macrophages

Cytokines IL-1, IL-6, TNFa

Central nervous system Lipid metabolism

Glucidic metabolism

↑ CRH and somatostatine

↓ Gh → anorexia

↓ IGF-1

Proteolysis

Nausea and vomiting

↓ Lipoprotein lipase

Lypolysis hypertriglyceridemia

↓ Adipocyte size

↓ Fat tissue

Damage to pancreatic beta cells

Hyperinsulinemia

Impaired glucose metabolism

Hypo/hyperglycemia

Tisdale MJ. Physiol Rev. 2009;89(2):381-410.

Symptoms Associated With Cancer Cachexia

• Nausea and vomiting • Anorexia • Weight loss • Anemia • Depletion of fat and muscle tissue • Fatigue • Immunodepression • Resistance to antineoplastic agents and increased

treatment-related toxicities

Fearon KC, et al. Cell Metab. 2012;16(2):153-166.

Fearon K, et al. Lancet Oncol. 2011;12(5):489-495.

Cancer Cachexia Diagnosis and Staging

Precachexia Cachexia Refractory Cachexia

Death Normal

Weight loss ≤5% Anorexia and Metabolic change

Weight loss >5% or BMI <20 and weight loss >2% or sarcopenia and weight loss >2% Often reduced food intake/ Systemic inflammation

Variable degree of cachexia Cancer disease both procatabolic and not responsive to anticancer treatment Low performance score <3 months expected survival

A Multimodal Approach to Cancer Cachexia Management

Fearon KC. Eur J Cancer. 2008:44(8):1124-1132.

Awareness (diagnostic

acumen) Optimal

oncologic management

Nutritional support (eg, high

protein ONS)

Exercise

Anemia therapy (eg,

erythropoietin)

Anti-inflammatory therapy (eg, NSAID, EPA)

Best supportive care (treat secondary

factors)

Early intervention

Multidisciplinary team work

Multimodal therapy

Current Available Treatment • Progestational agents (megestrol acetate)

– To improve appetite and weight

• Corticosteroids – For patients with limited life expectancy (<6 weeks)

• Nutrition counseling and dietary advice

• Treatment of nutritional impact symptoms such as pain,

nausea, vomiting, constipation, and depression

• Resistance exercise – To increase muscle mass

Agents in Clinical Trial for Cancer Cachexia

• Based on expanded understanding of the underlying biology of cachexia, several new molecularly targeted cachexia therapies are in development, including:

– Anti-IL-6 antibodies

– Cytokine antagonists

– Ghrelin receptor agonists

– Myostatin inhibitors

– Selective androgen receptor modulators

• Most non-molecularly targeted therapies (eg, melatonin, cannabis, eicosapentaenoic acid diester) have failed in clinical trials

Baracos VE. J Clin Oncol. 2013;31(10):1257-1258. Ebner N, et al. J Cachexia Sarcopenia Muscle. 2012:3(1):45-50.

Anamorelin for the Treatment of Cancer Anorexia-Cachexia in NSCLC:

Results From the Phase 3 Studies ROMANA 1 and 2

Temel J, Currow D, Fearon K, Gleich L, Yan Y, Friend J, Abernethy A

Abstract 1483O_PR

• Common and debilitating condition that can develop in up to 70% of patients with advanced cancer and often occurs in patients with advanced stage non-small cell lung cancer (NSCLC)1

• Characterized by low appetite and decreased body weight, mainly through the loss of lean body mass (LBM) / skeletal muscle2

• Associated with a worse prognosis and poorer quality of life3

• Current treatment has very limited efficacy and potential risks, especially in patients with advanced cancers4

1. Yavuzsen T, et al. J Clin Oncol. 2005;23(33):8500-8511. 2. Fearon K, et al. Lancet Oncol. 2011;12(5):489-495. 3. Suzuki H, et al. J Gastroenterol. 2013;48(5):574-594. 4. Tuca A, et al. Crit Rev Oncol Hematol. 2013;88(3):625-636.

Cancer Anorexia-Cachexia

Temel J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 1483O_PR.

