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Current Status and Future Directions of Targeted Agents and Immunotherapy in Gastric Cancer

Yung-Jue Bang

Seoul National University College of Medicine Seoul, KOREA Targeted agents in advanced gastric cancer

Bevacizumab

Cetuximab VEGF Pertuzumab Tumour cell membrane Endothelial cell membrane EGFR HER2 VEGFR mTOR

Signalling pathway inhibition

Proliferation Angiogenisis Apoptosis Invasion/metastasis Invasion/metastasis

mTOR = mammalian target of rapamycin 1st-Line Phase III studies

Target Agent Trial Regimen n Results

VEGF AVAGAST1 XP bevacizumab 774 Negative

VEGF Bevacizumab AVATAR2 XP bevacizumab 202 Negative

VEGFR Ramucirumab RAINFALL3 XP ramucirumab 645 Positive

EGFR Panitumumab REAL-34 EOC panitumumab 553 Negative

EGFR EXPAND5 XP cetuximab 904 Negative

HER2 Trastuzumab ToGA6 XP trastuzumab 584 Positive

HER2 Lapatinib LOGiC7 CapOx lapatinib 545 Negative

HER-2 Trastuzumab HELOISE8 XP + trastuzumab (2 doses) 248 Negative

HER2 Pertuzumab JACOB9 CP+trastuzumab pertuzumab 780 Negative

C-Met RILOMET-110 ECX rilotumumab 450 Negative

C-Met MetGastric11 FOLFOX6 onartuzumab 800 Negative

1. Ohtsu A et al. J Clin Oncol 2011; 2. Shen L et al. Gastric Cancer 2015; 3. Fuchs CS et al. ASCO-GI 2018; 4.Waddell T et al. Lancet Oncol 2013; 5. Lordick F et al. Lancet Oncol 2013; 6. Bang YJ et al. Lancet 2010; 7. Hecht JR et al, J Clin Oncol 2015; 8. Shah MA et al. J Clin Oncol 2017; 9. Taberno J et al. Lancet Oncol 2018; 10. Catenacci DVT et al. Lancet Oncol 2017; 11. Shah MA, et al. JAMA Oncol 2017 2nd-Line Phase II-III studies

Target Agent Trial Regimen n Results

mTOR Everolimus GRANITE-11 BSC everolimus 656 Negative

mTOR Everolimus RADPAC2¶ Paclitaxel everolimus 300 Negative

HER2 Lapatinib TyTAN3 Paclitaxel lapatinib 261 Negative

HER2 TDM-1 GATSBY4 Paclitaxel vs T-DM1 412 Negative

VEGFR2 Ramucirumab REGARD5 BSC ramucirumab 355 Positive

VEGFR2 Ramucirumab RAINBOW6 Paclitaxel ramucirumab 665 Positive

VEGFR2 Apatinib Chinese7† Apatinib vs placebo 267 Positive

VEGFR^ Regorafenib INTEGRATE8‡ Regorafenib vs placebo 152 Positive

FGFR2^ AZD4547 SHINE9 AZD4547 vs paclitaxel 71 Negative

PARP Olaparib GOLD10 Paclitaxel Olaparib 525 Negative

^ Phase II studies, ¶ 2nd ~ 4th line, † 3rd- or greater line, ‡ 2nd or 3rd-line

1. Ohtsu A et al. J Clin Oncol 2013; 2. Al-Batran SE et al. ASCO GI 2017, 3. Satoh T et al. J Clin Oncol 2014; 4. Thuss-patientce PC et al. Lancet Oncol 2017, 5. Fuchs CS, et al. Lancet 2014; 6. Wilke H et al. Lancet Oncol 2014; 7. Li J et al. J Clin Oncol 2016; 8. Pavlakis N, et al. J Clin Oncol 2016; 9. Van Cutsem E & Bang YJ et al. Ann Oncol 2017; 10. Bang YJ et al. Lancet Oncol 2017 How about future?

