Background
Epidermal Growth Factor Receptor (EGFR)
Background of targeted therapies to EGFR
Clinical development of small-molecule EGFR tyrosine kinase inhibitors
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
Small-molecule EGFR TKIs | ||||||||||
1st Generation EGFR TKI | ||||||||||
Gefitinib (Iressa®/ZD1839) | ||||||||||
Gefitinib (250 mg/d) | NCT00322452 | IPASS | NSCLC | Chemotherapy | 2006–2010 | AstraZeneca | III | 1329 | 18.6 vs 17.3 | 5.7 vs 5.8/24.9 vs 6.7% |
Gefitinib (250 mg/d) | NCT01203917 | IFUM | NSCLC (EGFR+) | None | 2010–2013 | AstraZeneca | IV | 1060 | 19.2 | 7.0 |
Erlotinib (Tarceva®) | ||||||||||
Erlotinib (150 mg/d) | NCT00036647 | BR.21 | NSCLC | Placebo | 2001–2004 | OSI Pharmaceuticals | III | 731 | 6.7 vs 4.7 | 2.2 vs 1.8 |
Erlotinib (150 mg/d) | NCT00556712 | SATURN | NSCLC | Placebo | 2010–2013 | Hoffmann-La Roche | Obs | 289 | 12.4 vs 11.0 | 12.3 vs 11.1 |
Erlotinib (150 mg/d) | NCT01328951 | IUNO | NSCLC | Placebo | 2011–2016 | Hoffmann-La Roche | III | 643 | 9.7 vs 9.5 | 3.0 vs 2.8 |
Erlotinib (100 mg/d) + Gemcitabine (1000 mg/m2/w) | NCT02694536 | Pancreatic cancer | None | 2006–2009 | Hoffmann-La Roche | III | 80 | 7.5 | 4.9 | |
Lapatinib (Tykerb®) | ||||||||||
Lapatinib (1250 mg/d) + capecitabine (2000 mg/m2) | NCT00078572 | Breast (HER2+) | Capecitabine | 2004–2006 | GSK | III | 408 | 17.3 vs 14.9 | 7.2 vs 4.3 | |
Lapatinib (1500 mg/d) + letrozole (2.5 mg/d) | NCT00073528 | Breast (ER/PR +) | Letrozole | 2003–2018 | Norvatis | III | 1285 | 33.3 vs 32.3 | 8.1 vs 3.0 | |
Lapatinib (1500 mg/d) | NCT00374322 | TEACH | Breast (HER2+) | Placebo | 2006–2013 | GSK | III | 3166 | 7.3 vs 8.0% | 13.3 vs 15.8% |
2nd Generation EGFR TKI | ||||||||||
Afatinib (BIBW 2992/Gilotrif®) | ||||||||||
Afatinib (50 mg/d) | NCT00525148 | LUX-Lung 2 | NSCLC | None | 2007–2015 | Boehringer Ingelheim | II | 129 | 26.8 | 10.2 |
Afatinib (40 mg/d) | NCT00949650 | LUX-Lung 3 | NSCLC, Adenocarcinoma | Pemetrexed + cisplatin | 2009–2017 | Boehringer Ingelheim | III | 345 | 28.2 vs 28.2 | 11.2 vs 6.9 |
Afatinib (40 mg/d) | NCT01121393 | LUX-Lung 6 | NSCLC, Adenocarcinoma | Gemcitabine + cisplatin | 2010–2017 | Boehringer Ingelheim | III | 364 | 23.1 vs 23.5 | 11.0 vs 5.6 |
Afatinib (40-50 mg/d) | NCT01523587 | LUX-Lung 8 | NSCLC | Erlotinib | 2012–2017 | Boehringer Ingelheim | III | 795 | NR | 2.4 vs 1.9 |
Afatinib (40 mg/d) + vinorelbine (25 mg/m2) | NCT01125566 | LUX-Breast 1 | Breast (HER2+) | Trastuzumab + vinorelbine | 2010–2018 | Boehringer Ingelheim | III | 508 | 19.6 vs 28.6 | 5.5 vs 5.6 |
Afatinib (40 mg/d) | NCT01271725 | LUX-Breast 2 | Breast (HER2+) | Afatinib + vinorelbine + paclitaxel | 2011–2017 | Boehringer Ingelheim | II | 74 | NR | NR |
Afatinib (40 mg/d) | NCT01441596 | LUX-Breast 3 | Breast (HER2+) | Investigator’s choice | 2011–2015 | Boehringer Ingelheim | II | 121 | 13.3 vs 12.0 | 2.7 vs 4.2 |
Dacomitinib (Vizimpro®) | ||||||||||
Dacomitinib (45 mg/d) | NCT01774721 | ARCHER 1050 | NSCLC (EGFR mutant) | Gefitinib | 2013–2016 | SFJ Pharmaceuticals | III | 440 | 16.9 vs 11.9 | 14.7 vs 9.2 |
