ESMO SUMMIT RUSSIA 2019

Practice changing trials in pancreatic and liver cancer

Pokataev Ilya

N/N/ Blokhin Russian Cancer Research Center

CONFLICT OF INTEREST DISCLOSURE

Sanofi, AstraZeneca, Merck, Биокад – honoraria for educational reports, advisory boards and travel grants

RESECTABILITY CRITERIA FOR NONMETASTATIC PANCREATIC CANCER

NCCN guidelines V. 1.2019 Pancreatic adenocarcinoma

RESECTABILITY CRITERIA FOR NONMETASTATIC PANCREATIC CANCER

NCCN guidelines V. 1.2019 Pancreatic adenocarcinoma

Neoadjuvant chemotherapy ±RT

PREOPANC TRIAL: NEOADJUVANT CRT IN RESECTABLE AND BORDERLINE RESECTABLE PANCREATIC CANCERReduces resection rate but increases overall survival

(Borderline) resectable PC RGem + RTGemcitabine

Gemcitabine х 6 cyclesSurgery

Gem Surgery Gemcitabine х 4 cyclesN=244 patients

Neoadjuvant therapy

Versteijne E. et al. ASCO 2018

Versteijne E. et al. ASCO 2018

Overall survival (all patients - ITT) R0/R1 resections

Р=0.074

(Borderline) resectable PC RGem + RTGemcitabine

Gemcitabine х 6 cyclesSurgery

Gem Surgery Gemcitabine х 4 cyclesN=244 patients

Neoadjuvant therapy

PREOPANC TRIAL: NEOADJUVANT CRT IN RESECTABLE AND BORDERLINE RESECTABLE PANCREATIC CANCERReduces resection rate but increases overall survival

PREP-02/JSAP-05: PREOPERATIVE CHEMOTHERAPY IN RESECTABLE PCIncreases resection rate

Resectable PC R

Gem+ S1

Adjuvant S1Surgery

Surgery

Michiaki Unno et al. ASCO GI 2019

n=180

Adjuvant S1 n=180

Stratification:•Са19-9 level•Center

PREP-02/JSAP-05: PREOPERATIVE CHEMOTHERAPY IN RESECTABLE PCIncreases overall survival

26,7 mo 36,7 mo

Overall survival

Р=0,015

Subgroup analysis

Michiaki Unno et al. ASCO GI 2019

Lancet Gastroenterol Hepatol 2018 in Print

Confirmed PCI-II stages

No SMV, SMA, PV, CA, CHA

KPS>60%

Surgery

PEXG х 3 cyclesSurgery

Gemcitabine х 6 cycles

N=88

Surgery

PEXG х 6 cycles(cisplatin 30 mg/m2, epirubicin 30 mg/m2, gemcitabine800 mg/m2 1, 15 days q4 weeks and capecitabine 1250 mg/m2 1-28 days)

A

B

C PEXG х 3 cycles

PACT15 results (median follow-up 55 months)Overall survival

20,4 26,4 38,2

Lancet Gastroenterol Hepatol 2018 in Print

SWOG S1505 TRIAL: FIRST DATA

Sohal D. et al. ASCO 2019

Findings at central radiology review Adverse events

SWOG S1505 TRIAL: FIRST DATAReasons for not reaching surgery

Sohal D. et al. ASCO 2019

TALE HOME MESSAGE

Preoperative therapy of initially resectable pancreatic cancer increases survival The risk associated with the following:

- time for morphological confirmation, - time for bile duct decompression,- adverse events of preoperative therapy, - progression on the preoperative therapy,

is acceptable.We are awaiting the results of other studies on pre- / perioperative treatment with combination chemotherapy (eg, FOLFIRINOX)

- What is the role of radiation therapy in preoperative treatment?

Adjuvant chemotherapy is the standard of care in pancreatic cancer

ESPAC-1: фторурацил CONCO001: гемцитабин

ESPAC4: GEMCAP

Inclusion criteria : 18 -79 years old ECOG 0 or1 No prior radio- or chemotherapy No postoperative complications Total bilirubin ≤ 1.5 х ULN, creatinine clearance ≥ 50 ml/min

35 54,4 12,8 21,6

Conroy T. et al. N Engl J Med 2018;379:2395-406.

PRODIGE24: THE TOXICITY OF THE ADJUVANT THERAPY FOLFIRINOX AND GEMCITABINE

Conroy T. et al. N Engl J Med 2018;379:2395-406.

