Chemotherapy for metastatic disease

Priv. Doz. Dr. Dr. med. T.O. GötzeInstitute of Clinical Cancer Research

Director: Prof. Dr. S.-E. Al- BatranUniversity Cancer Center Frankfurt

Chemotherapy for metastaticGastric cancer

• First-line chemotherapy: what`s “standard” and what`s best?

• Second-line chemotherapy: where do we stand?

• poor prognosis– 2- Year survival 10-20%– median survival <1 year

• Chemotherapy prolongation of survival(4-11 months)

• Preservation / improvement of QoL

metastatic disease

First-line chemotherapy: general data

• offers survival benefit over BSC1 HR 0.37 [0.24, 0.55]• improvement symptom control1

• Combination better than single-agent 5-FU1

✓ Higher RR: OR 2.91 [2.15, 3.93]✓ Prolonged TTP and OS: HR 0.82 [0.74, 0.90]

• Question: is there an optimal combination?

1Wagner AD et al. Cochrane Database Syst Rev 2010

First-line chemotherapy: active agents

Fluoropyrimidines• 5-FU• Capecitabine• S-1

Camptothecines• Irinotecan

Platinum derivatives• Cisplatin• Oxaliplatin

Taxanes• Docetaxel

Other agents• Epirubicin• MTX• Etoposide• …

First-line chemotherapy: active agents

First-line chemotherapy: what is the standard/ best regimen?

• Platinum + fluoropyrimidine accepted as an international “standard”

✓ OS benefit for platinum vs. non-platinum containig regimen1

• Oxaliplatin and cisplatin equally effective2-4

✓ different side effects

• Oral fluoropyrimidines (capecitabine / S-1) equally effective than intravenous 5-FU2,5,6

1Wagner AD et al. Cochrane Database Syst Rev 2010; 2Cunningham D et al. N Engl JMed 2008; 3Al-Batran SE et al. J Clin Oncol 2008; 4Yamada Y et al. Ann Oncol 2014;5Kang YK et al. Ann Oncol 2009; 6Ajani JA et al. J Clin Oncol 2010

Oral vs. i.v. 5-FU and cis- vs. oxaliplatin

ECF(X): Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided into two doses d1-d21), every three weeks

Oral vs. i.v. 5-FU and cis- vs. oxaliplatin

FU 2.6 g/m2 24h Cl d1Leucovorin 200 mg/m2 d1Oxaliplatin 85 mg/m2 d1q2w

Oral vs. i.v. 5-FU and cis- vs. oxaliplatin

First-line chemotherapy: third-drug for triplet regimen

• Anthracycline = epirubicin, commen but still sustainable?

initial OS benefit for anthra vs. non-anthra1 was not confirmed in metaanalysis of Mohammad NH et al2 2015

In a randomized trial by Yun J et al. 2010 [cisplatin/capecitabine (CX) vs. epirubicinplus CX (ECX)] there was no beneftit due tu adding E to CX3

1Wagner AD et al. Cochrane Database Syst Rev 2010; 2Mohammad NH et al. Cancer Metastasis Rev 2015; 3Yun J et al. Eur J Cancer 2010;

Fluoropyrimidines• 5-FU• Capecitabine• S-1

Camptothecines• Irinotecan

Platinum derivatives• Cisplatin• Oxaliplatin

Taxanes• Docetaxel

Other agents• Epirubicin• MTX• Etoposide• …

First-line chemotherapy: active agents

Grade 3/4 Toxicity %

Neutropenia 82%

Febrile Neutropenia 29%

Stomatitis 21%

Diarrhea 19%

Lethargy 19%

First-line chemotherapy: third-drug for triplet regimen

• Docetaxel increases efficacy

Significantly increased

RR (37% vs. 25%),

TTP (5.6 vs. 3.7 months)

OS (9.2 vs. 8.6 months)

but adds toxicity (V325 phase III trial 1: DCF vs. CF)

Higher grade 3-4 toxicity: neutropenia 82% vs. 57% (Complicatedneutropenia/febrile: 29% vs. 12%)

1Van Cutsem E et al. J Clin Oncol 2006

First-line chemotherapy: third-drug for triplet regimen

Bi- rather than three- weekly = mDCF- modified DCF schedules are preferable

mDCF1: (5-FU 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2

IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks)