• Better agents/combinations for validated targets

• Agents targeting novel molecular targets DS-8201a: A novel HER2 ADC

• ORR 43.2% (19/44) • DCR 79.5% (35/44) • PFS 5.6 months Iwata H et al. ASCO 2018 (Abst 1031) GOLD study: Asian Phase III trial

Olaparib 100 mg tablet twice daily + weekly Co-primary endpoint 2 Patients with advanced gastric c paclitaxel 80 mg/m iv - OS all patients ancer* who progressed following 1:1 - OS for patients with an ATM first-line therapy (n=525) Placebo + weekly paclitaxel 80 mg/m2 iv protein-negative tumour

1.0 FAS (n=525; 72.6% OS maturity) Olaparib/paclitaxel (N=263) 0.9 Placebo/paclitaxel (N=262) 0.8 Olaparib/paclitaxel Placebo/paclitaxel

0.7 Events:total patients (%) 181:263 (68.8) 200:262 (76.3) 0.6 Median OS, months 8.8 6.9 0.5 HR=0.79 0.4 97.5% CI (0.63, 1.00); P=0.0262* Probability of OS of Probability 0.3

0.2

0.1

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Time from randomization (months) Bang YJ et al. Lancet Oncol 2017 FAST study: Randomized Phase II study

• EOX ± IMAB362 (anti-CLDN18.2 Ab) • Eligibility: CLDN18.2 2+/3+ in ≥ 40% tumor cells • Primary endpoint: PFS

Progression-free survival Overall survival

Al-Batran SE et al. ASCO 2016 Cancer-Immunity Cycle

• The cancer-immunity cycle consists of stepwise events leading to effective killing of cancer cells • Various factors released in the microenvironment can stimulate or inhibit cycle activity; thus their pathways may be targetable

Chen DS & Mellman I. Immunity 2013, Kim JM & Chen DS Ann Oncol 2016 ATTRACTION-2 study

Nivolumab • Metastatic gastric or GEJ cancer 3 mg/kg q 2 weeks • ≥ 2 prior treatment R 2:1 • ECOG PS of 0 or 1 (N = 493) Placebo

* Previous chemo regimens; 2 (20%), 3 (40%), ≥4 (40%)

Overall survival Median follow-up: 15.7 months (range, 12.1–27.2) 100 Median OS, months (95% CI) 90 • ORR 11.2% 80 • DCR 40.3% (N = 330) 5.3 (4.6–6.4) P < 0.0001 70 Placebo (N = 163) 4.1 (3.4–4.9) 60 Hazard ratio, 0.62 (95% CI, 0.50–0.76) 50 12-month OS rate 40 27% 30 24-month OS rate 20 12% 12% 10 5% 0

Probability of Survival (%) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 No. at Risk Months Nivolumab 330 275 192 143 123 97 84 54 34 22 12 7 6 1 0 Placebo 163 121 82 54 37 24 18 8 6 5 4 3 3 2 0 Kang YK et al. Lancet 2017 Keynote-059 trial: in GC

• No of pts: 259 • ORR 11.6%, DCR 27.0% • PFS, median: 2.0 months (95% CI, 2.0-2.1) • 6-month PFS: 14.1% (95% CI, 10.1-18.7) • OS, median: 5.6 months (95% CI, 4.3-6.9) • 12-month OS: 23.4% (95% CI, 17.6-29.7)

100 PFS 100 OS

80 80

60 60

40 OS (%) OS 40 PFS (%)

20 20

0 0 0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22 Mos Mos Fuchs CS, et al. JAMA Oncol 2018 Keynote-059: Response by PD-L1 expression

PD-L1 & 3rd-line of PD-L1 Line of therapy Confirmed therapy Response, % (95% CI) Positive Negative Third ≥ Fourth Positive Negative (n = 148) (n = 109) (n = 134) (n = 125) (n = 75) (n = 58) 15.5 6.4 16.4 6.4 22.7 8.6 ORR (10.1-22.4) (2.6-12.8) (10.6-23.8) (2.8-12.2) (13.8-33.8) (2.9-19.0) 2.0 2.8 3.0 1.6 2.7 3.4 CR (0.4-5.8) (0.6-7.8) (0.8-7.5) (0.2-5.7) (0.3-9.3) (0.4-11.9) 13.5 3.7 13.4 4.8 20.0 5.2 PR (8.5-20.1) (1.0-9.1) (8.2-20.4) (1.8-10.2) (11.6-30.8) (1.1-14.4) 33.1 19.3 31.3 22.4 38.7 22.4 DCR* (25.6-41.3) (12.3-27.9) (23.6-39.9) (15.4-30.7) (27.6-50.6) (12.5-35.3)

Median DOR (95% CI), mos All patients 8.4 (1.6+b to 17.3+) PD-L1 positive 16.3 (1.6+ to 17.3+) PD-L1 negative 6.9 (2.4 to 7.0+)

• 57.1% (148/259) of patients had PD-L1-positive GC Fuchs CS, et al. JAMA Oncol 2018 JAVELIN Gastric 300 study

Avelumab • Metastatic GC/GEJC 10 mg/kg Q2W • Primary endpoint: OS R + BSC • 2 prior treatment • Secondary endpoints: 1:1 • ECOG PS of 0 or 1 BSC + PFS, ORR, safety, (N=371) Stratification: Asia vs non-Asia physician’s choice of PROs/QoL chemotherapy

Treatment until confirmed disease progression, unacceptable toxicity, or withdrawal OS PFS

Bang YJ et al. Ann Oncol 2018 How about future?

