Systemic antitumor therapies: Do we have real algorithms in ......Patients with well-differentiated...

Jaume Capdevila, MD, PhD

GI and Endocrine Tumor UnitVall d’Hebron University Hospital Developmental Therapeutics UnitVall d’Hebron Institute of Oncology (VHIO)

Systemic antitumor therapies: Do we have real algorithms in advanced NENs?

� Personal conflicts of interest: Scientific consultancy role (speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi and Merck Serono.

� Research support : Research grants from Novartis, Pfizer, Astrazeneca, Advanced Accelerator Applications, Eisai and Bayer.

Disclosure slide

TREATMENT OPTIONS = TREAMENT ALGORITHM?

Unresectable NENs

Si-NET panNET LUNG NET NEN G3

G1 G2 G1 G2 G1 G2 NETG3 NECG3

Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy

Lanreotide (CLARINET) Somatostatin Analogues? Somatosta tin Analogues?

Everolimus RADIANT-3 & RADIANT-4 Chemotherapy? Targeted agents?

PRRT NETTER-1

Sunitinib

Interferon Chemotherapy

TREATMENT SEQUENCE BASED ON GUIDELINES?

Pavel M, et al. Neuroendocrinology 2016

SSAs

CHT

EVEROLIMUS

SUNITINIB

SSAs

EVEROLIMUS

SUNITINIB

CHT

SSAs

PRRT

CHT

SUNITINIB

EVEROLIMUS

SUNITINIB

SSAs

CHT

SEQUENTIAL THERAPIES: COUNTRY-BASED…

panNETs

ADVANCED NENs: THERAPEUTIC ALGORITHM

Unresectable NENs






PRRT NETTER-1

Sunitinib


PROMID AND CLARINET STUDIES

Screening period Treatment period

Study visits (weeks)

Lanreotide Autogel 120 mg s.c. every 28 days

Placebo s.c. every 28 days

Randomization 1:1

12–24 weeks*

CT scan 1 CT scan 2

24 48 72 9636 12 1

(baseline)

RADIANT PROGRAM: EVEROLIMUS IN NETs

Phase IIPancreatic

NETs

Everolimusw/wo

Octreotide LAR

EORR 9.6%PFS 9.7m

E+OORR 4.4%

PFS 16.7m

Phase IIINon-

PancreaticNETs

Octreotide LAR + Everolimus

vsOctreotide LAR

+ placebo

16.4 vs 11.3mHR 0.77 P=0.026 (one

sided)

Phase IIIPancreatic

NETs

Everolimusvs

Placebo

11 vs 4.6mHR 0.35 P<0.001

Phase IIIGI & Lung

NETs

Everolimusvs

Placebo

11 vs 3.9mHR 0.48 P<0.00001

RADIANT-1

RADIANT-2

RADIANT-3

RADIANT-4

RADIANT-4 STUDY DESIGN

*Based on prognostic level, grouped as: Stratum A (better prognosis) − appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worst prognosis) − lung, stomach, rectum, and colon except caecum.Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

Endpoints: • Primary: PFS (central)• Key Secondary: OS• Secondary: ORR, DCR, safety, HRQoL

(FACT-G), WHO PS, NSE/CgA, PK

Everolimus 10 mg/day N=205

Treated until PD, intolerable AE, or consent withdrawal

Patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N=302)

• Absence of active or any history of carcinoid syndrome

• Pathologically confirmed advanced disease

• Radiologic disease progression in ≤ 6 months

2:1

RANDOMIZE

Placebo N=97

Stratified by:• Prior SSA treatment (yes vs. no)• Tumor origin (stratum A vs. B)*• WHO PS (0 vs. 1)

Yao JC, et al. Lancet 2016

PRIMARY ENDPOINT: PFS BY CENTRAL REVIEW

52% reduction in the relative risk of progression o r death with everolimus vs placebo

HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.CI, confidence interval; HR, hazard ratio.

