An in-depth analysis of the LI-1 Trial assessing Ganetespib combined with low-dose cytarabine for older patients with Acute Myeloid Leukaemia
An aggressive blood cancer where the bone marrow produces abnormal white blood cells. Primarily affects older adults with a median age of 67 at diagnosis 1 .
A "molecular chaperone" that helps proteins fold correctly. Cancer cells are addicted to HSP90 as it stabilizes proteins driving their growth and survival 2 .
A second-generation HSP90 inhibitor that blocks HSP90 function. Pre-clinical studies showed it was more effective than cytarabine at killing AML blasts 2 6 .
The LI-1 trial employed an innovative and efficient model known as a "pick-a-winner" design 1 . This approach allows researchers to rapidly test several potential new treatments simultaneously against a common control group.
After 50 patients: need 2.5% improvement in remission rates
After ~170 deaths: need hazard ratio for survival < 0.85
The ultimate benchmark for success was ambitious: to double the two-year overall survival rate from 11% with LDAC alone to 22% with the combination, equivalent to a hazard ratio of 0.70 1 .
218 patients with median age of 75.5, unfit for intensive chemotherapy 1 .
Patients randomly assigned to treatment groups.
Experimental Group: Ganetespib + LDAC
Control Group: LDAC alone
Primary goal: improved overall survival with combination therapy.
Complete Marrow Response Rates
| Outcome Measure | Ganetespib + LDAC | LDAC Alone | Hazard Ratio/Odds Ratio | P-value |
|---|---|---|---|---|
| Complete Marrow Response | 18% | 16% | OR 0.85 (0.41-1.73) | p = 0.6 |
| 2-Year Overall Survival | 19% | 12% | HR 0.89 (0.65-1.21) | p = 0.5 |
| Relapse-Free Survival | No significant difference | No significant difference | HR 0.97 (0.42-2.25) | p = 0.9 |
| 30-Day Mortality | 10% | 14% | HR 0.65 (0.29-1.42) | p = 0.3 |
| Toxicity Measure | Ganetespib + LDAC | LDAC Alone | P-value |
|---|---|---|---|
| Significant Toxicity | Greater | Less | Not reported |
| Median Inpatient Days | 11 | 5 | p = 0.04 |
This trial is a classic example of the "valley of death" between promising lab results and real-world clinical efficacy.
Cancer cells in patients have redundant survival pathways, making them more resilient than lab cells.
Increased toxicity and hospitalization may have offset any potential anti-leukaemic benefits 1 .
Very elderly patients (median age 75.5) with significant health challenges may have been too compromised.
| Reagent / Material | Function in the Research Context |
|---|---|
| Primary AML Blasts | Fresh cancer cells collected from consenting AML patients. Used for in vitro testing to determine ganetespib's potency and mechanism 2 . |
| Cytarabine (Ara-C) | A standard chemotherapy drug used as the control treatment (LDAC) and in combination with ganetespib to test for synergistic effects 1 6 . |
| Ganetespib (STA-9090) | The investigational drug, a second-generation synthetic small molecule inhibitor of HSP90. Used to treat cell lines and primary blasts to analyze its effects 2 . |
| Cell Viability Assays | Laboratory tests to measure what percentage of cancer cells were killed by exposure to ganetespib and other drugs 2 . |
| Flow Cytometry | A technology used to analyze physical and chemical characteristics of cells, such as determining purity of AML blast samples or measuring apoptosis markers 2 . |
| Immunoblotting (e.g., Western Blot) | A technique to detect specific proteins. Used to confirm ganetespib was working by showing degradation of HSP90 client proteins like AKT 2 6 . |
The story of ganetespib in the LI-1 trial is not one of breakthrough success, but it is far from a failure. It is a story of rigorous, collaborative science doing its essential work.
The innovative "pick-a-winner" trial design performed exactly as intended: it efficiently identified that this particular drug, despite a strong scientific premise, was unlikely to achieve its ambitious goal and should not consume further vast resources.
The results underscore a critical lesson in drug development: promising pre-clinical data does not always translate to patient benefit. The increased toxicity and lack of survival gain with ganetespib highlight the unique challenges of treating frail, elderly AML patients.
However, the journey does not end here. The investigation into HSP90 as a target continues, and the knowledge generated by this trial—from the biological mechanisms to the clinical trial design—informs future research. Each "negative" trial helps scientists ask better questions, design smarter drugs, and ultimately narrow the path toward more effective and kinder treatments for acute myeloid leukaemia.
This article was constructed based on the scientific publication "A Randomised Assessment of Ganetespib Combined with Low Dose Ara-C Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial" and related primary sources.