Motexafin Gadolinium (MGd) Combined With Prompt Whole Brain Radiation Therapy Prolongs Time to Neurologic Progression in Non-Small Cell Lung Cancer (NSCLC) Patients With Brain Metastases: Results of a Randomized Phase 3 Trial

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2006

Presenter: M.P. Mehta
Presenter's Affiliation: University of Wisconsin, Madison, WI
Type of Session: Scientific

Background

Motexafin gadolinium (MGd) is a radiosensitizer that is MRI-detectable and selectively localizes in tumors.
MGd is an inhibitor of thioredoxin reductase, an enzyme whose overexpression is correlated with poor prognosis in NSCLC.
A subgroup analysis of a randomized trial showed that there was a time-to-neurologic-progression (TNP) benefit from the addition of MGd to whole brain radiation (WBI) for metastatic NSCLC only (p=0.048).
That subgroup analysis prompted this randomized phase III trial of MGd in patients with intracranial NSCLC metastasis
The results of this trial were initially presented at ASCO 2006 in Atlanta, GA.

Materials and Methods

Patients had to have brain metastases from non-small cell lung cancer and a KPS >70.
Patients were excluded for history of: prior brain radiation, surgical resection of a single brain metastasis, liver metastasis, or >2 sites of extracranial disease.
Patients were assessed every month for 8 months, and then every 2 months.
Patients had a standardized neurologic examination and neurocognitive testing.
Phase III study design:
International (34% USA, 29% Canada, Europe, Australia, etc.)
550 patients with NSCLC diagnosed with brain metastasis randomized to:
- WBI (30 Gy in 10 fractions) vs. WBI + MGd, 5 mg/kg daily for 10 days
- Criteria: KPS >=70. No liver metastasis or greater than 2 extracranial sites of metastasis
Endpoints:
- Primary: TNP as assessed centrally
- Secondary: TNP as assessed by physician, time-to-neurocognitive-progression, survival

Results

MGd was well-tolerated, with >92% of intended doses given
Most common adverse events were skin and urine discoloration
Analysis of TNP by intent-to-treat, as measured from time from randomization, showed a benefit from MGd that did not reach statistical significance
- 15.4 months (95% CI 10.7-24.2) for WBI + MGd vs. 10 months (95% CI 7.4-13.5) for WBI (p=0.12, HR 0.78)
Analysis of TNP, as measured from time from diagnosis of brain metastasis, showed a significant benefit from MGd (p=0.05)
It turned out that more patients in North America were promptly randomized after diagnosis of brain metastasis for planned WBI. However, in the other geographic sites, there was a delay attributed to the practice of treating brain metastases with chemotherapy before WBI (3% in North America vs. 32% in the rest of the world)
In the subset of North American patients (n=348), TNP was significantly increased by MGd: 8.8 months vs. 24.2 months, HR 0.53, p=0.004
In the subset of patients where WBI was initiated within 3 wks of diagnosis (n=378), TNP was significantly prolonged by MGd (HR 0.59, p=0.006).
In patients with a delay, the benefit from MGd disappeared

Author's Conclusions

MGd significantly prolonged TNP in NSCLC patients with brain metastasis when combined with prompt WBI.
Beneift depended on prompt initiation of whole brain radiation therapy.
MGd was well tolerated.

Clinical/Scientific Implications

Once again, the study of MGd combined with WBI is plagued by a non-significant primary endpoint result, but a very intriguing subset analysis. There was a clear benefit of MGd in the subset of North American and/or promptly treated patients The unanticipated, routine use of chemotherapy that delayed WBI initiation in non-North American sites hampered this study. This could have been prevented by mandating an interval between diagnosis and initiation of treatment, but it is difficult to predict all possible scenarios during study design. This agent is being tested as a radiosensitizer in other CNS malignancies, such as glioblastoma multiforme and pediatric tumors. MGd needs further study before it should be regularly adopted. When it requires subset analyses of subset analyses to show significance, one needs to be somewhat suspect regarding a new therapy's true benefit.