GastroTax – 1 Regime2(T-PLF): Docetaxel 40mg/m2 + cisplatin 40mg/m2 2-weekly 5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly

1Shah MA et al. J Clin Oncol 20152Lorenzen et al. Ann Oncol 2007 ; 18: 1673- 9

Taxotere 50 mg/m2 d1Oxaliplatin 85 mg/m2 d1Leucovorin 200 mg/m2 d1FU 2.6 g/m2 24h Cl d1q2w

Al-Batran S, et al. Ann Oncol 2008

– Responserate 58% (FLO 34%)– Med. survival 11.1 Mo – Febrile Neutropenia 3.8%

• Oxaliplatin is a appropiate in triplet regimen with 5-FU/Docetaxel FLOT1: oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 and fluorouracil 2600

mg/m2 as a 24-h infusion in combination with docetaxel 50 mg/m2 on day 1 every 2 weeks

TEF2: docetaxel 50 mg/m2 on D1 + oxaliplatin 85 mg/m2 on D1+ 5- fluorouracil 2400 mg/m2CIV 46h/ folinic acid 400mg/m2 on D1 q2w

1Al-Batran SE et al. Ann Oncol 2008

First-line chemotherapy: third-drug for triplet regimen

2Van Cutsem E et al., Ann Oncol. 2015

meta-analysis by Mohammad NH et al.

Mohammad NH et al. Cancer Metastasis Rev 2015

„ triplet versus doublet chemotherapy “

Mohammad NH et al. Cancer Metastasis Rev 2015

5-Fu better than without

meta-analysis by Mohammad NH et al.„ triplet versus doublet chemotherapy “

No benefit for Mito C

„ triplet versus doublet chemotherapy “

meta-analysis by Mohammad NH et al.

meta-analysis by Mohammad NH et al.

Mohammad NH et al. Cancer Metastasis Rev 2015

No benefit for Epirubicin

„ triplet versus doublet chemotherapy “

meta-analysis by Mohammad NH et al.

Mohammad NH et al. Cancer Metastasis Rev 2015

Cisplatin based regimenbetter than non- cisplatin

„ triplet versus doublet chemotherapy “

meta-analysis by Mohammad NH et al.

Mohammad NH et al. Cancer Metastasis Rev 2015

Taxan based better thannon- taxan

„ triplet versus doublet chemotherapy “

• 21 studies with a total of 3475 participants

improvement in

• overall survival (OS) (hazard ratio (HR) 0.90, 95% (CI) 0.83-0.97)

• progression-free survival (PFS) (HR 0.80, 95% CI 0.69-0.93)

• better objective response rate (ORR) (risk ratio 1.25, 95% CI 1.09-1.44)

• risks of grade 3-4 thrombocytopenia (6.2 vs 3.8%), infection (10.2 vs 6.4%), and mucositis (9.7 vs 4.7%) significantly increased

first-line triplet therapy is superior to doublet therapy

meta-analysis by Mohammad NH et al.„ triplet versus doublet chemotherapy “

First-line irinotecan + 5-FU

Regimen No. Overall Neutropenia(febrileneutropenia)

Diarrhea Tox death

Irinotecan + 5-FU

170 NR 24.8% (4.8%) 21.6% 1

Cis + 5-FU 163 NR 51.6%(10.2%) 7.2% 5

P-value <0.001 <0.001 NR

Dank M et al. Ann Oncol 2008

Regimen No. RR PFS OS TTF

Irinotecan + 5-FU

170 31.8% 5.0 9.0 4.0

Cis + 5-FU 163 25.8% 4.2 8.7 3.4

P-value 0.23 0.088 HR=1.08 0.018

• IF did not yield a significant TTF or OS superiority over CF• IF is a platinum-free regimen that has similar efficacy to CF • but with improved tolerance

FOLFIRI vs. ECX in Firstlinie

Guimbaud et at JCO 2014

First-line irinotecan + 5-FURegimen No. RR PFS OS TTF

FOLFIRI 207 37.8% 5.8 9.7 5.1

ECX 209 39.2% 5.3 9.5 4.2

P-value NS 0.96 HR=1.01 0.008

Regimen No. Overall Hematologic Non-hematologic

Tox death

FOLFIRI 207 69% 38.4% 53.2% 7

ECX 209 83.5% 64.5% 53.5% 5

P-value <0.001 <0.001 0.81 NR

Guimbaud R et al. J Clin Oncol 2014

• FOLFIRI as first-line treatment significantly better TTF than ECX• not original ECX- Regimen from REAL-2-study• no difference in PFS and OS