Ghrelin • Released by the stomach and is the ligand of the ghrelin receptor

that produces the release of growth hormone • Stimulates multiple pathways, which regulate body weight, lean

body mass, appetite, and metabolism

Anamorelin HCl (ANAM) • Orally active, ghrelin

mimetic/receptor agonist

• In a phase 2 trial, patients with advanced NSCLC treated with ANAM experienced a significant increase in mean body weight at 12 weeks1

HN

HN

H2N

Me

N N

Me

Me O HCI

O O

Bn

Me Me

N

Molecular weight: 538.16

Anamorelin HCl

1. Temel J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 1308.

Ghrelin and Anamorelin HCl (ANAM)


Study Design • Two international, double-

blind, Phase 3 trials

• Patients with unresectable stage III or IV NSCLC and cachexia (≥5% weight loss within prior 6 months or BMI <20 kg/m2)

• Randomized (2:1) to receive either 100 mg ANAM or placebo, administered daily orally for 12 weeks

• Assess ANAM efficacy and safety


Week 12

Week 0

Week 12

Inclusion Criteria Key inclusion criteria

• Unresectable stage III or IV NSCLC • Cancer anorexia-cachexia (weight loss of ≥5% body

weight <6 months prior to screening or screening BMI <20 kg/m2)

• Life expectancy of >4 months • ECOG performance status ≤2 • BMI ≤30 kg/m2


Inclusion Criteria Concomitant chemotherapy inclusion criteria • Patients who began a new line of chemotherapy within ±14 days of

randomization • Patients receiving maintenance chemotherapy • Patients with no plan to initiate new chemotherapy within 12 weeks

from randomization − Previous chemotherapy must have been completed >14 days prior

to randomization Concomitant radiation therapy inclusion criteria • Patients who began radiation therapy within ±14 days of

randomization • Patients with no plan to initiate new radiation therapy within 12 weeks

from randomization − Previous radiation therapy must have been completed >14 days

prior


Statistical Analysis Co-primary endpoints • Change from baseline over 12 weeks in:

− Lean body mass (measured by dual-energy X-ray absorptiometry) − Hand grip strength of the non-dominant hand − 477 patients per study 90% power to detect 2 kg difference in lean body mass and

hand grip strength between treatment arms

Secondary endpoints • Change from baseline over time in:

− Body weight − Quality of life as assessed by the Functional Assessment of

Anorexia/Cachexia Therapy (FAACT) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaires

• Overall survival


• Patients were treated for up to 12 weeks and followed for 1 year from randomization (every 3 months)

ROMANA 1 ROMANA 2

First patient enrolled

Jul 8, 2011

Jul 14, 2011

Last patient completed

Jan 28, 2014

Oct 31, 2013

Database locked (excluding OS)

Mar 19, 2014

Dec 6, 2013

Study Conduct


ROMANA 1 ROMANA 1 Both:

Patient Population ROMANA 1 ROMANA 2

Placebo (N = 161)

100 mg ANAM (N = 323)

Placebo (N = 165)

100 mg ANAM (N = 330)

Mean age (SD) 62.6 (8.52) 61.7 (9.65) 62.8 (9.26) 63.3 (8.25) Male, n (%) 121 (75.2) 247 (76.5) 122 (73.9) 240 (72.7) Race, n (%)

Caucasian 159 (98.8) 319 (98.8) 162 (98.2) 326 (98.8) Black/African American 0 (0) 1 (0.3) 1 (0.6) 2 (0.6) Asian 0 (0) 1 (0.3) 1 (0.6) 0 (0) Other/Unknown 2 (1.2) 2 (0.6) 1 (0.6) 2 (0.6)

Mean weight, kg (SD) 68.0 (13.3) 67.6 (13.0) 62.7 (12.9) 63.9 (13.3) Mean BMI, kg/m2 (SD) 23.3 (3.7) 23.2 (3.6) 22.1 (3.7) 22.5 (3.7)

ECOG PS, n (%)

0 16 (9.9) 40 (12.4) 10 (6.1) 26 (7.9) 1 119 (73.9) 218 (67.5) 114 (69.1) 215 (65.2) 2 26 (16.1) 64 (19.8) 41 (24.8) 89 (27.0)

Unknown 0 (0) 1 (0.3) 0 (0) 0 (0)


Baseline Disease Characteristics

ROMANA 1 ROMANA 2

Placebo (N = 161)

100 mg ANAM

(N = 323)

Placebo (N = 165)