Vandetanib (Caprelsa®) | ||||||||||
Vandetanib (300 mg/d) | NCT00410761 | ZETA | Thyroid | Placebo | 2006–2019 | Sanofi | III | 437 | 13.9 vs 16.0% | 30.5 vs 19.2 |
Vandetanib (300 mg/d) | NCT00409968 NCT00411671 NCT00411632 NCT00410059 NCT00410189 | BATTLE Program | NSCLC | Erlotinib, erlotinib + bexarotene, sorafenib | 2006–2018 | United States Department of Defense | II | 255 | 33.0% | 1.8 |
Neratinib (Nerlynx®) | ||||||||||
Neratinib (240 mg/d) | NCT00878709 | ExteNET | Breast Cancer | Placebo | 2009–2020 (active) | Puma Biotechnology, Inc. | III | 2840 | 4.7 vs 8.0 (DFS) | NR |
3rd Generation EGFR TKI | ||||||||||
Osimertinib (Tagrisso®) | ||||||||||
Osimertinib (80 mg/d) | NCT01802632 | AURA extension | NSCLC (EGFR-T790 M) | None | 2013–2018 | AstraZeneca | I/II | 201 [603] | NR | 9.7 |
Osimertinib (80 mg/d) | NCT02094261 | AURA 2 | NSCLC (EGFR-T790 M) | None | 2014–2019 | AstraZeneca | II | 210 | NR | 8.6 |
Osimertinib (80 mg/d) | NCT02151981 | AURA 3 | NSCLC | Chemotherapy | 2014–2018 (active) | AstraZeneca | III | 419 | NR | 10.1 vs 4.4 |
Rociletinib | ||||||||||
Rociletinib (500–750 mg BD) | NCT01526928 | NSCLC | None | 2012–2019 | Clovis Oncology, Inc. | I/II | 605 | 13.1 | ||
Naquotinib | ||||||||||
Naquotinib (dose NR) | NCT02588261 | SOLAR | NSCLC | Erlotinib or gefitinib | 2016–2017 (terminated) | Astellas Pharma Inc | III | 530 | NR | NR |
Clinical development of monoclonal antibodies targeting EGFR
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
Monoclonal antibodies to EGFR | ||||||||||
Cetuximab (Erbitux®) | ||||||||||
Cetuximab (400 mg/m2 initial + 250 mg/m2/week) + cisplatin + vinorelbine | NCT00148798 | FLEX | NSCLC | Cisplatin + vinorelbine | 2005–2014 | Merck KGaA | III | 1861 | 11.3 vs 10.1 | 4.8 vs 4.8 |
Cetuximab (400 mg/m2 initial + 250 mg/m2/week) | NCT01001377 | ASPECCT | Metastatic CRC | Panitumumab | 2010–2017 | Amgen | III | 1010 | 10.0 vs 10.4 | 4.4 vs 4.1 |
Cetuximab [400/250 mg/m2 (initial/weekly)] + Chemotherapy | NCT00122460 | EXTREME | H&N Cancer | Chemotherapy | 2004–2011 | Merck KGaA | III | 442 | 10.1 vs 7.4 | 5.6 vs 3.3 |
Cetuximab [400/200 mg/m2 (initial/weekly)] + FOLFIRI | NCT00154102 | CRYSTAL | Metastatic CRC (KRAS WT) | FOLFIRI | 2004–2011 | Merck KGaA | III | 1221 | 23.5 vs 20.0 | 9.9 vs 8.4 |
Cetuximab + 5-FU/FA + oxaliplatin (FOLFOX-4) | NCT00125034 | OPUS | Metastatic CRC (KRAS WT) | 5-FU/FA + oxaliplatin | 2005–2010 | Merck KGaA | II | 344 | 22.8 vs 18.5 | 8.3 vs 7.2 |
Panitumumab (Vectibix®) | ||||||||||
Panitumumab (6 mg/kg/2w) + FOLFOX | NCT00364013 | PRIME | Metastatic CRC (WT KRAS) | FOLFOX | 2006–2013 | Amgen | III | 1183 | 23.9 vs 19.7 | 9.6 vs 8.0 |
Panitumumab (6 mg/kg/2w) + FOLFOX | NCT00364013 | PRIME | Metastatic CRC (Mutant KRAS) | FOLFOX | 2006–2013 | Amgen | III | 1183 | 15.5 vs 19.3 | 7.3 vs 8.8 |
Panitumumab (6 mg/kg/2w) + BSC | NCT01412957 | ‘0007 | Metastatic CRC (WT RAS) | BSC | 2011–2017 | Amgen | III | 377 | 10.0 vs 6.9 | 5.2 vs 1.7 |
Necitumumab (Portrazza®) | ||||||||||
Necitumumab (800 mg/ m2/3w) + gemcitabine + cisplatin | NCT00981058 | SQUIRE | NSCLC | Gemcitabine + cisplatin | 2010–2018 | Eli Lilly and Company | III | 1093 | 11.5 vs 9.9 | 5.7 vs 5.5 |
