Update in Systemic and Targeted Therapies in Gastrointestinal Oncology
Abstract
:1. Introduction
2. Update of Systemic and Targeted Therapies
3. Pancreatic Carcinoma
3.1. Targeting Tumor-Associated Stroma Using Pegylated Hyaluronidase
3.2. Targeting Cancer Stem Cells by a STAT3 Inhibitor
3.3. Targeting Asparagine by Enzymatic Degradation
4. Gastric, Gastroesophageal Junction, and Esophageal Carcinoma
4.1. Peri-Operative FLOT in Resectable Tumors
4.2. Pembrolizumab in PD-L1-Expressing Gastric and Gastroesophageal Carcinoma
4.3. Nivolumab and Ipilimumab in Gastric, Gastroesophageal Junction, and Esophageal Carcinoma
4.4. Pembrolizumab in PD-L1-Expressing Esophageal Carcinoma
5. Hepatocellular Carcinoma
5.1. Nivolumab
5.2. Ramucirumab
5.3. Lenvatinib
5.4. BLU-554
6. Biliary Tract Carcinoma
6.1. Adjuvant Capecitabine in Resected BTC
6.2. Combination of nab-Paclitaxel, Gemcitabine, and Cisplatin in Advanced BTC
7. Colorectal Carcinoma
7.1. Nivolumab
7.2. Adjuvant FOLFOX or CAPOX: 3 Months vs. 6 Months
7.3. Irinotecan and Cetuximab ± Vemurafinib
7.4. Trifluridine/Tipiracil and Bevacizumab
8. Conclusions and Future Perspectives
Author Contributions
Conflicts of Interest
References
- Yee, N.S.; Kazi, A.A.; Yee, R.K. Current systemic treatment and emerging therapeutic strategies in pancreatic adenocarcinoma. Curr. Clin. Pharmacol. 2015, 10, 256–266. [Google Scholar] [CrossRef] [PubMed]
- Yee, N.S. Towards the goal of personalized therapy in pancreatic cancer by targeting the molecular phenotype. Adv. Exp. Med. Biol. 2013, 779, 91–143. [Google Scholar] [PubMed]
- Hingorani, S.R.; Bullock, A.J.; Seery, T.E.; Zheng, L.; Sigal, D.; Ritch, P.S.; Braiteh, F.S.; Zalupski, M.; Bahary, N.; Harris, W.P.; et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine vs. nab-paclitaxel plus gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Bekaii-Saab, T.S.; Starodub, A.; El-Rayes, B.F.; O’Neil, B.H.; Shahda, S.; Ciombor, K.K.; Noonan, A.M.; Hanna, W.T.; Sehdev, A.; Shaib, W.L.; et al. A phase Ib/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). Ann. Oncol. 2017, 28 (Suppl. S3). [Google Scholar] [CrossRef]
- Krall, A.S.; Xu, S.; Graeber, T.G.; Braas, D.; Christofk, H.R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 2016, 7, 11457. [Google Scholar] [CrossRef] [PubMed]
- Hammel, P.; Bachet, J.B.; Portales, F.; Mineur, L.; Metges, J.P.; de la Fouchardiere, C.; Louvet, C.; El Hajbi, F.; Faroux, R.; Guimbaud, R.; et al. A phase 2b of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pancreatic adenocarcinoma. Ann. Oncol. 2017, 28 (Suppl. S5), v209–v268. [Google Scholar] [CrossRef]
- Fonkoua, L.K.; Yee, N.S. Immunotherapy in gastric carcinoma: Current status and emerging strategies. Clin. Cancer Drugs 2015, 2, 91–99. [Google Scholar] [CrossRef]