• Who get benefits?

• How about combinations? – With other immune check-point blocking agents – With targeted agents – With chemotherapeutic agents Potential biomarkers

• Microsatellite instability (MSI) status • PD-L1 expression • Mutation (or neoantigen) burden • Immune gene signatures • Tumor infiltrating lymphocytes • T-cell receptor clonality • Gut microbiome • Peripheral blood markers • Multiplex immunohistochemistry Keynote-059: Response by MSI status

• 4.0% (7/174) of patients had MSI-high tumor

MSI-H (n = 7) Non–MSI-H (n = 167) Response % 95% CI % 95% CI

ORR 57.1 18.4-90.1 9.0 5.1-14.4

Complete response 14.3 0.4-57.9 2.4 0.7-6.0

Partial response 42.9 9.9-81.6 6.6 3.3-11.5

DCR* 71.4 29.0-96.3 22.2 16.1-29.2

Response duration NR 5.3+-14.1+ 8.4 2.4-19.4+

* CR + PR + SD ≥ 2 mos.

Fuchs CS, et al. JAMA Oncol 2018 KEYNOTE-061 study: 2nd-Line treatment

Pembrolizumab Key Eligibility Criteria N = 296 200 mg Q3W • Adenocarcinoma of the stomach or GEJ that was for 35 cycles or until confirmed PD, intolerable metastatic or locally advanced but unresectable toxicity, patient withdrawal, or investigator • PD per RECIST v1.1 after first-line platinum- and f decision luoropyrimidine-containing therapy R (1:1) • ECOG PS 0 or 1 2 • Provision of a sample for PD-L1 assessmenta Paclitaxel 80 mg/m • First 489 patients: any PD-L1 CPS on days 1, 8, and 15 of • Final 103 patients: PD-L1 CPS ≥1b 4-week cycles N = 296 until confirmed PD, intolerable toxicity, patient withdrawal, or investigator decision Stratification Factors • Region (Eur/Israel/N America/Australia vs Asia vs ROW) • ECOG PS (0 vs 1) • TTP on first-line therapy (<6 mo vs ≥6 mo) • PD-L1 CPS (<1 vs ≥1)

• Primary endpoint: OS and PFS in the CPS ≥1 population • Secondary endpoint: ORR and DOR in the CPS ≥1 population; safety in all treated patients

Shitara K, et al. Lancet 2018 Overall survival, CPS ≥ 1

1 0 0 Events HR (95% CI) P Pembrolizumab 151 0.82 0.04205 9 0 (0.66-1.03) Paclitaxel 175 8 0

7 0 39.8% 25.7%

6 0 27.1% 14.8% %

Median (95% CI)

, 5 0 9.1 mo (6.2-10.7) S

O 8.3 mo (7.6-9.0) 4 0

3 0

2 0

1 0

0 0 6 1 2 1 8 2 4 3 0 M o n th s N o . a t ris k

1 9 6 1 1 4 78 39 14 0 1 9 9 1 3 0 54 23 7 0

• Data cutoff date: Oct 26, 2017. Shitara K, et al. Lancet 2018 Overall survival by PD-L1 CPS

CPS <1 CPS ≥1a CPS ≥10

Events/ HR Events/ HR Events/ HR Pts (95% CI) Pts (95% CI) Pts (95% CI) Pembrolizumab 87/99 1.20 151/196 0.82 34/53 0.64 Paclitaxel 86/96 (0.89-1.63) 175/199 (0.66-1.03) 46/55 (0.41-1.02)

1 0 0 Median (95% CI) 1 0 0 Median (95% CI) 1 0 0 Median (95% CI) 9 0 4.8 mo (3.9-6.1) 9 0 9.1 mo (6.2-10.7) 9 0 10.4 mo (5.9-17.3) 8.2 mo (6.8-10.6) 8.3 mo (7.6-9.0) 8.0 mo (5.1-9.9) 8 0 8 0 8 0