Necitumumab (500 mg/m2/3w) + Chemotherapy | NCT00982111 | INSPIRE | NSCLC | Chemotherapy | 2009–2018 | Eli Lilly and Company | III | 633 | 11.3 vs 11.5 | 5.6 vs 5.6 |
Conclusion
Vascular Endothelial Growth Factor (VEGF)
Background of targeted therapies to VEGF
Clinical development of VEGF inhibitors
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
VEGF inhibitors | ||||||||||
Sorafenib (Nexavar®) | ||||||||||
Sorafenib (400 mg BD) | NCT00073307 | TARGET | Metastatic RCC | Placebo | 2003–2006 | Bayer | III | 903 | 17.8 vs 15.2 | 5.5 vs 2.8 |
Sorafenib (400 mg BD) | NCT00984282 | Thyroid cancer | Placebo | 2009–2012 | Bayer | III | 417 | 52.7 vs 54.8% | 10.8 vs 5.8 | |
Bevacizumab (Avastin®) | ||||||||||
Bevacizumab (10 mg/kg/2w) | NCT00281697 | RIBBON 2 | Metastatic Breast Cancer | Placebo | 2006–2009 | Genentech | III | 684 | 18.6 vs 17.8 | 7.2 vs 5.1 |
Bevacizumab (5 mg/kg/w) | NCT00528567 | BEATRICE | Breast cancer (triple negative) | Standard adjuvant chemotherapy | 2007–2012 | Hoffmann-La Roche | III | 2591 | NR | NR |
Bevacizumab (10 mg/kg/2w) | NCT00028990 | E2100 | Metastatic breast cancer | Paclitaxel | 2001–2006 | Eastern Cooperative Oncology Group | III | 722 | NR | 11.8 vs 5.9 |
Bevacizumab (5 mg/kg/w) | NCT01169558 | Metastatic CRC | Combination with Fluoropyrimidine-based Chemotherapy | 2006–2009 | Hoffmann-La Roche | III | 162 | 21.6 | 11.0 | |
Bevacizumab (15 mg/kg/3w) | NCT01239732 | Ovarian cancer | Paclitaxel + Carboplatin | 2010–2015 | Hoffmann-La Roche | III | 1021 | NA | 25.5 | |
Bevacizumab (dose NR) + chemotherapy | NCT00565851 | GOG-0213 | Ovarian, Epithelial, Peritoneal, Fallopian Tube Cancer | Chemotherapy | 2007–2019 | National Cancer Institute | III | 1038 | 42.2 vs 37.3 | 13.8 s 10.4 |
Bevacizumab (15 mg/kg/3w) + chemotherapy | NCT00434642 | OCEANS | Ovarian cancer | Chemotherapy | 2007–2013 | Genentech | III | 484 | 33.6 vs 32.9 | 12.4 vs 8.4 |
Bevacizumab (10 mg/kg/w) + IFNα2A | NCT00738530 | AVOREN | RCC | IFNα2A | 2004–2008 | Hoffmann-La Roche | III | 649 | 23.3 vs 21.3 | 10.2 vs 5.5 |
Bevacizumab (15 mg/kg/3w) + chemotherapy | NCT00803062 | GOG-240 | Cervical cancer | Chemotherapy | 2008–2017 | National Cancer Institute | III | 452 | 17.5 vs 14.3 | 9.6 vs 6.7 |
Bevacizumab (10 mg/kg) | NCT00345163 | BRAIN | Glioblastoma | Chemotherapy | 2006–2007 | Genentech | II | 167 | 8.7 vs 9.2 | 50.3 vs 42.6% |
Bevacizumab (10 mg/kg) | NCT01351415 | NSCLC | Chemotherapy | 2006–2014 | Hoffmann-La Roche | III | 485 | 11.9 vs 10.2 | 5.5 vs 4.0 | |
Ramucirumab (Cryamza®) | ||||||||||
Ramucirumab (8 mg/kg/2w) | NCT00917384 | REGARD | Metastatic gastric or gastroesophageal junction cancer | Placebo | 2009–2015 | Eli Lilly and Company | III | 355 | 2.1 vs 1.3 | 5.2 vs 3.8 |
Aflibercept (EYLEA®) | ||||||||||
Aflibercept (4 mg/kg) + FOLFIRI | NCT00561470 | VELOUR | CRC | FOLFIRI | 2007–2012 | Sanofi | III | 1226 | 13.5 vs 12.1 | 6.9 vs 4.7 |
Aflibercept (4 mg/kg) + docetaxel | NCT00532155 | VITAL | Metastatic NSLC | Docetaxel | 2007–2011 | Sanofi | III | 913 | 10.1 vs 10.4 | 5.2 vs 4.1 |
