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ESMO PRECEPTORSHIP ON ADVANCED NON RESECTABLEHEPATOCELLULAR CARCINOMA,BILIARY AND PANCREATIC CANCER

1st line treatment in advanced BTCs and the continuum

of care

Konstantinos Kamposioras, FRCP, PhD

Department of Medical Oncology

The Christie NHS Foundation Trust

Manchester, UK

Paris, 06/12/2019

DISCLOSURES

No conflicts of interest

OVERVIEW

❖ Introduction

❖ Diagnostic Challenges

❖ 1st line Chemotherapy

❖ 2nd line Chemotherapy

❖ Future Perspectives

BTCs are a group of different diseases which includes iCCA, eCCA,

and gallbladder cancer.

Valle et al. Cancer Discov 2017, Lamarca Current Med Chem 2018

BTCS – EPIDEMIOLOGY

Rare cancers

◆ Incidence: <6/100,000

Incidence increasing

◆ iCCA

Poor prognosis

◆ 5 year OS (<20%)

◆ Late diagnosis

◆ 70% advanced stages

◆ High relapse rate

Bañales Nat Rev G&H 2018; DeOliveira ML Ann Surg 2007; Valle JW Ann Oncol 2016

DIAGNOSTIC CHALLENGES

❖ Delayed Diagnosis

❖ Non-specific symptoms

❖ Jaundice/biliary obstruction may present in already advanced stage

(common in eCCA)

❖ No adequate screening - population at risk poorly defined

Forner et al Liver International 2019


➢ eCCA vs. ampulla vs. head of

pancreas (distal)

➢ iCCA vs. HCC vs. CUP

- Initial arterial rim enhancement

followed by centripetal enhancement

- capsular retraction

- Carcinoma of unknown primary

misdiagnosis (21%)

Forner et al Liver International 2019; Hainsworth et al J Clinic Oncolo 2013

Differential Diagnosis


HCC: 90% of primary liver cancer

(underlying cirrhosis)

iCCA: 10% (mainly non-cirrhotic liver)

But, Cirrhotic patients may develop iCCA

(may display a vascular pattern similar to

HCC) - Biopsy needed

Combined HCC/CCA rare but it does exist

(1.3%)

Forner et al Liver International 2019; Lleo et al her Adv Med Oncol. 2019; Connell et al Chin Clin Oncol 2016; Moeini et al Clin Cancer Res.2016

Differential Diagnosis

MANAGEMENT OF BTCS

ESMO GUIDELINES

Valle et al Ann Oncol 2016

Level of

recommendation now

I,A

LOCALLY-ADVANCED-BTC: INITIAL CONSIDERATIONS

Limited evidence on best approach from large trials

Chemotherapy similar to metastatic disease

• RFA/MWA is feasible for small metastases

Liver-directed strategies

◆ Chemo-embolisation: small studies

Transarterial chemoembolisation (TACE) with

drug-eluting beads (DEB) or with Gem/Ox:

feasible with some activity

◆ Liver radio-embolisation with Y-90 particles

(SIRCCA trial)RFA: Radiofrequency Ablation; MWA: Microwave Ablation

Liver-directed therapies

Lack of RCTsProspective trials needed

Labib 3t al. Hepat. Oncol. 2017

ADVANCED-BTC: INITIAL CONSIDERATIONS

Surgery limited role; Chemotherapy-based management◆ Limited benefit with limited response rate (20%)

◆ Expected median OS◆ BSC: 2.5 - 4.5 months

◆ Chemotherapy: 12 months

◆ Around 15% fit for second-line chemotherapy ◆ Rapid clinical deterioration

• Discussion in multidisciplinary team: liver-directed therapies

Biliary obstruction can recur despite adequate stenting◆ Median time to stent-related event 4.4 months (include PDAC patients)

◆ Increased risk if plastic stent in situ: secure metal stent before initiation of chemotherapy

Valle Annals of Oncol 2016; Glimelius Annals of Oncol 1996; Sharma JCO 2010; Valle NEJM 2010; Lamarca WJG 2016; Bridgewater EJC 2013

FIRST LINE TREATMENT-CHT

Best Supportive Care (no chemo)

• Median OS 2.5 - 4.5 months 1,2

Cisplatin & gemcitabine (CisGem) improves survival (over

Gem alone)

1 Glimelius 1996 Ann Oncol, 2 Sharma 2010 J Clin Oncol, 3 Valle 2010 New Eng J Med, 4 Okusaka 2010 Br J Cancer, 5 Valle 2014 Ann Oncol

Gemcitabine alone5

Cisplatin + gemcitabine5

Hazard ratio = 0.65 95% CI 0.54–0.78P < 0.001

Months

% o

f p

atie

nts

al

ive

STUDY

PFS (months) OS (months)

