Table 2.
Clinical trials with FTIs*
| Disease | Phase | Patients (median age) | Clinical response and number of patients‡ | FT activity or prenylation | Response rate (%) | Other comments |
|---|---|---|---|---|---|---|
| Tipifarnib | ||||||
| Acute leukaemia | I | 34 (63) | 2 CR and 8 PR | FT ↓§ and HDJ2 ↓ | 29.4 | No NRAS mutations in patient tumours |
| Advanced bladder cancer | II | 34 (64) | 2 PR and 13 SD | ND | 5.9 | Response rate does not warrant further investigation |
| Advanced breast cancer | II | 76 (54) | 9 PR and 9 SD | ND | 11.8 | All responders had wild-type RAS genes |
| Advanced colon cancer | II | 55 (69) | 1 PR, 11 SD, and 31 PD and MD | ND | 1.8 | Tipifarnib is ineffective |
| Advanced NSCLC | II | 44 (71) | 7 SD | HDJ2 ↓ and prelamin A ↓. FT ↓ in 83% of patients | 0 | No objective response. Future studies should be done with combinations |
| Advanced solid tumours | I | 25 (58) | 0 CR, 0 PR, 8 SD, and 17 PD and MD | Data not shown | 0 | No objective response |
| Advanced solid tumours | I | 9 (53) | 1 SD, and 8 PD and MD | ND | 0 | No objective response |
| Advanced solid tumours | I | 28 (56) | 2 PR and 3 SD | ND | 7.1 | 5 of 15 patients had KRAS mutations |
| Advanced solid tumours | I | 21 | 6 SD | ND | 0 | No objective response. Phase II trial recommended |
| AML | II | 252 (62) | 11 CR and 8 PR | ND | 7.5 | MS for patients with CR: 369 days |
| AML | II | 145 (74) | 22 CR, 3 PR, 50 SD and 58 PD and MD | HDJ2 ↓ | 17.2 | Median duration of CR: 7.3 months |
| AML | III | 228 (76) | 18 CR, 20 PR, 105 SD, and 36 PD and MD | ND | 16.7 | MS: 107 days. 8% of patients had a CR with an MS of 666 days |
| 229‖ | 0 CR, 3 PR, 130 SD, and 46 PD and MD | 1.3 | MS: 109 days | |||
| Brain tumours | II | 81 (11) | 2 PR | ND | 2.5 | Very little activity |
| CML, myelofibrosis and multiple myeloma | 40 (57) | 7 CR and 7 PR | ND | 17.5 | Clinical activity in CML and myelofibrosis | |
| Metastatic pancreatic cancer | II | 20 (61) | 1 SD | FT ↓ by 50% and HDJ2 ↓ by 33% | 0 | No objective response. MS: 19.7 weeks |
| Multiple myeloma | II | 36 (62) | 0 CR, 0 PR, 23 SD, and 13 PD and MD | FT ↓ and HDJ2 ↓ | 0 | No objective response. No correlation between FT ↓ and disease stabilization |
| MDS | I | 20 (66) | 1 CR, 5 PR, and 1 PD and MD | FT ↓ and HDJ2 ↓ | 30 | No correlation between FT ↓ and response. No correlation between RAS mutation status and response |
| MDS | II | 27 (66) | 2 CR and 1 PR | ND | 11.1 | Modest antitumour activity |
| MDS | II | 82 (67) | 26 PR and 37 SD | ND | 31.7 | Median duration of CR: 11.5 months |
| MDS | I | 61 (68) | 3 CR and 13 PR | FT ↓ by 75% | 26.2 | Only one responder with a KRAS mutation. No correlation between FT ↓ and dose |
| Neuro-fibromatosis and neurofibromas | I | 40 (≤15) | FT ↓ by 43% and HDJ2 ↓ | 0 | No objective response | |
| Pancreatic cancer | II | 53 (65) | ND | 0 | No objective response. MS: 2.6 months | |
| Small-cell lung cancer | II | 20 (62) | 1 SD | ND | 0 | No objective response. MS: 6.8 months. Progression-free MS: 1.4 months |
| Advanced colon cancer | III | 235 (61) | 0 CR, 1 PR, 57 SD, and 155 PD and MD | ND | 0.4 | MS: 174 days. SD >3 months: 24% |
| 133¶ (62) | 0 CR, 0 PR, 17 SD, and 107 PD and MD | 0 | MS: 185 days. SD >3 months: 13% | |||