7 0 7 0 7 0

6 0 6 0 6 0

% % %

, ,

5 0 5 0 , 5 0

S S S

O O 4 0 4 0 O 4 0

3 0 3 0 3 0

2 0 2 0 2 0

1 0 1 0 1 0

0 0 0 0 6 1 2 1 8 2 4 3 0 0 6 1 2 1 8 2 4 3 0 0 6 1 2 1 8 2 4 3 0 M o n t h s M o n t h s M o n t h s N o . a t r is k N o . a t r is k N o . a t r is k 9 9 4 1 2 3 1 4 2 0 1 9 6 1 1 4 7 8 3 9 1 4 0 5 3 3 4 2 4 1 3 6 0 9 6 6 1 2 9 1 3 5 0 1 9 9 1 3 0 5 4 2 3 7 0 5 5 3 3 1 3 7 4 0

• aPrimary end point. Data cutoff date: Oct 26, 2017. Shitara K, et al. Lancet 2018 Response to pembrolizumab

Kim ST et al. Nat Med 2018 How about future?

• Who get benefits?

• How about combinations? – With other immune check-point blocking agents – With targeted agents – With chemotherapeutic agents CheckMate 032 trial: Nivolumab +

Nivo 1 mg/kg + Nivo 3 mg/kg + Response Category Nivo 3 mg/kg IPI 3 mg/kg IPI 1 mg/kg (RECIST 1.1) (n=59) (n=49) (n=52) ORR*, % (95% CI) 12 (5~23) 24 (13~39) 8 (2~19) Complete response, % 2 2 0 Partial response, % 10 22 8 Stable disease, % 20 16 29 Progressive disease, % 58 47 46 Not determined, % 10 12 17 Disease control rate, % 32 41 37 Median TTR, months (range) 1.6 (1.2–4.0) 2.7 (1.2–4.5) 2.6 (1.3–2.8) Median DOR, months (95% CI) 7.1 (3.0~13.2) 7.9 (2.8~NE) NA (2.5~NE) 12-month PFS, % 8 17 10 12-month OS, % 39 35 24 Grade ¾ TRAEs, % 17 47 27

* Investigator-assessed Janjigian YY et al. J Clin Oncol 2018;36:2836-44. • • PD PD MSS I >> MSS >> - - JVDJ study: JVDJ L1low: <25% tumorcell PD L1high: ≥25% tumorcell PD NA MSS MSS MSS I MSS I MSS MSS MSS NA NA MSS I NA MSS I MSS MSS MSS I MSS - L1staining - NA L1staining MSS NA * MSS I MSS I * I MSS Ramucirumab I+T MSS * I and MSS * or MSS I I+T MSI-High * ≥25%immune cell PD <25%immune cell PD • • • - L1staining - L1staining ORR in PD (16/29) 55% DCR ORR 17% (5/29) + Durvalumab - Bang etYJ al. ASCO L1 - high high 36% 36% (5/14) - GI 2018 M7824: Bifunctional protein of PD-L1 Ab & TGF-β trap in GC

• ORR 22.6% (by Investigator) • PFS: 2.1 months (1.2~3.9) • OS: 10.1 months (4,5~12.8)

Bang YJ et al. ESMO 2018 Anti-PD-1 Ab + Chemotherapy in AGC

Pembrolizumab + CF KEYNOTE-059

• ORR 60% (73% in CPS≥1) • PFS 6.6 months

Nivolumab + SOX ATTRACTON-4 • ORR 67%

Nivolumab + CapeOX

• ORR 71%

Bang YJ et al. ASCO 2017, Kang YK et al ESMO 2017 Standard-of-Care at present

Early stage Advanced stage

Continuum of Care

1st-Line 2nd-Line 3rd-Line

Surgery HER-2(-) + Pac/Ram Nivoulmab - XELOX, FOLFOX, Paclitaxel Pembrolizumab* - Adjuvant chemoRx SOX, FP - FLOT Irinotecan - Perioperative chemoRx Ramucirumab Apatinib - CCRT - FOLFIRI HER-2(+) - Trastuzumab+XP

* Only in PD-L1-positive tumor Conclusion

• Trastuzumab + chemotherapy is SOC in 1st line HER2-positive AGC

• Paclitaxel + ramucirumab is associated with the best outcome in 2nd-line AGC

• Anti-PD-1 Ab is effective in 3rd-line AGC, especially in MSI-H and/or PD-L1-positive AGC

• Novel targeted agents and combinations of anti-PD-1 Ab and chemotherapy are being tested in Phase III trials