- Al-Batran, S.E.; Homann, N.; Schmalenberg, H.; Kopp, H.G.; Haag, G.M.; Luley, K.B.; Schmiegel, W.H.; Folprecht, G.; Probst, S.; Prasnikar, N.; et al. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Fuchs, C.S.; Doi, T.; Jang, R.W.; Muro, K.; Satoh, T.; Machado, M.; Sun, W.; Jalal, S.I.; Shah, M.A.; Metges, J.P.; et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Kang, Y.K.; Satoh, T.; Ryu, M.H.; Chao, Y.; Kato, K.; Chung, H.C.; Chen, J.S.; Muro, K.; Kang, W.K.; Yoshikawa, T.; et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemother-apy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Ott, P.A.; Calvo, E.; Kim, J.W.; Ascierto, P.A.; Sharma, P.; Peltola, K.J.; Jaeger, D.; Evans, T.J.; De Braud, F.G.; et al. Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophage-al (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Doi, T.; Piha-Paul, S.A.; Jalal, S.I.; Saraf, S.; Lunceford, J.; Koshiji, M.; Bennouna, J. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef] [PubMed]
- Marks, E.I.; Yee, N.S. Molecular genetics and targeted therapy in hepatocellular carcinoma. Curr. Cancer Drug Targets 2016, 16, 53–70. [Google Scholar] [CrossRef] [PubMed]
- Todd, S.C.; El-Khoueiry, A.B.; Yau, T.; Melero, I.; Sangro, B.; Kudo, M. Nivoluman in sorafenib-naïve and–experienced patients with advanced hepatocellular carcinoma: CheckMate040 Study. J. Clin. Oncol. 2017, 35 (Suppl. 15), 4013. [Google Scholar]
- Zhu, A.X.; Baron, A.D.; Malfertheiner, P.; Kudo, M.; Kawazoe, S.; Pezet, D.; Weissinger, F.; Brandi, G.; Barone, C.A.; Okusaka, T.; et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score. JAMA Oncol. 2017, 3, 235–243. [Google Scholar] [CrossRef] [PubMed]
- Cheng, A.L.; Finn, R.S.; Qin, S.; Han, K.H.; Ikeda, K.; Piscaglia, F.; Baron, A.D.; Park, J.W.; Han, G.; Jassem, J.; et al. Phase III trial of lenvatinib (LEN) vs. sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Wu, A.-L.; Coulter, S.; Liddle, C.; Wong, A.; Eastham-Anderson, J.; French, D.M.; Peterson, A.S.; Sonoda, J. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLoS ONE 2011, 6, e17868. [Google Scholar] [CrossRef] [PubMed]
- Kang, Y.-K.; Macarulla, T.; Yau, T. Clinical activity of Blu-554, a potent, highly-selective FGFR4 inhibitor in advanced hepatocellular carcinoma (HCC) with FGFR4 pathway activation. Presented at 2017 ILCA Annual Conference, Seoul, Korea, 15–17 September 2017. Abstract 0-032. [Google Scholar]
- Marks, E.I.; Yee, N.S. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J. Gastroenterol. 2016, 22, 1335–1347. [Google Scholar] [CrossRef] [PubMed]
- Wyluda, E.; Yee, N.S. Systemic treatment of advanced biliary tract cancer: Emerging roles of targeted therapy and molecular profiling. Clin. Cancer Drugs 2015, 2, 80–86. [Google Scholar] [CrossRef]
- Ghidini, M.; Tomasello, G.; Botticelli, A.; Barni, S.; Zabbialini, G.; Seghezzi, S.; Passalacqua, R.; Braconi, C.; Petrelli, F. Adjuvant chemotherapy for resected biliary tract cancers: A systemic review and meta-analysis. HPB 2017, 19, 741–748. [Google Scholar] [CrossRef] [PubMed]