205 168 145 124 101 81 65 52 26 10 3 0 097 65 39 30 24 21 17 15 11 6 5 1 0Placebo

Everolimus

No.of patients still at risk

0 2 4 6 8 10 12 15 18 21 24 27 30

Months

0

10

20

30

40

50

60

70

80

90

100P

roba

bilit

y of

Pro

gres

sion

-fre

e S

urvi

val (

%) Kaplan–Meier medians

Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43)

Censoring TimesEverolimus (n/N = 113/205)Placebo (n/N = 65/97)


PFS HR BY PRIMARY ORIGINRETROSPECTIVE CENTRALLY REVIEWED


Lung

GI†

NET of unknown

primary

Hazard Ratio (95% CI)Subgroups*

90

175

36

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.56 (0.37-0.84)

0.60 (0.24-1.51)

Everolimus Better Placebo Better

*One patient with thymus as primary tumor origin was not included.†Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI.

Hazard ratio obtained from unstratified Cox model.

GI, gastrointestinal; NET, neuroendocrine tumors.

WHAT ABOUT FUNCTIONING TUMORS?

Pavel M, et al. Lancet, 2011

NETTER-1 STUDY DESIGN

Aim

Design International, multicenter, randomized, comparator-controlled, parallel-group

Evaluate the efficacy and safety of 177Lu-Dotatate (Lutathera®) plus Octreotide30 mg compared to Novartis Octreotide LAR 60mg (off-label use)1 in patients with inoperable, somatostatin receptor positive, midgut NET, progressive under Octreotide LAR 30mg (label use)

Baseline and

Randomization

n = 115

Dose 1

n = 115

Treatment and AssessmentsProgression free survival (Recist criteria) every 12 weeks

5 Years follow

up

Dose 2 Dose 3 Dose 4

4 administrations of 7.4 GBq of LUTATHERAevery 8 weeks + Octreotide30 mg

Octreotide LAR 60mg every 4 weeks

Strosberg J, et al. N Engl J Med 2017

PATIENTS’ CHARACTERISTICS

177Lu-Dotatate

(n=116)

Octreotide LAR 60mg

(n=113)

Age (years), mean (SD) 63 (±9) 64 (±10)

Gender, n (%)

Male

Female

53 (46%)

63 (54%)

60 (53%)

53 (47%)

Primary tumor site, n (%)

Jejunum

Ileum

Appendix

Right colon

Other

6 (5%)

86 (74%)

1 (1%)

3 (3%)

20 (17%)

9 (8%)

82 (73%)

2 (2%)

1 (1%)

19 (17%)

Site of metastasis, n (%)

Liver

Lymph nodes

Bone

Lungs

Other

97 (84%)

77 (66%)

13 (11%)

11 (10%)

40 (35%)

94 (83%)

65 (58%)

12 (11%)

5 (4%)

37 (33%)

Strosberg J, et al. N Engl J Med 2017

PRIMARY ENDPOINT: PFS

Strosberg J, et al. ENETS 2018

TREND ON OVERALL SURVIVAL BENEFIT

Strosberg J, et al. ENETS 2018

SWOG S0518: STUDY DESIGN

Bevacizumab 15 mg/kg q21 d octreotide LAR 20 mg q21 d

Interferon α-2b 5 mu 3 d/wkoctreotide LAR 20 mg q21 d

Treatment until disease progression

RANDOMIZE

Study populationAdvanced G1/2 NET with poor prognosis• Progressive disease• Refractory

syndrome• G2 with 6+ lesion• Colorectal or gastric

primary

1:1

Multiphasic CT or MRI performed every 9 wk

Primary endpoint:• PFS (Central radiology review)

Stratification factors:• Primary site: Midgut vs others• PD since diagnosis• Histologic grade: G1 vs G2 • Octreotide 2 months prior to registration

Yao JC, et al. J Clin Oncol 2017

MY TENTATIVE ALGORITHM FOR siNETs

• SOMATOSTATIN ANALOGUES: • Functioning & non-functioning• SSRT scintigraphy +ive & -ive (?)• Ki67 up to 10% (and over…)

1st Treatment option

• EVEROLIMUS (EVEROLIMUS + SSAs)• Non-functioning (functioning)• SSRT scintigraphy +ive & -ive• High & low tumor burden2nd Treatment option

• 177Lu-DOTATATE• Functioning & non-functioning• SSRT scintigraphy +ive

3rd Treatment option

4th Treatment option • Interferon… ¿?• Indication based on a

negative trial & old trials…

• CHT?