Aflibercept (4 mg/kg) + gemcitabine | NCT00574275 | VANILLA | Metastatic pancreatic cancer | Gemcitabine | 2007–2010 | Sanofi | III | 546 | 7.8 vs 6.5 | 3.7 vs 3.7 |
Conclusion
Human Epidermal Growth Factor Receptor (HER2)
Background of targeted therapies to HER2
Clinical development of HER2 inhibitors
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
HER2 inhibitors | ||||||||||
Trastuzumab (Herceptin®) | ||||||||||
Trastuzumab (4 mg/kg followed by 2 mg/kg) + doxorubicin + cyclophosphamide | NCT00004067 | Breast cancer (HER2+) | Doxorubicin + cyclophosphamide + paclitaxel | 2000–2020 | NSABP Foundation Inc | 3 | 42,130 | NA | NA | |
Trastuzumab (8 mg/kg followed by 6 mg/kg) + chemotherapy | NCT01998906 | Breast cancer (HER2+) | Chemotherapy | 2002–2012 | Hoffmann-La Roche | 3 | 330 | NA | NA | |
Trastuzumab (4 mg/kg followed by 2 mg/kg) + docetaxel | Marty et al. (2005) | M77001 | Breast cancer (HER2+) | Docetaxel | 2000–2005 | Hoffmann-La Roche | 2 | 186 | 31.2 vs 22.7 | 11.7 vs 6.1 |
Trastuzumab (4 mg/kg followed by 2 mg/kg) + lapatinib | NCT00320385 | Breast cancer (HER2+) | Lapatinib | 2005–2010 | GlaxoSmithKline | 3 | 296 | 51.6 vs 39 (weeks) | 12 vs 8.1 (weeks) | |
Trastuzumab (8 mg/kg followed by 6 mg/kg) + fluorouracil + cisplatin + capecitabine | NCT01041404 | ToGA Study | HER2+ advanced gastric cancer | Fluorouracil + Cisplatin + Capecitabine | 2005–2010 | Hoffmann-La Roche | 3 | 584 | 11.1 vs 13.8 | 5.5 vs 6.7 |
Trastuzumab (4 mg/kg followed by 2 mg/kg) + chemotherapy | NCT00021255 | Breast cancer (HER2+) | Chemotherapy | 2001–2014 | Sanofi | 3 | 3222 | 78.9 vs 86 | NA | |
Trastuzumab (2 mg/kg i.v. weekly, or 6 mg/kg i.v. every 3 weeks) + chemotherapy | NCT00448279 | THOR | Breast cancer (HER2+) | Chemotherapy | 2007–2010 | Hoffmann-La Roche | 3 | 58 | 19.1 vs 26.7 | 9.7 vs 9.4 |
T-DM1 (Trastuzumab Emtansine/ Kadcyla®) | ||||||||||
T-DM1 (3.6 mg/kg/3w) | NCT00829166 | EMILIA | Breast cancer (HER2+) | Lapatinib + Capecitabine | 2009–2015 | Hoffmann-La Roche | III | 991 | 30.9 vs 25.1 | 9.6 vs 6.4 |
T-DM1 (3.6 mg/kg/3w) | NCT01419197 | TH3RESA | Breast cancer (HER2+) | Physician’s choice | 2011–2015 | Hoffmann-La Roche | III | 602 | 22.7 vs 15.8 | 6.2 vs 3.3 |
Pertuzumab (Perjeta®) | ||||||||||
Pertuzumab (420 mg/3w) + trastuzumab + docetaxel | NCT00567190 | CLEOPATRA | Breast cancer (HER2+) | Trastuzumab and Docetaxel | 2008–2018 | Hoffmann-La Roche | III | 808 | 56.5 vs 40.8 | 18.7 vs 12.4 |
Pertuzumab (420 mg/3w) + trastuzumab + capecitabine | NCT01026142 | PHEREXA | Breast cancer (HER2+) | Trastuzumab + capecitabine | 2010–2017 | Hoffmann-La Roche | III | 452 | 37.2 vs 28.1 | 11.1 vs 9.0 |
Pertuzumab (420 mg/3w) + trastuzumab + chemotherapy | NCT01358877 | APHINITY | Breast cancer (HER2+) | Trastuzumab + chemotherapy | 2011–2016 | Hoffmann-La Roche | III | 4804 | NR | 8.7 vs 7.1% |
Pertuzumab + T-DM1 | NCT01120184 | MARIANNE | Breast cancer (HER2+) | T-DM1 + Placebo | 2010–2016 | Hoffmann-La Roche | III | 1095 | 51.8 vs 53.7 | 15.2 vs 14.1 |
