Table 2. Activity of Single Agent IGF-1R Inhibitors on a Selection of Tumor Xenograft Models.
| Drug code (name) and source | Tumor typea | End point | Comments | Cell line and estimated %TGIb |
|---|---|---|---|---|
| AMG479 (ganitumab) | ||||
| Fahrenholtz et al,17 2013 | Prostate (VACaP) | Regression and cytostasis | Twice weekly for 3 wk; tumor regrowth following cessation of treatment | VACaP, 92% |
| Beltran et al,18 2009 | Pancreatic (BxPC3 and MiaCaPa2) | Growth delay | Palpable tumors remaining | BxPCR, 82%; MiaCaPa2, 83% |
| Beltran et al,19 2014 | Ovarian (OV90, OVCAR3, and TOV −21G) | Stasis (OV90); growth delay (OVCAR3); no effect (TOV-21G) | Twice weekly to end point | OV90, 100%; OVCAR3 57%; TOV-21G, 0% |
| Tabernero et al,20 2015 | Colon (colon-205) | Modest growth delay, leaving palpable tumors | Twice weekly to end point (3 wk) | Colon-205, 35% |
| Beltran et al,21 2011 | Ewing sarcoma (SK-ES-1 and A673) and osteosarcoma (SJSA-1) | Growth delay leaving palpable tumors | Twice weekly to end point (3 wk) | SK-ES-1, 50%; A673, 43%; SJSA-1, 33% |
| AVE1642 | ||||
| Geoerger et al,22 2010 | Neuroblastoma (IGR-N91 and SK-N-AS) | Modest growth delay leaving palpable tumors | Twice weekly to end point (21 or 28 d) | IGR-N91, 22%; SKN-AS, 19% |
| BMS-754807 | ||||
| Litzenburger et al,23 2011 | Triple negative breast cancer tumor graft | Growth delay leaving palpable tumors | Daily until end point (28 d) | 61% |
| Kolb et al,24 2011 | Pediatric tumors: KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 (osteosarcoma) | Variable growth delay; most effective in rhabdomyosarcoma | Twice daily for 6 d/wk for 6 consecutive wk to end point (6 wk) | KT-5, 88%; KT-14, 83%; Rh28, 0% (regrowth); OS-1, 97% |
| Awasthi et al,25 2012 | Pancreas (PDAC) | Modest growth delay | 25 mg/kg 5 times weekly to end point (12 d) | PDAC, 80% |
| Lee et al,26 2013 | Non-small cell lung cancer (H292) | Ineffective | 50 mg/kg/d from day 0 to day 11 | H292, 0% |
| Halvorson et al,27 2015 | Glioma, genetically engineered mouse model | Ineffective | 50 mg/kg/d for 21 d | No increase n survival |
| Carboni et al,16 2009 | Colon carcinoma (GEO) | Modest growth delay | 25 mg/kg twice daily for 17 d; a list of other xenograft results is reported | GEO, 25% |
| CP-751, 871 (figitu-mumab) | ||||
| Cohen et al,28 2005 | Colon (colon 205); breast (MCF7) | Modest growth delay | Single dose (antibody) | COLO 205, 56%; MCF7, 20% |
| Iwasa et al,29 2009 | Non–small cell lung (H460 and H1299) | Negligible effect | Single dose (antibody) | H460, 22%; H1299, 17% |
| Chakraborty et al,30 2015 | Breast cancer (BT474 and MCF7) | Ineffective | Weekly for 8 wk | BT474 0%; MCF7 0% |
| IMCA12 (cixutu-mumab) | ||||
| Barnes et al,31 2007 | Head and neck cancer (TU159) | Cytostasis | Highly variable growth patterns between individual mice with some showing no response | TU159, 100% |
| Lu et al,32 2005 | Pancreatic and colon cancers (BxPC3 & HT29) | Growth delay | Twice weekly for 6 wk | BxPC3, 63%; HT29, 57% |
| Tonra et al,33 2009 | Colon carcinoma (HCT-8 &HT29-LP) | Modest growth delay | 3 times weekly to end point | HCT-8, 15%; HT29-LP, 33% |