Gem CisGem Gem CisGem

ABC-023 5.0 8.0 8.1 11.7

BT-224 3.7 5.8 7.7 11.2

Meta-analysis5 6.7 8.8 8.0 11.6

FIRST LINE TREATMENT-CHT

DFS

Valle 2014 Ann Oncol

OS

First Line Treatment-QoL

Bridgewater et al Br J Cancer 2016

Intrahepatic cholangioCa (iCCA)- Seem to have a better prognosis

– 50% liver-predominant disease (better prognosis)

Lamarca JNCI 2019

Subgroup analysis ABC-01/02/03

FIRST LINE TREATMENT - FAVOURABLE SUBGROUP

FIRST LINE TREATMENT – WHAT’S NEW?

Sakai et al. Annals Of Oncol 2018 Abstr# 1405

First Line Treatment - ChT

Diarrhea, stomatitis, sensory neuropathy and rash statistically more frequent in GCS arm (p<0.05)

FIRST LINE CHT-WHAT ELSE?

Phase 3 SWOG 1815: Recruiting

Gemcitabine,Cisplatin

Q3W

Gemcitabine,Cisplatin,

Nab-Paclitaxel

Q3W

Primary endpoint

OS

Secondary endpoints

PFS, ORR, DCR, safety,

Ca199 response

Key inclusion criteria

• Untreated locally advanced,

metastatic BTC

• ECOG PS: 0-1

N=268

Random

ized

2:1

OS:overall survival; PFS: progression-free survival; ORR:overall response rate; DCR: Disease control Rate

clinicaltrials.gov NCT03768414 Accessed 23/11/2019

https://clinicaltrials.gov/ct2/show/NCT03768414

First Line Treatment-Biological Agents

1 Malka 2014 Lancet Oncol, 2 Chen 2013 J Clin Oncol, 3 Lee 2012 Lancet Oncol, 4 Leone 2015 Cancer , 5 Moehler Eur J Cancer 2014, 6 Valle et al Lancet Oncol 2015 7Valle 2010 NEJM

RR

(%)

Median PFS

(months)

Median OS

(months)

Study Regimens PhaseChemo

alone

With

biological

Chemo

alone

With

biological

Chemo

alone

With

biological

Malka1 GemOx +/- cetuximab 2 23 23 5.5 6.1 12.4 11.0

Chen2 GemOx +/- cetuximab 2 15 27 4 7.1 8.8 10.3

Lee3 GemOx +/- erlotinib 3 16 30 4.2 5.8 9.5 9.5

Leone4 Gem/Ox +/- panitumumab 2 18 27 4.4 5.3 10.2 9.9

Moehler5 Gemcitabine +/- sorafenib 2 10 14 4.9 3 11.2 8.4

Valle6 CisGem +/- cediranib 2 19 44* 7.4 8 11.9 14.1

ABC-027 CisGem (for reference) 26 8.0 11.7

Understanding the molecular biology

Nakamura et al. Nature Genetics 2015; 1Ross (ASCO GI) J Clin Oncol 33, 2015

• Multiple pathways investigated

• Variability of mutations across BTCs

• Most promising data: IDH and FGFR (iCCA)

First Line Treatment-What Next?

Intrahepatic cholangiocarcinoma CCA has a different profile to extrahepatic CCA or GBC


Rizvi et al. Nat Rev Clin Oncol. 2018

Understanding the molecular biology


◆ A Phase 3, Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of

Pemigatinib Versus Gemcitabine Plus Cisplatin Chemotherapy in First-Line Treatment of Participants With

Unresectable or Metastatic Cholangiocarcinoma With FGFR2 Rearrangement (FIGHT-302)


Q3W

Pemigatinib 13.5mg QD,

Continuous dosing

Primary endpoint

PFS

Secondary endpoints

OS, ORR, DOR, DCR

TEAEs. QoL


• Patient with unresectable/metastatic

CCA with FGFR2 rearrangement

N=432

Random

ized

1:1

OS:overall survival; PFS: progression-free survival; ORR:overall response rate; DOR: Duration of response; DCR: Disease control Rate; TEAEs; Number of treatment-emergent adverse events




◆ A Phase 3 Multicenter, Open-Label, Randomized, Controlled Study of Oral Infigratinib Versus Gemcitabine With

Cisplatin in Subjects With Advanced/Metastatic or Inoperable Cholangiocarcinoma With FGFR2 Gene

Fusions/Translocations: The PROOF Trial


Q3W

Infigratinib 125 mg OD; 3

weeks on, 1 week off.