Lapatinib (Tykerb®) | ||||||||||
Lapatinib (1250 mg/d) + capecitabine | NCT00078572 | Metastatic breast cancer (HER2+) | Capecitabine | 2004–2010 | GSK | III | 408 | 10.4 vs 8.0 | 8.4 vs 4.4 | |
Lapatinib (1500 mg/d) | NCT00073528 | Metastatic breast cancer | Letrozole | 2003–2018 | Novartis | III | 1285 | 33.3 vs 32.3 | 8.1 vs 3.0 | |
Lapatinib (1500 mg/d) | NCT00374322 | TEACH | Early stage breast cancer | Placebo | 2006–2013 | GSK | III | 3166 | NR | NR |
Conclusion
Anaplastic lymphoma kinase (ALK)
Background of targeted therapies to ALK
Clinical development of ALK inhibitors
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
ALK inhibitors | ||||||||||
1st Generation ALK-inhibitors | ||||||||||
Crizotinib (Xalkori®) | ||||||||||
Crizotinib (50–2000 mg/d) | NCT00585195 | PROFILE 1001 | Advanced cancer | Rifampin, Itraconazole | 2006–2023 | Pfizer | I | 600 | NR | 9.7 |
Crizotinib (250 mg BD) | NCT00932451 | PROFILE 1005 | NSCLC | None | 2010–2015 | Pfizer | II | 1069 | 21.8 | 8.1 |
Crizotinib (250 mg BD) | NCT0093283 | PROFILE 1007 | NSCLC | Permetrexed or docetaxel | NR | Pfizer | III | 172 | 20.3 vs 22.8 | 7.7 vs 3.0 |
Crizotinib (250 mg BD) | NCT01154140 | PROFILE 1014 | Non-squamous lung cancer | Platinum + permetrexed | 2011–2013 | Pfizer | III | 343 | NR | 10.9 vs 7.0 |
Ceritinib (Zykadia®) | ||||||||||
Ceritinib (750 mg/d) | NCT01283516 | ASCEND-1 | Tumors (ALK+) | None | 2011–2013 | Novartis | I | 304 | 16.7 | 7.0 |
Ceritinib (750 mg/d) | NCT02336451 | ASCEND-2 | NSCLC | None | 2015–2018 | Novartis | II | 160 | NR | 5.7 |
Ceritinib (750 mg/d) | NCT01685138 | ASCEND-3 | NSCLC | None | 2008–2018 | Novartis | II | 125 | NR | 10.8 |
Ceritinib (750 mg/d) | NCT01828099 | ASCEND-4 | NSCLC | Chemotherapy | 2013–2016 | Novartis | III | 375 | NR | 16.6 vs 8.1 |
Ceritinib (750 mg/d) | NCT01828112 | ASCEND-5 | NSCLC | Chemotherapy | 2013–2017 | Novartis | III | 232 | 20.1 vs 18.1 | 5.4 vs 1.6 |
Ceritinib (750 mg/d) | NCT02299505 | ASCEND-8 | NSCLC | None | 2015–2016 | Novartis | I | 318 | NR | NR |
Alectinib (Alcensa®) | ||||||||||
Alectinib (600 mg BD) | NCT01871805 | NP28761 | NSCLC | None | 2013–2017 | Hoffmann-La Roche | I/II | 134 | 27.9 | 8.2 |
Alectinib (600 mg BD) | NCT01801111 | NP28673 | NSCLC | None | 2013–2014 | Hoffmann-La Roche | I/II | 138 | 12.1 | 7.5 |
Alectinib (600 mg BD) | NCT02075840 | ALEX | NSCLC | Crizotinib | 2014–2017 | Hoffmann-La Roche | III | 303 | NR | 25.7 vs 10.4 |
Brigatinib (Alunbrig™) | ||||||||||
Brigatinib (90 mg/d) | NCT01449461 | NSCLC | None | 2011–2015 | Ariad | I/II | 137 | NR | 16.3 | |
Brigatinib (90 mg/d) | NCT02094573 | NSCLC | None | 2014–2016 | Ariad | II | 222 | 46% | 9.2 | |
Brigatinib (90 mg/d) | NCT02737501 | ALTA-L1 | NSCLC | Crizotinib | 2016–2020 | Ariad | III | 275 | 85 vs 86% | 67 vs 43% |
Lorlatinib | ||||||||||
Lorlatinib (10-200 mg/d) | NCT01970865 | CROWN | NSCLC | None | 2014–2017 | Pfizer | II | 367 | 22.3 | 5.3 |
Conclusions
BRAF
Background of targeted therapies to BRAF
Clinical development of small-molecule BRAF tyrosine kinase inhibitors
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