| SCH717454 (robatu-mumab) | ||||
| Wang et al,34 2010 | Pediatric tumors: (SK-N-FI neuroblastoma, SJSA-1 osteosarcoma, RD rhabdomyosarcoma) | Tumor regression | Treatments started in unestablished tumors | SK-N-F1, 100%; SJSA-1, 49%; RD, 57% |
| Kolb et al,35 2008 | Pediatric tumor xenografts: (EW5 and CHLA-258, Ewing sarcomas; NB-SD neuroblastoma; OS-1 and OS9, osteosarcomas) | CHLA: regression and regrowth; NB-SD: regression and regrowth | Individual tumor growth curves presented with regrowth after initial inhibition | EW5, 100%; CHLA-258, 0%; NB-SD, 0%; OS-1, 100%; OS-9, 100% |
| MK0646 (dalotuzumab) | ||||
| Fagan et al,36 2012 | Breast cancer (MCF7L) | Modest growth delay with regrowth | Twice weekly to end point | MCF-7L 0% |
| Di Cosimo et al,37 2015 | Lung adenocarcinoma LXFA629 | Left palpable tumors after growth inhibition | Once weekly until 28-d end point (reported TGI 70%) | LXFA629 67% |
| Lamhamedi-Cherradi et al,38 2016 | Ewing sarcoma (EW5 and TC71) | Ineffective as a single agent | Growth delay with regrowth | EW5 0%; TC71 0% |
| MM141 (istiratumab) | ||||
| Fitzgerald et al,39 2014 | Pancreas (BxPC-3) | Growth delay | Bispecific antibody to IGF-1R and ERBB3 | BxPC-3 97% |
| Camblin et al,40 2018 | Pancreas (CFPAC-1, HPAF-11) | Initial growth delay and regrowth | Every 3 d to end point | CFPAC-1 98%; HPAF-11 0% |
| OSI906 (linsitinib) (dual IGF-1R and InsR antagonist) | ||||
| Pitts et al,41 2010 | Colon (CUCRC007 and CUCRC026) | Growth delay reported 50% CUCRC007) and approximately 75% CUCRC026) | Once daily until end point (25 d) | CUCRC007 61%; CUCRC026 92% |
| Zeng et al,42 2012 | Breast (LCC6) | Modest growth delay | Daily to end point (30 d) | LCC6 56% |
| Kuhn et al,43 2012 | Multiple myeloma (8226.BR) | No growth delay | Stimulation of growth at 20 mg/kg twice weekly | 8226.BR −44% |
| Flanigan et al,44 2010 | Colon (HCT15 and CUCRC006) | Growth delay (HCT15) or no effect (CUCRC006) | Dosing to end point (20 or 62 d) | HCT15 48%; CUCRC006 7% |
| Kim et al,45 2012 | Lung (H226B–K-Ras) | No effect | Daily to end point (8 d) | H226B-K-ras 0% |
| Zinn et al,46 2013 | Small cell lung cancer (NCI-H187 and PDXs LX 33, LX36) | Modest growth delay | Daily to end point | H187 64%; LX33 39%; LX36 50% |
| Ma et al,47 2016 | Glioblastoma (GBN76 and 39) | Modest growth delay (GBN76) and stimulation of growth (GBN 39) | Daily to end point | GBM76 44%; GBM39 − 53% |
| Ramcharan et al,48 2015 | Melanoma (A375M) | Growth delay | 3 times week to end point (approximately 48 d) | A375M 61% |
| Min et al,49 2015 | Non–small cell lung cancer (H1975) | Modest growth delay | Daily to end point | H1975 17% |
| Murakami et al,50 2016 | Ewing sarcoma (PDX) | Cytostasis | Daily to 14 d; end point 21 d | PDOX 80% |
Abbreviations: IGF-1R, insulin-like growth factor-1 receptor; %TGI, percentage of tumor growth inhibition.
a
Cell lines used for xenografts.
b
Calculated as in Carboni et al.16 Estimations of %TGI of single-agent IGF-1R inhibitors on a selection of tumor xenograft models as published in the literature.