100 mg ANAM

(N = 330) Stage, n (%) Stage IIIA 16 (9.9) 19 (5.9) 16 (9.7) 29 (8.8) Stage IIIB 30 (18.6) 48 (14.9) 36 (21.8) 62 (18.8) Stage IV 114 (70.8) 256 ( 79.3) 113 (68.5) 238 ( 72.1)

Stage unknown 1 (0.6) 0 (0) 0 (0) 1 (0.3)

Median time from initial diagnosis to enrollment (months)

6.30 8.45 8.28 9.80


Concomitant Cancer Therapy

ROMANA 1 ROMANA 2

Placebo (N = 161)

100 mg ANAM

(N = 323)

Placebo (N = 165)

100 mg ANAM

(N = 330) Chemotherapy 139 (86.3) 288 (89.2) 125 (75.8) 256 (77.6)

Active therapy 134 (83.2) 275 (85.1) 101 (61.2) 225 (68.2) Maintenance therapy 7 (4.3) 11 (3.4) 26 (15.8) 32 (9.7) Adjuvant therapy 0 (0.0) 3 (0.9) 1 (0.6) 6 (1.8)

Radiation therapy 18 (11.2) 37 (11.5) 14 (8.5) 31 (9.4)

No cancer therapy 22 (13.7) 35 (10.8) 40 (24.2) 74 (22.4)


Lean Body Mass ROMANA 1 ROMANA 2

P < .0001

N = 157

N = 321

P < .0001

N = 158

N = 316

Median change ANAM: 1.10 kg (95% CI: 0.76, 1.42) Placebo: -0.44 kg (95% CI: -0.88, 0.20)

Median change ANAM: 0.75 kg (95% CI: 0.51, 1.00) Placebo: -0.96 kg (95% CI: -1.27, -0.46)

1.10

-0.44

0.75

-0.96

Placebo ANAM


1.2

1

0.8

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

-1

-1.2

Med

ian

Cha

nge

From

B

asel

ine,

kg

1.2

1

0.8

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

-1

-1.2

Med

ian

Cha

nge

From

B

asel

ine,

kg

Observed Change in Lean Body Mass

Baseline Week 6 Week 12 Placebo : 156 127 101 ANAM : 319 257 199

Baseline Week 6 Week 12 156 117 96 320 229 202

ROMANA 1 ROMANA 2

-1

-0.5

0

0.5

1

1.5

2

2.5

Med

ian

Cha

nge

in L

BM

(kg)

-1

-0.5

0

0.5

1

1.5

2

2.5

Med

ian

Cha

nge

in L

BM

(kg)


Placebo ANAM

Hand Grip Strength

ROMANA 1 ROMANA 2

N.S. N.S.

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Med

ian

Cha

nge

From

Bas

elin

e N

ondo

min

ant H

and

(kg)

N = 158 N = 316

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Med

ian

Cha

nge

From

Bas

elin

e N

ondo

min

ant H

and

(kg)

N = 157 N = 321

-1.45

-1.00 -0.95 -1.15

Median change ANAM: -1.00 kg (95% CI: -1.60, -0.30) Placebo: -1.45 kg (95% CI: -2.69, -1.05)

Placebo ANAM

Median change ANAM: -1.15 kg (95% CI: -2.05, -0.45) Placebo: -0.95 kg (95% CI: -1.60, 0.00)


-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

3

Mea

n ch

ange

from

bas

elin

e (k

g)

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

3

Mea

n ch

ange

from

bas

elin

e (k

g)

P<.0001 P<.0001

N = 283 N = 267

N = 135 N = 141

2.20

0.14

0.95

-0.57

Placebo ANAM

Body Weight ROMANA 1 ROMANA 2


ROMANA 1 ROMANA 2

Baseline Week 3 Week 6 Week 9 Week 12

Placebo 141 140 139 126 120

ANAM 284 281 276 247 230


136 135 133 121 117

268 267 265 248 236

Observed Change in Body Weight

-2

-1

0

1

2

3

Mea

n C

hang

e Fr

om B

asel

ine

in B

ody

Wei

ght (

kg)

-2

-1

0

1

2

3

Mea

n C

hang

e Fr

om B

asel

ine

in B

ody

Wei

ght (

kg)