First-line chemotherapy: FOLFIRI

FOLFIRI a “standard” first-line option ?o comparable activity and efficacy compared to CF and ECX

o lower hematologic toxicity compared to CF and ECX

Not a new standard but an alternative to a platinum based regimen

Doublet vs. triplet: criteria/ open questions

1. age of patient2. fixed treatment period or until PD?3. Patient`s condition as a prognostic factor 4. intestinal vs. diffuse type

1.) elderly patients• doublet preferable over triplet in fit elderly patients ! FLOT vs. FLO: no increase in efficacy over 70 years, at the price of increased toxicity

and QoL deterioration1

V325: phase III trial 2: DCF vs. CF

• Doublet vs. monotherapy

capecitabine vs. XELOX: RR 31% vs. 42%, median PFS 3.1 vs. 7.1 months, median OS 5.4 vs. 13.5 months3

XELOX combination chemotherapy results in improved efficacy

does not increase toxicities in elderly patients with AGC

DSMB stopped trial based on the evidence of superiority with XELOX

In vulnerable elderly patients, single-agent fluoropyrimidine can be considered

When doublets are administered, early stop (after 3-4 months) may be reasonable

fluoropyrimidine maintenance an option 1Al-Batran SE et al. Eur J Cancer 2013

3Hwang IG et al. ASCO Ann Meeting 2015 (abstr. 4051)2Van Cutsem E et al. J Clin Oncol 2006

2.) fixed treatment period or until PD?

o in randomized trials Chemotherapy generally scheduled until PD risk of cumulative toxicity

PFS rarely exceeding 6 months in first-line trials

o Optimal treatment duration unknown trials ongoing (e.g. RAINFALL/ MATEO)

o De-escalation (e.g. fluoropyrimidine maintenance) or treatment holidays after 6 months can be considered

Discontinuation of first-line chemotherapy (CT) after 6 weeks of CT in patients with metastatic squamous-cell esophageal cancer: A randomized phase II trial.

Presented By Antoine Adenis at 2016 ASCO Annual Meeting

SCC at ASCO 2016

Background<br />Metastatic esophageal cancer

Presented By Antoine Adenis at 2016 ASCO Annual Meeting

The E-DIS trial

Presented By Antoine Adenis at 2016 ASCO Annual Meeting

Results<br />Flow Chart

Presented By Antoine Adenis at 2016 ASCO Annual Meeting

Conclusion. 2

Presented By Peter Enzinger at 2016 ASCO Annual Meeting

Conclusion. 2 (modified)

Presented By Peter Enzinger at 2016 ASCO Annual Meeting

(my) Conclusion. 2

Presented By Peter Enzinger at 2016 ASCO Annual Meeting

3.) Clinical prognostic factors

• Among 1080 UK patients treated with 5-FU-based regimens, the following factors resulted associated with worse OS:

✓ ECOG performance status ≥2

✓ liver involvement

✓ peritoneal involvement

✓ alkaline phosphatase ≥100 U/L

Chau I et al. J Clin Oncol 2004

Good risk: no risk factorsModerate risk: 1-2 risk factorsPoor risk: 3-4 risk factors

Clinical prognostic factors

• Among 1445 Asian patients treated with different first-line regimens, the factors associated with worse OS:

✓ ECOG performance status ≥2

✓ bone metastases

✓ no prior gastrectomy

✓ ascites

✓ alkaline phosphatase >85 U/L

✓ albumin <3.6 g/dL

Lee J et al. Ann Oncol 2007

Good risk: 0-1 risk factorsModerate risk: 2-4 risk factorsPoor risk: 5-6 risk factors

4.) Lauren classification and path. remission: FLOT vs. ECF/ECX

Rates of ypCR according to Lauren’s histological subtypes

Al- Batran et al. Lancet Oncol in press

Regimen Intestinal (n) Mixed (n) Diffuse (n)

Total 16% (112) 6% (18) 3% (73)

FLOT 23% (52) 0% (11) 3% (34)

