Background
Targeted pathway | Agent | Trial | Selection biomarker/trial design | Overall survival benefit/months (experimental versus control) |
---|---|---|---|---|
HER2 | Trastuzumab | ToGA/1st-line [13] | HER2/chemotherapy with or without trastuzumab | Positive (HR 0.74)/13.8 versus 11.1 |
Trastuzumab | HELOISE/1st-line phase IIIb [14] | HER2/chemotherapy with standard-dose versus high-dose trastuzumab | Negative (HR 1.24)/12.5 versus 10.6 | |
Trastuzumab/pertuzumab | JACOB/1st-line [21] | HER2/trastuzumab plus chemotherapy with pertuzumab or placebo | Negative (HR 0.84)/17.5 versus 14.2 | |
Trastuzumab emtansine (T-DM1) | GATSBY/2nd-line [29] | HER2/T-DM1 versus taxane | Negative (HR 1.15)/7.9 versus 8.6 | |
Lapatinib | LoGIC/1st-line [41] | HER2/chemotherapy with lapatinib or placebo | Negative (HR 0.91)/12.2 versus 10.5 | |
Lapatinib | Tytan/2nd-line [43] | HER2/paclitaxel with or without lapatinib | Negative (HR 0.84)/11.0 versus 8.9 | |
Angiogenesis | Bevacizumab | AVAGAST/1st-line [75] | None/chemotherapy with bevacizumab or placebo | Negative (HR 0.87)/12.1 versus 10.1 |
Bevacizumab | AVATAR/1st-line [78] | None/chemotherapy with bevacizumab or placebo in Chinese patients | Negative (HR 1.11)/10.5 versus 11.4 | |
Ramucirumab | RAINFALL/1st-line [66] | HER2(−)/chemotherapy with ramucirumab or placebo | Negative (HR 0.96)/11.2 versus 10.7 | |
Ramucirumab | RAINBOW/2nd-line [61] | None/paclitaxel with ramucirumab or placebo | Positive (HR 0.807)/9.6 versus 7.4 | |
Ramucirumab | REGARD/2nd and 3rd-line [60] | None/ramucirumab versus placebo | Positive (HR 0.776)/5.2 versus 3.8 | |
Apatinib | NCT01512745/3rd-line [73] | None/apatinib versus placebo | Positive (HR 0.71)/6.5 versus 4.7 | |
PD-1/PD-L1 | Nivolumab | ATTRACTION 2/3rd-line [102] | None/nivolumab versus placebo in Asian patients | Positive (HR 0.63)/5.26 versus 4.14 |
Pembrolizumab | KEYNOTE-061/2nd-line [96] | PD-L1/pembrolizumab versus paclitaxel | Negative (HR 0.82)/9.1 versus 8.3 | |
Pembrolizumab | KEYNOTE-181/2nd-line [97] | PD-L1/pembrolizumab versus chemotherapy | Positive (HR 0.69)/9.3 versus 6.7 in PD-L1 ≥ 10% | |
Pembrolizumab | KEYNOTE-062/1st-line [98] | PD-L1 & HER2(−)/pembrolizumab alone or pembrolizumab plus chemotherapy versus chemotherapy alone | Noninferior for Pembrolizumab (HR 0.91)/10.6 versus 11.1. Negative for Pembrolizumab and chemotherapy (HR 0.85)/12.5 versus 11.1 | |
Avelumab | JAVELIN Gastric 300/3rd-line [103] | None/avelumab versus chemotherapy | Negative (HR 1.1)/4.6 versus 5.0 | |
DNA | TAS-102 | TAGS/3rd-line [106] | None/TAS-102 versus placebo | Positive (HR 0.69)/5.7 versus 3.6 |
EGFR | Cetuximab | EXPAND/1st-line [120] | None/chemotherapy with or without cetuximab | Negative (HR 1.03)/9.4 versus 10.7 |
Panitumumab | REAL3/1st-line [121] | None/chemotherapy with or without panitumumab | Negative (HR 1.37)/8.8 versus 11.3 | |
STAT3 | Napabucasin | BRIGHTER/2nd-line [132] | None/paclitaxel with napabucasin or placebo | Negative (HR 1.01)/6.93 versus 7.36 |
PARP | Olaparib | GOLD/2nd-line [137] | None/paclitaxel with olaparib or placebo | Negative (HR 0.79 [97.5% CI 0.63–1.00])/8.8 versus 6.9 |
MMP-9 | Andecaliximab | GAMMA-1/1st-line [138] | HER2(−)/mFOLFOX6 with andecaliximab or placebo | Negative (HR 0.93)/12.5 versus 11.8 |
MET | Onartuzumab | METGastric/1st-line) [144] | MET and HER2(−)/mFOLFOX6 with onartuzumab or placebo | Negative (HR 0.82)/11.0 versus 11.3 |
Rilotumumab | RILOMET-1/1st-line) [143] | MET and HER2(−)/chemotherapy with rilotumumab or placebo | Negative (HR 1.34)/8.8 versus 10.7 | |
mTOR | Everolimus | GRANITE-1/3rd-line) [140] | None/everolimus versus placebo | Negative (HR 0.90)/5.4 versus 4.3 |