P<.0001 P<.0001 P<.0001 P<.0001 P<.0001 P<.0001 P<.0001 P<.0001


Placebo ANAM

-2

0

2

4

6

8

10

12

Mea

n C

hang

e Fr

om B

asel

ine

in F

AA

CT

Tota

l Sco

re

-2

0

2

4

6

8

10

12

Mea

n C

hang

e Fr

om B

asel

ine

in F

AA

CT

Tota

l Sco

re

Observed Change in FAACT Total Score ROMANA 1 ROMANA 2


Placebo 139 137 132 120 117

ANAM 278 273 264 238 223


133 130 130 118 114

266 260 262 242 230

P = .4771 P = .1122 P = .0532 P = .0516 P = .3940 P = .3628 P = .4351 P = .5352


Placebo ANAM

Anorexia / Cachexia Domain of FAACT

Ribaudo JM, et al. Qual Life Res. 2000;9(10):1137-1146.

• I have a good appetite • The amount I eat is sufficiant to meet my needs • I am worried abouth weight • Most food tastes unpleasant to me • I am concerned about how thin I look • My interest in food drops as soon as I try to eat • I have difficulty eating rich or “heavy” foods • My family and friends are pressuring me to eat • I have been vomiting • When I eat, I seem to get full quickly • I have pain in my stomach erea • My general health is improving


0

1

2

3

4

5

6

Mea

n Ch

ange

Fro

m B

asel

ine

0

1

2

3

4

5

6

Mea

n Ch

ange

Fro

m B

asel

ine

FAACT Anorexia/Cachexia Domain ROMANA 1 ROMANA 2

P = .0016 P = .0004

N = 141 N = 282 N = 133 N = 266

4.12

1.92

3.48

1.34

Improving

Placebo ANAM



Placebo 141 139 137 125 119

ANAM 283 279 271 244 227

-1

0

1

2

3

4

5

6

Mea

n Ch

ange

Fro

m B

asel

ine

in F

AACT

An

orex

ia/C

ache

xia

Dom

ain

Scor

e

-1

0

1

2

3

4

5

6

Mea

n Ch

ange

Fro

m B

asel

ine

in F

AACT

An

orex

ia/C

ache

xia

Dom

ain

Scor

e

ROMANA 1 ROMANA 2


134 132 131 119 116

268 261 265 243 232

P = .0184 P = .0007 P = .0004 P = .0012 P = .0070 P = .0013 P = .0033 P = .0150

Data shown are from mixed-effects pattern-mixture model

Observed Change in FAACT Anorexia/Cachexia Domain


Placebo ANAM

Summary of Common (>2%) Drug-Related Adverse Events

ROMANA 1 ROMANA 2

Placebo (N = 161)

100 mg ANAM (N = 320)

Placebo (N = 161)

100 mg ANAM (N = 330)

Patients with any drug-related TEAEs

15 (9.3) 46 (14.4) 12 (7.5) 32 (9.7)

Grade 1/2 13 (8.1) 43 (13.4) 8 (5.0) 22 (6.7)

Grade 3/4 2 (1.2) 3 (0.9) 4 (2.5) 9 (2.7)

Gastrointestinal disorders 3 (1.9) 20 (6.3) 6 (3.7) 6 (1.8) Nausea 1 (0.6) 12 (3.8) 3 (1.9) 5 (1.5)

Metabolism and nutrition disorders

9 (5.6) 19 (5.9) 2 (1.2) 21 (6.4)

Diabetes mellitus, including inadequate control

4 (2.5) 3 (0.9) 0 (0.0) 7 (2.1)

Hyperglycemia 5 (3.1) 17 (5.3) 1 (0.6) 14 (4.2)


Conclusions • ANAM significantly increased lean body mass

and body weight in patients with advanced NSCLC

• ANAM did not improve hand grip strength • Patients receiving ANAM also experienced an

improvement in anorexia-cachexia symptoms and concerns

• ANAM was well tolerated when administered daily over 12 weeks

• Results on overall survival are pending


Documents

Clinical Spotlight in Cancer Cachexia · 2018-06-01 · Lipid metabolism . Glucidic metabolism ↑ CRH and somatostatine ↓ Gh → anorexia ↓ IGF -1 Proteolysis . Nausea and vomiting