Unresectable NENs






PRRT NETTER-1

Sunitinib


CLARINET: PFS IN panNETs

PFS in midgut vs pancreatic NET

0 3 6 9 12 18 24 270

10

20

30

40

50

60

70

80

90

100

Time, months

Lanreotide Autogel 120 mg8 events / 33 patientsmedian, not reached

Placebo21 events / 40 patientsmedian, 21.1 months [95% CI: 17.0, NC]

Midgut NETs (n =73)Lanreotide Autogel vs placeboP = .0091 HR = 0.35 [95% CI: 0.16, 0.80]

0

10

20

30

40

50

60

70

80

90

100

Time, months

Lanreotide Autogel 120 mg18 events / 42 patientsmedian, not reached

Placebo31 events / 49 patientsmedian, 12.1 months [95% CI: 9.4, 18.3]

pNETs (n = 91)Lanreotide Autogel vs placeboP = .0637 HR = 0.58 [95% CI: 0.32, 1.04]

0 3 6 9 12 18 24 27

Pat

ient

s A

live

and

With

No

Pro

gres

sion

, %

Caplin ME, et al. N Engl J Med. 2014

RADIANT-3: STUDY DESIGN

Everolimus 10 mg/d +best supportive care 1

n = 207

Placebo +best supportive care 1

n = 203

Multiphasic CT or MRI performed every 12 weeks

Treatment until disease progression

Patients with advanced pNET (N = 410)• Advanced well or

moderately differentiated• Radiologic progression ≤12 months

• Prior antitumour therapy allowed

• WHO PS ≤2

Stratified by:• WHO PS

• Prior chemotherapy

Crossover at disease progression

1Concurrent somatostatin analogues allowed

RANDOMISE

Phase III, Double-Blind, Placebo-Controlled Trial

Primary Endpoint: Progression-free survival By investigator reviewSecondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK)

1:1

Yao JC, et al. N Engl J Med. 2011


Yao JC, et al. N Engl J Med. 2011

Kaplan-Meier median PFSEverolimus: 11.0 monthsPlacebo: 4.6 months

Hazard ratio = 0.35; 95% CI 0.27-0.45P value: <.0001

Time (months)

100

80

% E

vent

-fre

e

Censoring timesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

BENEFIT OBSERVED REGARDLESS PRIOR CHT

p value is obtained from the unstratified one-sided log-rank test. Hazard ratio is obtained from unstratified unadjusted Cox model.

� In the everolimus arm, median PFS did not significantly differ in patients who did and did not receive prior chemotherapy

� In the placebo arm, a trend toward shorter median PFS was observed in patients who had received prior chemotherapy compared

with chemo-naive patients

Lombard-Bohas C, et al Pancreas 2015

Raymond E, et al. N Engl J Med. 2011

• Phase III randomised, placebo-controlled, double-blind trial• Trial terminated after unplanned early analysis

Primary Endpoint:• PFS

Sunitinib 37.5 mg/day orallyContinuous daily dosing*

n = 86

Placebo*n = 85

* With best supportive careSomatostatin analogues were permitted

Secondary Endpoints:• OS • ORR • TTR • Duration of response • Safety• Patient-reported outcomes

RANDOMISE

1:1

Well differentiated advanced pNET patients (N = 171 enrolled / 340 planned)