- Ben-Josef, E.; Guthrie, K.A.; El-Khoueiry, A.B.; Corless, C.L.; Zalupski, M.M.; Lowy, A.M.; Thomas, C.R., Jr.; Alberts, S.R.; Dawson, L.A.; Micetich, K.C.; et al. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J. Clin. Oncol. 2015, 33, 2617–2622. [Google Scholar] [CrossRef] [PubMed]
- Primrose, J.N.; Fox, R.; Palmer, D.H.; Prasad, R.; Mirza, D.; Anthoney, D.A.; Corrie, P.; Falk, S.; Wasan, H.S.; Ross, P.J.; et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Shroff, R.T.; Borad, M.J.; Xiao, L.; Kaseb, A.O.; Varadhachary, G.R.; Wolff, R.A.; Raghav, K.P.; Iwasaki, M.; Masci, P.; Ramanathan, R.K.; et al. A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs). J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Overman, M.J.; McDermott, R.; Leach, J.L.; Lonardi, S.; Lenz, H.-J.; Morse, M.A.; Desai, J.; Hill, A.; Axelson, M.; Moss, R.A.; et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicenter, phase 2 study. Lancet Oncol. 2017, 18, 1182–1191. [Google Scholar] [CrossRef]
- Shi, Q.; Sobrero, A.F.; Shields, A.F.; Yoshino, T.; Paul, J.; Taieb, J.; Sougklakos, I.; Kerr, R.; Labianca, R.; Meyerhardt, J.A.; et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs. 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Iveson, T.; Kerr, R.; Saunders, M.P.; Hollander, N.H.; Tabernero, J.; Haydon, A.M.; Glimelius, B.; Harkin, A.; Scudder, C.; Boyd, K.; et al. Final DFS results of the SCOT study: An international phase III randomized (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Kopetz, S.; McDonough, S.L.; Lenz, H.J.; Magliocco, A.M.; Atreya, C.E.; Diaz, L.A.; Allegra, C.J.; Raghav, K.P.; Morris, V.K.; Wang, S.E.; et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
- Kuboki, Y.; Nishina, T.; Shinozaki, E.; Yamazaki, K.; Shitara, K.; Okamoto, W.; Kajiwara, T.; Matsumoto, T.; Tsushima, T.; Mochizuki, N.; et al. TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): An investigator-initiated, open-label, single-arm, multicenter, phase 1/2 study. Lancet Oncol. 2017, 18, 1172–1181. [Google Scholar] [CrossRef]
- Le, D.T.; Durham, J.N.; Smith, K.N.; Wang, H.; Bartlett, B.R.; Aulakh, L.K.; Lu, S.; Kemberling, H.; Wilt, C.; Luber, B.S.; et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017, 357, 409–413. [Google Scholar] [CrossRef] [PubMed]
Outcomes | PEGPH20 + nab-Paclitaxel + Gemcitabine | nab-Paclitaxel + Gemcitabine |
---|---|---|
PFS (months) All patients | 6.0 HR 0.73, * P < 0.05 | 5.3 |
PFS (months) HA-High (35%) | 9.2 HR 0.51, * P < 0.048 | 5.2 |
OS (months) HA-High (35%) | 11.5 | 8.5 |
Efficacy Endpoints | Outcome |
---|---|
Complete Response | 1 (1.8%) |
Partial Response | 26 (47.3%) |
Stable Disease | 24 (43.6%) |
Overall Response Rate | 55% |
Disease Control Rate | 93% |
Disease Progression | 3 (on treatment), 1 after off treatment due to toxicity |
Progression-Free Survival | 7.1 months |
1-Year Overall Survival Rate | 56% |
Regimens | PFS (Months) | OS (Months) | PD during or after Pre-Op | pT0/T1 | R0 Resection |
---|---|---|---|---|---|