Target | Agent | Trial | Selection biomarker/trial design | Progression-free survival benefit/months (experimental versus control) |
---|---|---|---|---|
HER2 | Trastuzumab | WJOG7112G (T-ACT)/2nd-line [18] | HER2/paclitaxel with or without trastuzumab | Negative (HR 0.91)/3.68 versus 3.19 |
Angiogenesis | Sorafenib | STARGATE/1st-line [80] | None/chemotherapy with or without sorafenib | Negative (HR 0.92)/5.6 versus 5.3 |
Ziv-aflibercept | MEGA/1st-line [79] | None/mFOLFOX6 with ziv-aflibercept or placebo | Negative (HR 1.11)/9.7 versus 7.4 | |
Sunitinib | NCT01238055/2nd-line [83] | None/docetaxel with or without sunitinib | Negative (HR 0.77 [95% CI 0.52–1.16])/3.9 versus 2.6 (time to progression) | |
Regorafenib | INTEGRATE/3rd-line [81] | None/regorafenib versus placebo | Positive (HR 0.40)/2.6 versus 0.9 | |
Ramucirumab | RAINSTORM/1st-line [69] | HER2(−)/chemotherapy with ramucirumab or placebo in Asian patients | Negative (HR 1.07)/6.34 versus 6.74 | |
Ramucirumab | NCT01246960/1st-line [65] | None/mFOLFOX6 with ramucirumab or placebo | Negative (HR 0.98)/6.4 versus 6.7 | |
Pazopanib | NCT01503372/1st-line [85] | HER2(−)/chemotherapy with or without pazopanib | Negative (HR 0.93)/5.1 versus 3.9 | |
FGFR | AZD4547 | SHINE/2nd-line [112] | FGFR/AZD4547 versus paclitaxel | Negative (HR 1.57)/1.8 versus 3.5 |
Claudin 18.2 | IMAB362 | FAST/1st-line [118] | Claudin 18.2 & HER2(−)/chemotherapy with or without IMAB362 | Positive (HR 0.44)/7.5 versus 5.3 |
Smoothened (Hedgehog signaling) | Vismodegib | NCT00982592/1st-line [129] | None/mFOLFOX6 with vismodegib or placebo | Negative/7.3 versus 8.0 |
Targeted pathway | Agent/selection biomarker | Trial design | ClinicalTrials.gov identifier |
---|---|---|---|
HER | Varlitinib/HER1 and HER2 | Phase II/III 1st-line comparing varlitinib plus mFOLFOX6 versus placebo plus mFOLFOX6 | NCT03130790 |
Nimotuzumab/HER1 | ENRICH 2nd-line comparing irinotecan with or without nimotuzumab in Asian patients | NCT01813253 | |
Angiogenesis | Ramucirumab/HER2(−) | ARMANI comparing maintenance therapy with ramucirumab plus paclitaxel versus continuation of 1st-line chemotherapy | NCT02934464 |
Regorafenib/none | INTEGRATEII 3rd-line comparing regorafenib versus placebo | NCT02773524 | |
Apatinib/none | ANGEL 3rd-line comparing apatinib versus placebo | NCT03042611 | |
Fruquintinib/none | FRUTIGA 2nd-line comparing fruquintinib plus paclitaxel versus placebo plus paclitaxel | NCT03223376 | |
Anlotinib/none | ALTER0503 3rd-line comparing anlotinib versus placebo | NCT02461407 | |
PD-1/PD-L1 | Nivolumab with or without ipilimumab/HER2(−) | CheckMate649 1st-line comparing nivolumab plus ipilimumab or nivolumab plus chemotherapy against chemotherapy alone | NCT02872116 |
Nivolumab/HER2(−) | ATTRACTION-4 1st-line comparing nivolumab plus chemotherapy versus placebo plus chemotherapy | NCT02746796 | |
Pembrolizumab/PD-L1 | KEYNOTE-063 2nd-line comparing pembrolizumab versus paclitaxel in Asian patients | NCT03019588 | |
Pembrolizumab/HER2 | KEYNOTE-811 1st-line comparing pembrolizumab plus trastuzumab in combination with chemotherapy versus placebo plus trastuzumab in combination with chemotherapy | NCT03615326 | |
Pembrolizumab/none | KEYNOTE-590 1st-line in esophageal including gastroesophageal junction cancer comparing chemotherapy versus chemotherapy plus pembrolizumab in Chinese patients | NCT03189719 | |
Avelumab/HER2(−) | JAVELIN Gastric 100 comparing maintenance therapy with avelumab versus continuation of 1st-line chemotherapy | NCT02625610 | |
FGFR2 | FPA144/FGFR2 & HER2(−) | FIGHT/1st-line comparing FPA144 plus mFOLFOX6 versus placebo plus mFOLFOX6 | NCT03694522 |
Claudin 18.2 | IMAB362/claudin 18.2 & HER2(−) | SPOTLIGHT/1st-line comparing IMAB362 plus mFOLFOX6 versus placebo plus mFOLFOX6 | NCT03504397 |