• Disease progression in past 12 mos

• Not amenable to curative treatment

SUNITINIB PHASE III: STUDY DESIGN

Per

cent

age

of e

vent

-fre

e

Time (months)

Censoring timesSunitinib (n/N = 30/86)Placebo (n/N = 51/85)

Kaplan-Meier median PFSSunitinib: 11.4 monthsPlacebo: 5.5 months

HR = 0.42 ; 95% CI [0.26-0.66]P value <.001; nominal critical z value = 3.8506

0 5 10 15 20 25

8685

3928

197

42

01

00

Number at risk:SunitinibPlacebo

0

20

40

60

80

100

* Local review



DEGREE OF TUMOR SCHRINKAGE

Maximum change from baseline of target lesions in p atients from the sunitinib phase III study*

The RECIST-defined ORR in patients receiving suniti nib was 9.3%; however, the majority of patients had some degree o f tumour shrinkage

(Clinical Benefit Rate 72%) †

SD

PR: ≥30% decrease

PD: ≥20% increase

Sunitinib Placebo

Confirmed partial or complete response

−100

−80

−60

−40

−20

0

20

40

60

Cha

nge

from

bas

elin

e (%

)


OVERALL SURVIVAL

Faivre S, et al. Ann Oncol 2016

STZ-BASED CHEMOTHERAPY

Moertel C, et al. N Engl J Med, 1992

TEMOZOLOMIDE-BASED CHEMOTHERAPY

Kunz PL, et al. ASCO 2018

RR: 28% vs 33% (p=0.47)G3-4 AEs: 22% vs 44% (p=0.007)

• SOMATOSTATIN ANALOGUES: • Functioning & non-functioning• SSRT scintigraphy +ive• Ki up to 10%• Not too much liver involvement


• EVEROLIMUS / SUNITINIB / CHT• Progressive disease• Higher tumor burden• Symptoms related with tumor

burden

2nd Treatment option


• EVEROLIMUS / SUNITINIB / CHT• Sequential therapies

MY TENTATIVE ALGORITHM FOR panNETs

Refractory setting • PRRT ¿?• Alternative CHT regimens ¿?


Unresectable NENs






PRRT NETTER-1

Sunitinib


EVEROLIMUS THE ONLY APPROVED DRUG FOR LUNG NETS


Lung

GI†

NET of unknown

primary

Hazard Ratio (95% CI)Subgroups*

90

175

36

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.56 (0.37-0.84)

0.60 (0.24-1.51)

Everolimus Better Placebo Better

*One patient with thymus as primary tumor origin was not included.†Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI.

Hazard ratio obtained from unstratified Cox model.

GI, gastrointestinal; NET, neuroendocrine tumors.

LIMITED EFFICACY OF CHT IN LUNG NETs

Granberg D, et al. Ann Oncol 2011

SSAs IN LUNG NETs: ONLY RETROSPECTIVE DATA

Lopez C, et al. ENETS 2016; Sullivan I, et al. Eur J Cancer 2017

• SOMATOSTATIN ANALOGUES…• Functioning & non-functioning• SSRT scintigraphy +ive• Typical (atypical)


2nd Treatment option • EVEROLIMUS

3rd Treatment option • CHT (TMZ?) / PRRT ?

MY TENTATIVE ALGORITHM FOR LUNG NETs


Unresectable NENs






PRRT NETTER-1

Sunitinib


PLATINUM-BASED CHT IN G3 NENs

TREATMENT SUGGESTIONS…

Sorbye H, et al. Endocrinol Metab Clin North Am 2018

INITIAL DATA TO TREAT NET G3 AS NET G2…

RR: 43/31/57%

G1/G2/G3

RECIST ORR: 34% (Ki67<55%) vs 17% (Ki67>55%)

PRRT

SUNITINIB

TMZ-BASED CHT

Thank you ☺

@Ja_Capdevila

[email protected]

Systemic antitumor therapies: Do we have real algorithms in ......Patients with well-differentiated...

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