---|---|---|---|---|---|---|---|---|---|---|
BRAF inhibitors | ||||||||||
Sorafenib (Nexavar®) | ||||||||||
Sorafenib (400 mg BD) | NCT00105443 | SHARP | HCC | Placebo | 2005–2008 | Bayer | III | 602 | 10.8 vs 8.0 | 5.5 vs 2.8 |
Sorafenib (800 mg) | NCT00984282 | Thyroid | Placebo | 2009–2017) | Bayer | III | 417 | 52.7 vs 54.8% | 10.8 vs 5.8 | |
Sorafenib (400 mg BD) | NCT00119249 | Melanoma | 2005–2007 | NCI | II | 74 | NR | NR | ||
Vemurafenib (Zelboraf®) | ||||||||||
Vemurafenib (960 mg BD) | NCT01910181 | BRIM | Metastatic melanoma | None | 2013–2018 | Hoffmann-La Roche | I | 46 | 13.5 | 8.6 |
Vemurafenib (960 mg BD) | NCT00949702 | BRIM2 | Melanoma | None | 2009–2014 | Hoffmann-La Roche | II | 132 | NA | 6.1 |
Vemurafenib (960 mg BD) | NCT01006980 | BRIM3 | Metastatic melanoma | Dacarbazine | 2010–2015 | Hoffmann-La Roche | III | 675 | 13.6 vs 9.7 | NR |
Dabrafenib (Tafinlar®) | ||||||||||
Dabrafenib (150 mg BD) | NCT01153763 | BREAK-2 | Melanoma | None | 2010–2016 | GSK | II | 92 | 3.0 | 1.4 |
Dabrafenib (150 mg BD) | NCT01227889 | BREAK-3 | Melanoma | Dacarbazine | 2010–2014 | GSK | III | 251 | 20.0 vs 15.6 | 6.7 vs 2.9 |
Dabrafenib (150 mg BD) + trametinib | NCT01336634 | NSCLC | Dabrafenib | 2011–2015 | Norvatis | II | 174 | 18.2 vs 12.7 | 10.2 vs 5.5 | |
Dabrafenib (150 mg BD) | NCT01723202 | Thyroid | Trametinib | 2012–2018 | National Comprehensive Cancer Network | II | 53 | NR | NR | |
Regorafenib (Stivarga®) | ||||||||||
Regorafenib (160 mg/d) | NCT01103323 | CORRECT | Colorectal cancer | Placebo + BSC | 2010–2014 | Bayer | III | 760 | 6.4 vs 5.0 | 1.9 vs 1.7 |
Regorafenib (160 mg/d) | NCT01271712 | GRID | GIST | Placebo | 2011–2012 | Bayer | III | 199 | 2.7 vs 2.6 | 4.8 vs 0.9 |
Regorafenib (160 mg/d) | NCT01774344 | RESORCE | HCC | Placebo | 2013–2017 | Bayer | III | 573 | 10.6 vs 7.8 | 3.6 vs 1.5 |
Cobimetinib (Cotellic®) | ||||||||||
Cobimetinib (60 mg/d) + vemurafenib | NCT01689519 | coBRIM | Melanoma | Vemurafenib + Placebo | 2012–2015 | Hoffmann-La Roche | III | 495 | 22.3 vs 17.4 | 9.9 vs 6.2 |
Trametinib (Mekinist®) | ||||||||||
Trametinib (2 mg/d) + dabrafenib | NCT01682083 | COMBI-AD | Melanoma | Placebo | 2013–2017 | Norvatis | III | 870 | NR | NR |
Trametinib (2 mg/d) + dabrafenib | NCT02034110 | Thyroid | 2014–2020 | Norvatis | II | 100 | 80% | 79% |
Conclusions
Targeting T-cell immune checkpoints with CTLA-4 and PD-1 inhibitors
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
Background of targeted therapies to CTLA-4
Clinical development of CTLA-4 inhibitors
CTLA-4 inhibitors | ||||||||||
Ipilimumab (Yervoy®) | ||||||||||
Drug Name | Clinical Trial ID | Trial Name | Population | Comparator | Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) |
CTLA-4 inhibitors | ||||||||||
Ipilimumab (Yervoy®) | ||||||||||
Ipilimumab (3 mg/kg/3w) | NCT00094653 | MDX010–020 | Melanoma | Gp100 vaccine | 2004–2011 | Bristol-Myers Squibb | III | 1783 | 10.0 vs 6.4 | 2.9 vs 2.8 |
Ipilimumab (10 mg/kg/3w) | NCT00636168 | Melanoma | Placebo | 2008–2013 | Bristol-Myers Squibb | III | 1211 | 93.5 vs 87.7 | 63.5 vs 56.1 | |
