Pancreas e epatocarcinoma

(1)

Lorenzo Fornaro

U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana

Pisa

Novità e sequenze terapeutiche nelle neoplasie del tratto gastroenterico superiore

PANCREAS E EPATOCARCINOMA

Supernovae in Oncologia V edizione

Pisa, 19-20 Settembre 2019

(2)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(3)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(4)

PRODIGE 24-ACCORD 24-CCTG PA 6 trial

Conroy T et al. NEJM 2018

493 patients

resected pancreatic carcinoma 18-79 years, PS 0-1,

CA19.9<180 U/mL, R0/R1 resection, 3-12 weeks after surgery

mFOLFIRINOX

CPT-11 180 mg/sqm day 1 (amended: 150 mg/sqm) LOHP 85 mg/sqm day 1

LV 400 mg/sqm day 1

5-FU 2400 mg/sqm day 1-3 ci 46-h

every 2 weeks for 12 cycles

Gemcitabine

1000 mg/sqm day 1,8,15

every 4 weeks for 6 cycles

R

Primary endpoint: 3-year DFS (HR 0.74)

Stratification according to: center, nodal status (pN0 vs. pN1), resection status (R0 vs. R1) and CA 19-9 level (≤90 U/mL vs. 91-180 U/mL)

Monitoring committee recommended analysis at the time of 314 DFS events (91.8%)

(5)

Adjuvant mFOLFIRINOX: Compliance and Safety

mFOLFIRINOX Gemcitabine

Median no. of cycles (range) 12 (1-12) 6 (1-6)

% completing protocol 66.4% 79%

Relative dose intensity 70% or higher 48.7% 91.4%

Grade 3-4 AEs 75.9% 52.9%

Grade 3-4 neutropenia / FN 28.4% / 3% 26% / 4.1%

Grade 3-4 thrombocytopenia 1.3% 4.5%

Grade 3-4 anemia 3.4% 2.5%

Grade 3-4 diarrhea 18.6% 3.7%

Grade 3-4 sensory neuropathy 9.3% 0%

(6)

Adjuvant mFOLFIRINOX: DFS

21.6 vs. 12.8 months

(7)

Adjuvant mFOLFIRINOX: OS

54.4 vs. 35.0 months

(8)

APACT

Tempero MA et al. ASCO Ann Meeting 2019 (#4000)

(9)

APACT: Patients

(10)

APACT: Compliance and Safety

Gem-Nab-P Gemcitabine

Median no. of cycles (range) 6 (1-6) 6 (1-6)

% completing protocol 66% 71%

Median relative dose intensity Gem: 80%

Nab-P: 75.1%

91.2%

Grade 3-4 AEs 75.9% 52.9%

Grade 3-4 neutropenia / FN 49% / 5% 43% / 1%

Grade 3-4 anemia 15% 8%

Grade 3-4 diarrhea 5% 1%

Grade 3-4 sensory neuropathy 15% 0%

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APACT: DFS (independently assessed)

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APACT: DFS (investigator assessed)

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APACT: OS

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PRODIGE vs. APACT vs. ESPAC-4

1Conroy T et al. NEJM 2018

2Tempero MA et al. ASCO Ann Meeting 2019 (#4000)

3Neoptolemos JP et al. Lancet 2017

PRODIGE

¹

mFOLFIRINOX

APACT

²

Gem+Nab-P

ESPAC-4

³

Gem+Cape

No. included 493 866 730

Endpoint DFS DFS OS

Age, median 63 y 64 y 65 y

pN+ 76.1% 72% 79%

CA19.9, median (upper limit) NR (<180) 14.31 (<100) 17.6 (8112)

R1 40.1% 24% 61%

DFS, median (HR) 21.6 mos (0.58) 19.4 mos (0.88) 13.9 mos (0.86)

OS, median (HR) 54.4 mos (0.64) 40.5 mos (0.82) 28.0 mos (0.82)

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Adjuvant treatment of resected PC: ASCO guidelines

Khorana AA et al. JCO 2019

(16)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(17)