ECF/ ECX 10% (60) 14 % (7) 3% (39)

Complette andsubtotalpathologicalremissionaccording tosubtype ofLauren

Al-Batran et al Lancet Oncol 2016 (in press)

Untreated metastatic diffuse gastric adenocarcinoma (DGAC): the DIGEST trial

Randomized phase III study of S-1 and cisplatin vs. 5-FU and cisplatin

• The trial did not reach its primary endpoint (OS)

✓ no difference in OS: 7.5 vs. 6.6 months (HR=0.99, p=0.931)

✓ no difference in PFS

✓ higher RR with CS: 34.7% vs. 19.8% (p=0.012)

Ajani JA et al. ASCO Annual Meeting 2015

prognosis for metastatic DGAC is poor but first line therapy for DGAC is the same

analyses of the FLAGS study suggested S-1/Cisplatin might be better than 5-FU/cisplatin in DGAC

Second-line chemotherapy: overview

Trial/ regimen OS (months)

2011 Eur J CancerThuss-Patience et al.

Irinotecan vs. BSC AIO (n=40)

4,0 vs. 2,4 months (p=0,012)

2012 J Clin Oncol Kang et al.

Irinotecan or Docetaxel vs. BSC (n=202)

5,3 vs. 3,8 months (p=0,007)

2014 Lancet OncolFord HE et al.

Docetaxel vs. BSC Cougar-02 (n=168)

5,2 vs. 3,6 months (p=0,01)

2014 LancetFuchs CS et al.

Ramucirumab vs. BSC REGARD (n=348)

5,2 vs. 3,8 months (p=0,0473)

2014 Lancet Oncol Wilke H et al.

Paclitaxel+ Ramucirumab/Placebo

RAINBOW (n=665)

9,63 vs. 7,36 months (p=0,0169)

2013 J Clin OncolHironaka S et al.

Paclitaxel vs. Irinotecan(n=219)

9,5 vs. 8,4 months(p=0,38)

Irinotecan und Taxane beim vorbehandelten metastasierten Magenkarzinom wirksam

Docetaxel 60 mg/m2 qw3 or irinotecan 150 mg/m2 qw2 (Park et al JCO 2012)

Docetaxel 75mg/m2 qw3 (Ford et al 2013)

Irinotecan 250mg/m2 q3w (Thuss-Patience et al EJC 2011)

AIO

VEGFR- Ramucirumab:Second-line chemotherapy

REGARD RAINBOW

P=0.047

3.8 vs. 5.2 Monate

P=0.017

7.4 vs. 9.6 Monate

Fuchs et al. Lancet 2013 Wilke et al. Lancet Oncol 2014

VEGF/R?

VEGF/R: 2nd - 3rd - Line

VEGF/R: 1st- Line

HER 2 +: 1st vs. 2nd

HER 2 +: 1st line „JACOB“

Mono vs. combo: S-1 + Irinotecan vs. Irinotecan

Tanabe K et al. Ann Oncol 2015

Mono vs. combo: Cis + Irinotecan vs. Irinotecan

Higuchi K et al. Eur J Cancer. 2014 May

B I R I P significantly prolonged PFS compared with irinotecan alone was tolerated as SLC but did not demonstrate a survival benefit in this trial

Arm AOperation (R0-Resection or max. reduction ofmetastases)

RANDOMISATION

4x FLOTlimited

metastatic carcinoma of stomach or esophago-

gastric junction

N=271, HR of 0.65 for overall survival (power: 80%)

4x FLOT

Renaissance /FLOT5

Conclusion: first-line chemotherapy

• Combination chemotherapy should be offered to patients adequate performance status adequate organ function

• Doublet chemotherapies are accepted “standard” regimens Platinum + fluoropyrimidine FOLFIRI

• FLOT and modified DCF schedules may be considered in: Locally advanced, unresectable patients Bulky disease

• but before starting 1st Line - consider drugs you will use in further lines

Tumor burden

Conclusion: second-line (chemo)therapy

• Second-line therapy improves survival and QoL over BSC alone

• Paclitaxel + ramucirumab

the most promising drug combination

significant survival benefit over chemotherapy alone

• Single-agent chemotherapy or ramucirumab monotherapy

for unfit patients

• Second-line or even third

trials/ new agents