| Lonafarnib | ||||||
| Advanced solid tumours | I | 24 (57) | 0 CR, 0 PR and 2 SD | ND | 0 | No objective response |
| Advanced solid tumours | I | 12 (61) | 0 CR and 0 PR | Prelamin A ↓ | 0 | No objective response |
| Advanced solid tumours | I | 22 (54) | 1 CR and 1 PR | FT ↓ | 12.5# | Sponsor terminated study early owing to negative interim efficacy. FT ↓ not correlated with response |
| Advanced solid tumours | II | 15 (57) | 0 CR, 0 PR and 7 SD | ND | 0 | No objective response |
| CML | Pilot | 13 (62) | 0 CR and 2 PR | ND | 15.5 | |
| CNS tumours | I | 48 (12) | 0 CR, 1 PR and 9 SD | ND | 2.1 | |
| Metastatic colon cancer | II | 21 (64) | 0 CR, 0 PR and 3 SD | ND | 0 | No objective response |
| MDS or sAML | II | 16 (70) | 1 PR | ND | 6.7 | |
| NSCLC | II | 29 (58) | 3 PR, 11 SD, and 15 PD and MD | ND | 10.3 | MS: 39 months. Well-tolerated. Further clinical trials recommended |
| Refractory urothelial cancer (transitional cell carcinoma) | II | 10 (65) | 0 CR, 0 PR, 2 SD, and 8 PD and MD | Small HDJ2 ↓ | 0 | No objective response |
| Solid tumours | I | 20 (59) | 1 PR and 8 SD | Prelamin A ↓ | 5.0 | |
| BMS-214662 | ||||||
| Acute leukaemia | I | 30 (53) | 4 CR and 1 PR | Short-lived FT ↓ | 16.7 | |
| Advanced solid tumours | I | 44 (54) | 0 CR, 0 PR and 1 SD | Transient FT ↓ by 89.5% | 0 | No objective response. One patient with pancreatic cancer survived for >3.5 years |
| Advanced solid tumours | I | 68 (60) | 0 CR, 0 PR and 5 SD | Short-lived FT ↓ | 0 | No objective response |
| Advanced solid tumours | I | 19 (55) | 1 SD, and 18 PD and MD | ND | 0 | No objective response |
| Solid tumours | I | 25 (57) | 1 PR, 16 SR, and 8 PD and MD | Short-lived FT ↓ | 4.0 | Response was minor |
AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; CNS, central nervous system; CR, complete response; FNTB, farnesyltransferase β-subunit; FT, farnesyltransferase; FTIs, FT inhibitors; GGTI, geranylgeranyltransferase 1 inhibitor; HI, haematological improvement; MD, metastatic disease; MDS, myelodysplastic syndrome; MS, median survival; ND, not determined; NSCLC, non-small-cell lung cancer; OS, overall survival; PD, progressive disease; PR, partial response; sAML, secondary acute myeloid leukaemia; SD, stable disease.
See Supplementary information S4 (table) for a table with references. This table only considers FTIs because, to our knowledge, only one GGTI, GGTI-2418, is currently in clinical trials. Studies that did not evaluate tumour response are not included. Median ages are rounded to the closest integer. The number of evaluable patients is stated whenever possible. The response rate was calculated by dividing the sum of complete and partial responses by the number of evaluable patients.
PR includes haematological improvement.
Downward arrows indicate a reduction of enzyme activity (in the case of FT) or a reduction in farnesylation (in the case of HDJ2 or prelamin A).
This patient cohort received best supportive care.
In this study all patients received best supportive care, with 235 receiving tipifarnib and 133 receiving a placebo.
Number differs from the authors’ calculation as they included SD, resulting in a response rate of 37.5%.