Neoadjuvant CT in resectable PC

Mokdad AA et al. J Clin Oncol 2017

✓ Resected, clinical stage I or II adenocarcinoma of the head of the pancreas

✓ National Cancer Database from 2006 to 2012

✓ Patients who underwent NAT followed by curative-intent resection were matched

by propensity score with patients resected upfront

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PACT-15: Phase 2-3 study

R A N D O M

88 stage I-II PC

Age 18-75 years, KPS > 60, Pathologically confirmed stage I-II disease, Adequate baseline organ

function, Resectable disease

PEXG 3 cycles

PEXG 3 cycles Surgical

resection

Surgical resection

GEM 6 cycles

PEXG 6 cycles

Surgical resection

Primary endpoint: 1-year Event-Free Survival (EFS)

• freedom from PD, relapse, new tumour occurrence, distant metastases, or death

• 24 eligible patients in each group

• H0=20%; H1=40%; alpha=10%; beta=20%

• ≤16 events of 24 support further evaluation of experimental therapy Secondary endpoint: OS, pathologic response

A

B

C

GEM: gemcitabine 1000 mg/sqm d1,8,15 q28 PEXG: cisplatin 30 mg/sqm, epirubicin 30 mg/sqm,

gemcitabine 800 mg/sqm d1,14 q28,

capecitabine 1250 mg/sqm d1-28 Reni M et al. Lancet Gastroenterol Hepatol 2018

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PACT-15: Patients

Reni M et al. Lancet Gastroenterol Hepatol 2018

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PACT-15: Pathology

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PACT-15: Compliance

Gem adjuvant

PEXG adjuvant

PEXG

perioperative

% starting neoadj CT - - 91%

% starting adj CT 65% 67% 72%

% completing all scheduled CT 27% 46% 63%

% operated 100% 100% 94%

% resected 85% 90% 84%

Reason for not completing CT PD or evidence of M1

Toxicity

46%

15%

33%

3%

9%

Dose intensity 84% CDDP: 83%

Epi: 81%

Cape: 80%

Gem: 76%

CDDP: 89% > 75%

Epi: 87% > 75%

Cape: 86% > 72%

Gem: 82% > 63%

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PACT-15: EFS

Reni M et al. Lancet Gastroenterol Hepatol 2018 Median EFS:

Arm A: 4.8 months Arm B: 12.4 months Arm C: 16.9 months

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SWOG S1505: Neoadj mFOLFIRINOX vs. Gem-Nab

Sohal DPS et al. ASCO Ann Meeting 2019 (#4137)

(24)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(25)

BRCA1-2 mutations in PC

Spizzo G et al. ASCO Ann Meeting 2019 (#4133) BRCA mutant ➔ Higher TMB

4.8%

1.2%

22%

11%

BRCA mutant ➔ Higher rate MSI^high/PD-L1+

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POLO: Design

Kindler HL et al. ASCO Ann Meeting 2019 (#LBA4) – Golan T et al. NEJM 2019

76% received I-line FOLFIRINOX

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POLO: PFS (primary endpoint)

Golan T et al. NEJM 2019

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POLO: PFS (subgroups)

(29)

POLO: OS

Final OS analysis planned at 106 events

(30)

POLO: Activity

Kindler HL et al. ASCO Ann Meeting 2019 (#LBA4)

(31)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

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REFLECT: Lenvatinib (I-line)

Kudo M et al. Lancet 2018

Upper 95%CI limit for non-inferiority: 1.08

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REFLECT: Lenvatinib (I-line)

Kudo M et al. Lancet 2018

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REACH: Ramucirumab (II-line)

Zhu AX et al. Lancet Oncol 2015

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REACH-2: Ramucirumab (II-line, high alpha-FP)

Zhu AX et al. Lancet Oncol 2019 R

A N D O M

292 patients

ECOG PS 0-1, BCLC B or C, HCC confirmed by pathology or radiology, Child-Pugh A,

Alpha-FP 400 ng/mL or higher

Ramucirumab

8 mg/kg q14 days

Placebo

Primary endpoint: Overall survival

• H0=4.5 months

• H1=6.7 months

• alpha=0.025 (one-sided)