Primary endpoint

PFS; independent

assessment

Secondary endpoints

OS, PFS investigator

assessment


• Patient with unresectable/metastatic

CCA with FGFR2 gene fusions/

translocationst

N=350

Random

ized

1:1

OS:overall survival; PFS: progression-free survival; ORR:overall response rate; DOR: Duration of response; DCR: Disease control Rate; TEAEs; Number of treatment-emergent adverse events



SECOND-LINE TREATMENT

CHALLENGING SCENARIO FOR CLINICAL TRIALS

Second-line chemotherapy has been used historically based on retrospective and small phase II

evidence

Due to aggressive behaviour of CCA, few patients are considered to be fit enough for second-

line chemotherapy after progression to first-line (approx. 15%)

Good HPB medicine is still of relevance in this setting

◆ Active symptoms control: early detection and management of biliary tract obstruction and

cancer-related symptoms

◆ Pro-active medical management

Bridgewatter EJC 2013

SECOND LINE TREATMENT

Till Recently - No standard of care in second-line treatment

Lamarca Annals of Oncol 2014

➢ 25 studies (14 phase II), 761 patients

➢ Variety of schedules tested with limited benefit

Precision Medicine in BTCs

Verlingue Eur J Cancer 2017

*determined from first-line CisGem: sensitive (progression after three months (90 days) of day 1 of the last cycle of 1st-line CisGem), refractory (progression during 1st line CisGem), resistant (progression within the first three months (90 days) after completion of day 1 of the last cycle of 1st line CisGem)

Inclusion criteria• Histo/cytologically verified

advanced BTC

• ECOG performance score 0-1

• Progression after 1st-line CisGem

• Max 6 weeks progression to randomisation

• Adequate haematological, renal & hepatic function

ABC-06: Phase III, randomised, open-label clinical trial

Platinum sensitivity (yes vs. no; determined from first-line CisGem*)Serum albumin (<35 vs. ≥35 g/L)Stage (locally advanced vs. metastatic disease)

Stratification factors

1:1

R

Arm A: Active Symptom Control (ASC)• May include: biliary drainage, antibiotics,

analgesia, steroids, anti-emetics etc• 4-weekly clinical review

Arm B: Active Symptom Control + mFOLFOX• Chemotherapy every 14 days for up to 12 cycles• Day 1: Oxaliplatin 85mg/m2, L-folinic acid 175

mg (or folinic acid 350 mg), 5 FU 400 mg/m2

(bolus), 5 FU 2400 mg/m2 46 hours continuous infusion

• 4-weekly clinical review after chemotherapy • 3-monthly radiological assessment

Follow up

• Primary end-point: Overall Survival (OS)

(ITT, adjusted for stratification factors)

• Secondary end-points: PFS, response rate, QoL, HealthEcon

Second-line – FOLFOX (ABC-06)

Lamarca ASCO 2019

29


Enro

llme

nt

Allo

cati

on

Follo

w-u

pA

nal

ysis

Excluded (n=24)• Ineligible (n=21)•Withdrew consent (n=2)•Patient died (n=1)

Analysed (n=81)Intention-to-treat analysis

Randomised (n=162)

Consented (n=186)

Excluded (n=104)•Declined (n=52)• Ineligible (n=38)•Patient died (n=5)•Not specified (n=9)

Assessed for eligibility (n=290)

Lost to follow-up (patient decision) n=2; lost to follow-up with <3 months of follow-up

Lost to follow-up (patient uncontactable) n=1; lost to follow-up after 13.3 months

Allocated to Arm B (n=81)• Received allocated intervention (n=75)

; =1 cycle (n=9)• No chemotherapy (n=6)

Allocated to Arm A (n=81)• Received off-study

chemotherapy (n=9)

Analysed (n=81)Intention-to-treat analysis

◆ Baseline characteristics

were balanced between

treatment arms except

platinum sensitivity

◆ CCA: 70% (Arm A) and

74% (Arm B)

◆ Molecular profiling was not

routinely available for

patients

Lamarca ASCO 2019

% o

f p

atie

nts

aliv

e

100

Months from randomisation0

80

60

40

20

0

12 15 18 21 24 27 30

Number at riskASC alone

ASC + mFOLFOX

3 6 9

8181

6664

2841

1429

921

79

56

34

13

12

10

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)

Adjusted* HazardRatio

0.69 (95% CI 0.50-0.97) p=0.031

Overall survival by trial arm


Primary end-point: Overall Survival (ITT)

FOLFOX improved OS after progression to CisGemwith:

• A clinically meaningful reduction in risk of death (HR 0.69 (95% CI 0.50-0.97; p=0.031)