Ipilimumab (3 mg/kg/3w) | NCT01696045 | Melanoma | None | 2012–2016 | Bristol-Myers Squibb | II | 14 | 18.2 | 2.6 | |
Ipilimumab (1 mg/kg/3w) + nivolumab | NCT02231749 | CHECKMATE-214 | RCC | Sunitinib | 2014–2017 | Bristol-Myers Squibb | III | 1390 | NA vs 26.0 | 11.6 vs 8.4 |
Ipilimumab (1 mg/kg/3w) | NCT02060188 | CHECKMATE-142 | CRC | Chemotherapy | 2014–2018 | Bristol-Myers Squibb | II | 340 | NR | NR |
Ipilimumab (1 mg/kg/ 6w) + nivolumab | NCT03083691 | BIOLUMA | NSCLC, SCLC | Nivolumab | 2017–2019 | Bristol-Myers Squibb | II | 106 | NR | NR |
Ipilimumab (10 mg/kg/3mo) + bevacizumab | NCT00790010 | Melanoma | None | 2009–2018 | Bristol-Myers Squibb | I | 46 | NR | NR | |
Ipilimumab (10 mg/kg/3mo) | NCT01119508 | Melanoma | None | 2010–2016 | Bristol-Myers Squibb | II | 64 | NR | NR | |
PD-1/PD-1 L inhibitors | ||||||||||
Pembrolizumab (Keytruda®) | ||||||||||
Pembrolizumab (2-10 mg/kg/3w) | NCT01295827 | KEYNOTE-001 | Melanoma, NSCLC | None | 2011–2018 | Merck Sharp & Dohme Corp. | I | 1260 | 12.0 | 3.7 |
Pembrolizumab (2 mg/kg/3w) | NCT01704287 | KEYNOTE-002 | Melanoma | Chemotherapy | 2012–2015 | Merck Sharp & Dohme Corp. | II | 540 | 13.4 vs 11.0 | 2.9 vs 2.8 |
Pembrolizumab (10 mg/kg/2w) | NCT01866319 | KEYNOTE-006 | Melanoma | Ipilimumab | 2013–2015 | Merck Sharp & Dohme Corp. | III | 834 | 74.1 vs 58.2% | 5.5 vs 2.8 |
Pembrolizumab (10 mg/kg/2w) | NCT01848834 | KEYNOTE-012 | Head and Neck SCC | None | 2013–2016 | Merck Sharp & Dohme Corp. | I | 297 | 59% | 23% |
Pembrolizumab (200 mg/3w) | NCT02142738 | KEYNOTE-024 | NSCLC | BSC | 2014–2016 | Merck Sharp & Dohme Corp. | III | 305 | 80.2 vs 72.4% | 62.1 vs 50.3% |
Pembrolizumab (200 mg/3w) | NCT02453594 | KEYNOTE-087 | Hodgkin Lymphoma | None | 2015–2021 | Merck Sharp & Dohme Corp. | II | 211 | 97.5% | 63.4% |
Pembrolizumab (200 mg/3w) + chemotherapy | NCT02039674 | KEYNOTE-021 | NSCLC | Chemotherapy | 2014–2016 | Merck Sharp & Dohme Corp. | I/II | 267 | NR | 13.0 vs 8.9 |
Pembrolizumab (200 mg/3w) | NCT02335424 | KEYNOTE-052 | Urothelial cancer | None | 2015–2018 | Merck Sharp & Dohme Corp. | II | 374 | 67% | 30% |
Pembrolizumab (10 mg/kg/2w) | NCT01876511 | KEYNOTE-016 | CRC (MSI) | None | 2013–2021 | Merck Sharp & Dohme Corp. | II | 171 | 76% | 64% |
Pembrolizumab (200 mg/3w) | NCT02460198 | KEYNOTE-164 | CRC | None | 2015–2019 | Merck Sharp & Dohme Corp. | II | 124 | NR | NR |
Pembrolizumab (10 mg/kg/2w) | NCT02054806 | KEYNOTE-028 | Solid tumors | None | 2014–2019 | Merck Sharp & Dohme Corp. | I | 477 | 62.6% | 20.8% |
Pembrolizumab (200 mg/3w) | NCT02628067 | KEYNOTE-158 | Solid tumors | None | 2015–2023 | Merck Sharp & Dohme Corp. | II | 1350 | NR | NR |
Pembrolizumab (200 mg/3w) | NCT02335411 | KEYNOTE-059 | Gastric and gastroesophageal junction adenocarcinomas | None | 2015–2019 | Merck Sharp & Dohme Corp. | II | 316 | 5.6 | 2.0 |
Pembrolizumab (200 mg/3w) | NCT02576990 | KEYNOTE-170 | Large B-cell lymphoma | None | 2015–2019 | Merck Sharp & Dohme Corp. | II | 80 | NR | NR |