• beta=0.2

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REACH-2: OS

Median 8.5 vs. 7.3 months

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REACH (high alpha-FP) + REACH-2: OS

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CELESTIAL: Cabozantinib (II or III-line)

Abou-Alfa GK et al. NEJM 2018 R

A N D O M

707 patients

ECOG PS 0-1, HCC confirmed by pathology, Child-Pugh A, adequante organ function, previous sorafenib, up to 2 previous systemic

therapies, no solid organ transplantation

Cabozantinib

60 mg/day

Placebo

Primary endpoint: Overall survival

• HR 0.76; H0=8.2 months; H1=10.8 months; alpha=0.05 (two-sided); beta=0.1 Stratification factors:

• etiologic factor (HBV +/- HCV vs. HCV vs. other)

• geographic region (Asia vs. other)

• evidence of extrahepatic spread of disease (yes vs. no)

• macrovascular invasion (yes vs. no)

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CELESTIAL: OS

Abou-Alfa GK et al. NEJM 2018

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EMA approval in HCC

EMA website

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Treatment algorithm in advanced HCC

Lenvatinib Sorafenib

Regorafenib Cabozantinib Ramucirumab

Cabozantinib

intolerance or PD and alphaFP ≥400 ng/mL

PD and good tolerance

(≥400 mg for ≥20 of 28 days) PD

PD PD

I-line

II-line

III-line

(42)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(43)

KEYNOTE-240: Pembrolizumab (II-line)

Finn RS et al. ASCO Ann Meeting 2019 (#4004)

Primary endpoint:

• PFS (RECIST 1.1, central review)

• OS

(44)

KEYNOTE-240: OS

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KEYNOTE-240: PFS

(46)

KEYNOTE-240: RR

(47)

CheckMate-459: Nivolumab vs. Sorafenib

Available at: news.bms.com

(48)

Phase II BGB-A317: Tislelizumab

Sep 2018

Nov 2018

Apr 2019

(49)

Agenda

• Pancreatic cancer

• News in the adjuvant setting

• Moving CT preoperatively in resectable disease

• PARP inhibitors in advanced disease

• Hepatocellular carcinoma

• Finally, a therapeutic sequence even in HCC

• Immune revolution at stake?

• Conclusions

(50)

Conclusions

• Combination CT as standard in the adjuvant setting in PC

• mFOLFIRINOX preferred

• Gemcitabine + capecitabine is an option

• Trials with neoadjuvant CT show interesting results

• Compliance improves > improved efficacy?

• Different treatment options in I to III line advanced HCC

• Safety profile crucial in at-risk population

• Different populations among trials

• Immunotherapy stands still at the edge of the algorithm

• KEYNOTE-240: is it a negative trial?

• Research ongoing in any setting with multiple combinations

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Thank you!

lorenzo.fornaro@gmail.com

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Back up slides

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Adjuvant mFOLFIRINOX: Patients

(54)

APACT: Compliance and Safety

Gem-Nab-P Gemcitabine

Median no. of cycles (range) 6 (1-6) 6 (1-6)

% completing protocol 66% 71%

Median relative dose intensity Gem: 80%

Nab-P: 75.1%

91.2%

Grade 3-4 AEs 75.9% 52.9%

Grade 3-4 neutropenia / FN 49% / 5% 43% / 1%

Grade 3-4 anemia 15% 8%

Grade 3-4 diarrhea 5% 1%

Grade 3-4 sensory neuropathy 15% 0%

(55)

PACT-15: OS

Reni M et al. Lancet Gastroenterol Hepatol 2018 Median OS:

Arm A: 20.4 months Arm B: 26.4 months Arm C: 38.2 months

(56)

POLO: Rational for PARPi as maintenance

(57)

POLO: Patients

(58)

POLO: Safety

(59)

FOLFOX + Veliparib: Phase I/II

Pishvaian MJ et al. abstr. 4015

(60)

SWOG S1513: FOLFIRI +/- Veliparib random phase II

Chiorean EG et al. abstr. 4014

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REACH-2: OS (subgroups)

(62)

CELESTIAL: Safety

Abou-Alfa GK et al. NEJM 2018