*adjusted for platinum sensitivity, albumin and stageLamarca ASCO 2019

31

% o

f p

atie

nts

aliv

e

100


80

60

40

20

0

12 15 18 21 24 27 30


ASC + mFOLFOX

3 6 9

8181

6664

2841

1429

921

79

56

34

13

12

10

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)


0.69 (95% CI 0.50-0.97) p=0.031

Median OS 5.3 months 6.2 months


Lamarca ASCO 2019 *adjusted for platinum sensitivity, albumin and stage



• Survival with active symptom control was greater than anticipated (5.3 vs 4 months)



% o

f p

atie

nts

aliv

e

100


80

60

40

20

0

12 15 18 21 24 27 30


ASC + mFOLFOX

3 6 9

8181

6664

2841

1429

921

79

56

34

13

12

10

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)


0.69 (95% CI 0.50-0.97) p=0.031


6-month survival-rate 35.5% 50.6%


*adjusted for platinum sensitivity, albumin and stage




• A clinically meaningful increase on OS rate :

• at 6 months (+15%)



Lamarca ASCO 2019

% o

f p

atie

nts

aliv

e

100


80

60

40

20

0

12 15 18 21 24 27 30


ASC + mFOLFOX

3 6 9

8181

6664

2841

1429

921

79

56

34

13

12

10

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)


0.69 (95% CI 0.50-0.97) p=0.031



12-month survival-rate

11.4% 25.9%








• at 12 months (+15%)



Lamarca ASCO 2019

% o

f p

atie

nts

aliv

e

100


80

60

40

20

0

12 15 18 21 24 27 30


ASC + mFOLFOX

3 6 9

8181

6664

2841

1429

921

79

56

34

13

12

10

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)


0.69 (95% CI 0.50-0.97) p=0.031



12-month survival-rate

11.4% 25.9%


Second-line – FOLFOX (ABC-06)Primary end-point: Overall Survival (ITT)







• at 12 months (+15%)

FOLFOX + ASC new standard of care

Lamarca ASCO 2019

Exploratory subgroup analysis

The benefit of chemotherapy was

consistent across the exploratory subgroups

Subgroups with poorer prognosis seemed to

benefit the most from mFOLFOX

◆ Platinum resistant/refractory

◆ Low albumin

◆ Metastatic disease

*HRs are adjusted for platinum sensitivity, albumin and stage


Lamarca ASCO 2019

Impact of platinum-sensitivity (subgroup analysis)

• Trend towards better OS for patients with platinum sensitive disease [HR 0.71 (95% CI 0.49-1.001); p-value 0.050; adjusted for trial arm, albumin and stage in the whole population]

• The effect of mFOLFOX was apparent in both platinum sensitive and refractory/resistant patients

27 21 15 12 11 5 3 2 1 1 0ASC + mFOLFOX34 30 15 7 6 5 4 3 1 1 1ASC alone

Number at risk

0 3 6 9 12 15 18 21 24 27 30

Months from randomisation

54 43 26 17 10 4 3 2 2 1 0ASC + mFOLFOX47 36 13 7 3 2 1 0 0 0 0ASC alone

Number at risk

0

20

40

60

80

100

% o

f p

atie

nts

aliv

e

0

20

40

60

80

100

% o

f p

atie

nts

aliv

e

0 3 6 9 12 15 18 21 24 27 30

Months from randomisation

Platinum resistant/ refractory casesPlatinum sensitive casesArm A

(ASC alone)

Arm B (ASC +

mFOLFOX)

Hazard ratio* 0.81 (95% CI 0.47-1.4)

Median OS 5.7 months

(95% CI 3.9-7.0)6.6 months

(95% CI 3.5-14.6)

Arm A (ASC alone)

Arm B (ASC +

mFOLFOX)

Hazard ratio* 0.63 (95% CI 0.41-0.96)

Median OS 4.8 months

(95% CI 3.9-5.7)5.8 months

(95% CI 5.1-7.6)


*adjusted for platinum sensitivity, albumin and stageLamarca ASCO 2019

Lamarca Cancer Treat Rev 2018

(ABC-06)

MANAGEMENT OVERVIEW – THE CONTINUUM OF CARE

➢ Diagnosis of BTCs can be challenging

➢ Different clinical and molecular subgroups identified with potentially prognostic/predictive implications

➢ Well established first line chemotherapy with minimal improvement over the last decades

➢ Second-line chemotherapy with FOLFOX has confirmed OS benefit in the second-line setting

➢ Good HPB medicine remains of huge relevance

➢ Targeted treatments seem promising; trials on 1st line setting are awaited

TAKE HOME MESSAGES

esmo preceptorship on advanced non resectable ...€¦ · esmo preceptorship on advanced non...

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