•ECOG 0-1•T.bilirubin<1,5 x ULN, creatinine clearance > 50•Central venous access •The possibility of 46-hour 5FU infusion•The possibility of hospitalization in a specialized clinic in case of life-threatening complications

ECOG 2Elderly age

Concomitant pathology

mFOLFIRINOX

Gem or 5FU monotherapy

The adjuvant therapy selection algorithm is based on the patient’s condition

ECOG 3BSC

No chemo

ECOG 0-1,

Selected patients with ECOG 2 GEMCAP

RUSSCO Clinical guidelines 2018

APACT TRIAL: GEMCITABINE+ NAB-PACLITAXELVSGEMCUTABINE IN ADJUVANT CHEMOTHERAPY OF PANCREATIC CANCER

Stratification:•R0/R1•N0/N1•Region: North America, Europe, Australia vs Asia

Tempero M. et al. ASCO 2019

APACT TRIAL: GEMCITABINE+ NAB-PACLITAXELVSGEMCUTABINE IN ADJUVANT CHEMOTHERAPY OF PANCREATIC CANCER

Tempero M. et al. ASCO 2019

Primary end-pointDisease-free survival (independent radiology

review)Disease-free survival (investigator assessed )

APACT TRIAL: GEMCITABINE+ NAB-PACLITAXELVSGEMCUTABINE IN ADJUVANT CHEMOTHERAPY OF PANCREATIC CANCER

Tempero M. et al. ASCO 2019

Secondary end-pointOverall survival

CLINICAL GUIDELINES FOR METASTATIC PANCREATIC CANCER

RUSSCO 2018: in case of germline or somatic deleterious BRCA mutation FOLFIRINOX or platinum + gemcitabine is recommended options

RUSSCO clinical guidelines 2018Ducreux M. et al. Annals of Oncology 26 (Supplement 5): v56–v68, 2015

ESMO 2015

POLO TRIAL: OLAPARIB VS PLACEBO IN IN MAINTENANCE TREATMENT OF BRCA-ASSOCIATED PANCREATIC CANCER

Kindler H. et al. ASCO 2019

38% patients were not randomized due to progression on chemotherapy

POLO TRIAL

Kindler H. et al. ASCO 2019

POLO TRIALResults

Golan T. et al. n engl j med 2019 (in print)

Progression-free survival Overall survival (maturity 46%)

POLO TRIALThe rate of objective responses and their duration

Kindler H. et al. ASCO 2019

There is no benefit in overall survival yet Comparison with placebo (instead of maintenance chemotherapy until progression)

could affect the difference in progression-free survival Not all patients respond to treatment with olaparib Abstract 4132 (ASCO19): MSKCC data

33% patients with pancreatic cancer have monollagenic BRCA mutations in the tumor (germline and somatic)

TAKE HOME MESSAGES FROMPOLO TRIAL

CHOLANGIOCELLULARCANCER

CURRENT ESMO GUIDELINES FOR BILIARY TRACT CANCER

Valle J.W. et al. Annals of Oncology 27 (Supplement 5): v28–v37, 2016

BILCAP: capecitabine is a

standard of adjuvant chemo

•АВС-002: CisPt + Gem– the standard of I line CT (replacement for oxaliplatin in renal impairment)•No standard 2nd line chemotherapy

Slide 3

Presented By Angela Lamarca at 2019 ASCO Annual Meeting

Slide 11

Presented By Angela Lamarca at 2019 ASCO Annual Meeting

Slide 12

Presented By Angela Lamarca at 2019 ASCO Annual Meeting

HEPATOCELLULAR CANCER

Hepatocellular Carcinoma

Presented By Bruno Sangro at 2019 Gastrointestinal Cancer Symposium

RCT Design (from April 2009)

Presented By Namiki Izumi at 2019 ASCO Annual Meeting

Kaplan-Meier estimate of RFS

Presented By Namiki Izumi at 2019 ASCO Annual Meeting

Forest plots of RFS in patient subgroups

Presented By Namiki Izumi at 2019 ASCO Annual Meeting

Adverse Events

Presented By Namiki Izumi at 2019 ASCO Annual Meeting

Conclusion

Presented By Namiki Izumi at 2019 ASCO Annual Meeting

HEPATOCELLULAR CANCER (3 YEARS AGO)

Chemoresistance tumor: - - the response rate on any chemotherapy is less than 10%, there is no data on

the increase in life expectancy -Sorafenib - the standard of first-line treatment of metastatic HCC -Adding chemotherapy to sorafenib does not improve the outcome:

- - sorafenib + doxorubicin vs sorafenib: median OS 8.9 and 10.5 monthsThere was no second line chemotherapy standard

PHASE III STUDY: LENVATINIB VSSORAFENIBNon-inferiority design

Kudo M. et al. Lancet 2018; 391: 1163–73

Progression-free survival Overall survival

THE RESULTS OF PHASE II - III STUDIES IN 2ND LINE SETTING

Regorafenib Cabozantinib Ramucirunab

Bruix et al. Lancet 2017; Abou-Alfa NEJM 2018; Zhu et al. Lanet Oncol 2019; Finn at al. ASCO 2019

Pembrolizumab

Treatment Options for HCC in 2019

Sorafenib1 линия

2 линия

Approved New options with the data for 2018-2019

Lenvatinib

Regorafenib

Pembolizumab

Ramucirumab Cabozantinib

Durvalumab+/- tremelimumab?

Atezolizumab + bevacizumab?

Nivolumab

Nivolumab + ipilimumab?

Pembrolizumab + lenvatinib?