Pembrolizumab (200 mg/3w) | NCT02578680 | KEYNOTE-189 | NSCLC | Placebo | 2016–2017 | Merck Sharp & Dohme Corp. | III | 646 | 69.2 vs 49.4% | 8.8 vs 4.9 |
Nivolumab (Opdivo®) | ||||||||||
Nivolumab (3 mg/kg/2w) | NCT01721746 | CHECKMATE-037 | Melanoma | Chemotherapy | 2012–2016 | Bristol-Myers Squibb | III | 631 | 15.7 vs 14.4 | 3.1 vs 3.7 |
Nivolumab (3 mg/kg/2w) | NCT01642004 | CHECKMATE-017 | NSCLC | Docetaxel | 2012–2014 | Bristol-Myers Squibb | III | 352 | 9.2 vs 6.0 | 20.8 vs 6.4 |
Nivolumab (3 mg/kg/2w) | NCT01673867 | CHECKMATE-057 | NSCLC | Docetaxel | 2012–2015 | Bristol-Myers Squibb | III | 792 | 12.2 vs 9.4 | 2.3 vs 4.2 |
Nivolumab (3 mg/kg/2w) | NCT01668784 | CHECKMATE-025 | RCC | Everolimus | 2012–2015 | Bristol-Myers Squibb | III | 1068 | 25.0 vs 19.6 | 4.6 vs 4.4 |
Nivolumab (3 mg/kg/2w) | NCT02181738 | CHECKMATE-205 | Hodgkin Lymphoma | None | 2014–2017 | Bristol-Myers Squibb | II | 338 | 98·7% | 10.0 |
Nivolumab (3 mg/kg/2w) | NCT01592370 | CHECKMATE-039 | Hodgkin’s Lymphoma, | None | 2012–2020 | Bristol-Myers Squibb | I/II | 375 | NR | NR |
Nivolumab (3 mg/kg/2w) | NCT02105636 | CHECKMATE-141 | Head and Neck SCC | Chemotherapy | 2014–2015 | Bristol-Myers Squibb | III | 506 | 36.0 vs 16.6 | NR |
Nivolumab (3 mg/kg/2w) | NCT02387996 | CHECKMATE-275 | Advanced cancer | None | 2015–2016 | Bristol-Myers Squibb | II | 386 | 8.7 | 2.0 |
Nivolumab (3 mg/kg/2w) | NCT02060188 | CHECKMATE-142 | CRC | None | 2014–2018 | Bristol-Myers Squibb | II | 340 | 73% | 14.3 |
Nivolumab (3 mg/kg/2w) | NCT01928394 | CHECKMATE-032 | Advanced solid tumors | None | 2013–2018 | Bristol-Myers Squibb | I/II | 1150 | 9.7 | 16.2 |
Nivolumab (3 mg/kg/2w) | NCT01658878 | CHECKMATE-040 | HCC | None | 2012–2019 | Bristol-Myers Squibb | I/II | 620 | 10.7 | 4.0 |
Nivolumab (1 mg/kg/3w) + ipilimumab (3 mg/kg/3w) | NCT01844505 | CHECKMATE-067 | Melanoma | Ipilimumab + placebo | 2013–2016 | Bristol-Myers Squibb | III | 1296 | 63.8 vs 53.6% | 6.9 vs 2.9 |
Atezolizumab (Tecentriq®) | ||||||||||
Atezolizumab (1200 mg/3w) | NCT02108652 | IMVigor 210 | Urothelial cancer | None | 2014–2015 | Hoffmann-La Roche | II | 310 | 7.9 | 2.1 |
Atezolizumab (1200 mg/3w) | NCT01903993 | POPLAR | NSCLC | Docetaxel | 2013–2015 | Hoffmann-La Roche | II | 287 | 12.6 vs 9.7 | 2.7 vs 3.4 |
Atezolizumab (1200 mg/3w) | NCT02008227 | OAK | NSCLC | Docetaxel | 2014–2016 | Hoffmann-La Roche | III | 1225 | 13.8 vs 9.6 | 2.8 vs 4.0 |
Durvalumab (Imfinzi®) | ||||||||||
Durvalumab (10 mg/kg/2w) | NCT01693562 | Study 1108 | Advanced solid tumors | None | 2012–2019 | MedImmune LLC | I/II | 1022 | 1.5 | 18.2 |
Durvalumab (10 mg/kg/2w) | NCT02516241 | DANUBE | Urothelial cancer | None | 2015–2019 | AstraZeneca | III | 1200 | NR | NR |
Durvalumab (10 mg/kg/2w) | NCT02125461 | PACIFIC | NSCLC | Placebo | 2014–2017 | AstraZeneca | III | 713 | NR | 16.8 vs 5.6 |
Avelumab (Bavencio®) | ||||||||||
Avelumab (10 mg/kg/2w) | NCT02155647 | JAVELIN Merkel 200 | Merkel Cell Carcinoma | None | 2014–2019 | EMD Serono | II | 204 | 11.3 | 2.0 |
Avelumab (10 mg/kg/2w) | NCT01772004 | JAVELIN Solid Tumor | Advanced solid tumors | None | 2013–2018 | EMD Serono | I | 1758 | 13.7 | 2.7 |