FLOT | 30 HR 0.75, * P = 0.004 | 50 HR 0.77, * P = 0.012 | 1% * P = 0.001 | 25% * P = 0.001 | 84% * P = 0.001 |
ECF or ECX | 18 | 35 | 5% | 15% | 77% |
Outcomes | Nivolumab (3 mg/kg) Every 2 Weeks | Nivolumab (1 mg/kg) + Ipilimumab (3 mg/kg) every 3 Weeks | Nivolumab (3 mg/kg) + Ipilimumab (1 mg/kg) Every 3 Weeks |
---|---|---|---|
ORR (%) | 12 | 24 | 8 |
ORR (%) PD-L1 ≥ 1% | 19 | 40 | 23 |
ORR (%) PD-L1 ≤ 1% | 12 | 22 | 0 |
OS (months) | 6.2 | 6.9 | 4.8 |
Outcomes | Sorafenib-Naïve (n = 80) | Sorafenib-Treated (n = 182) |
---|---|---|
Overall response rate | 24% | 19% |
Complete response | 1% | 1% |
Partial response | 19% | 13% |
Stable disease | 34% | 41% |
Disease control rate | 63% | 56% |
Outcomes | Ramucirumab vs. Placebo | Ramucirumab vs. Placebo (AFP ≥ 400 ng/mL) |
---|---|---|
HR (Child-Pugh 5) | 0.80 (P = 0.06) | 0.61 (* P = 0.01) |
HR (Child-Pugh 6) | 0.96 (P = 0.76) | 0.64 (* P = 0.04) |
HR (Child-Pugh 7 or 8) | 1.00 (P > 0.99) | 0.67 (P = 0.28) |
Outcomes | Lenvatinib | Sorafenib |
---|---|---|
Median OS (months) | 13.6 HR 0.92; NS | 12.3 |
Median PFS (months) | 7.4 HR 0.66; * P < 0.00001 | 3.7 |
Median TTP (months) | 8.9 HR 0.63; * P < 0.00001 | 3.7 |
ORR (%) | 24 * P < 0.00001 | 9 |
Outcomes | Result |
---|---|
Complete Response | 1 patient |
Partial Response | 5 patients |
Stable Disease | 20 patients |
Overall Response Rate | 16% |
Disease Control Rate | 68% |
Regimen | Capecitabine | Observation |
---|---|---|
Overall survival | 51 months HR 0.75; * P = 0.028 | 36 months |
Recurrence-free survival | 25 months | 18 months |
Regimen | Progression-Free Survival | Overall Survival | 1-Year Survival Rate |
---|---|---|---|
nab-Paclitaxel + Gemcitabine + Cisplatin | 11.4 months | >20 months (estimated) | 66.7% |
Gemcitabine + Cisplatin | 8.0 months (Historical control) | 11.7 months (Historical control) | - |
Outcome | 3 Months of CAPOX or FOLFOX | 6 Months of CAPOX or FOLFOX |
---|---|---|
DFS Events | 734 | 735 |
3-Year DFS Rate (%) | 76.8 HR 1.008 (95% CI 0.910–1.117) Non-inferiority, * P = 0.014 | 77.4 |
Regimen | Vemurafenib + Irinotecan and Cetuximab | Irinotecan and Cetuximab |
---|---|---|
PFS (months) | 4.4 (5.7 if no prior irinotecan) | 2.0 (1.9 if no prior irinotecan) |
RR (%) | 16 # P = 0.08 | 4 |
DCR (%) | 67% | 22 |
© 2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Yee, N.S. Update in Systemic and Targeted Therapies in Gastrointestinal Oncology. Biomedicines 2018, 6, 34. https://doi.org/10.3390/biomedicines6010034
Yee NS. Update in Systemic and Targeted Therapies in Gastrointestinal Oncology. Biomedicines. 2018; 6(1):34. https://doi.org/10.3390/biomedicines6010034
Chicago/Turabian StyleYee, Nelson S. 2018. "Update in Systemic and Targeted Therapies in Gastrointestinal Oncology" Biomedicines 6, no. 1: 34. https://doi.org/10.3390/biomedicines6010034
APA StyleYee, N. S. (2018). Update in Systemic and Targeted Therapies in Gastrointestinal Oncology. Biomedicines, 6(1), 34. https://doi.org/10.3390/biomedicines6010034