Action to Cure Kidney Cancer

Sunitinib (Sutent) in Patients with Brain Metastases

Pfizer Researcher Dr. Subramanian Hariharan and his associates presented a poster on the efficacy of sunitinib (Sutent) as a first-line treatment in RCC patients with brain metastases, a historically under-represented and under-treated group. Sunitinib is an oral multi-targeted, tyrosine kinase inhibitor that blocks the VEGF and PDGF angiogenesis pathways, preventing tumors from growing blood vessels. It is an FDA-approved drug for RCC and has demonstrated high efficacy as a first-like treatment for RCC patients compared to interferon-alpha (IFN), with a median progression-free survival (PFS) of 11 months compared to IFN's 5 months) and an Objective Response Rate of 37% compared to 9% with IFN.

Unfortunately, for RCC patients with brain metastases (10-20% of all RCC patients), their poor prognosis (life expectancy 4-6 months) is generally prohibitive against entering any trials, therefore, there has been little evidence of efficacy of targeted therapies like sunitinib in this cohort. Dr. Hariharan writes that anecdotal cases of sunitinib's anti-tumor activity against brain metastases have been reported, and that there is a strong case to be made for the treatment of RCC patients with brain metastases with sunitinib, in spite of their poor prognosis. The results of this trial support that claim.

The following summary is from a report of an open-label, expanded-access trial using sunitinib in patients for whom brain metastasis did not preclude them from entering the trial as it usually does in a typical clinical trial setting.

Methods

4185 patients were eligible for study at the time of data analysis, and of those patients 313 (7%) had baseline brain metastases, and of those patients 75% had had prior cytokine (IFN or IL-2) treatment. Patients were administered sunitinib with a starting dose of 50 mg/day in the standard repeated 6-week cycles (4 weeks on, 2 weeks off). Approximately nine out of ten patients had clear cell pathology.

Adverse Events

The adverse events suffered by patients on sunitinib with brain metastases were generally the same in type and severity as those experienced by patients with no brain metastases. The most common were diarrhea, fatigue, nausea, mucosal inflammation and vomiting. Significant grade 3/4 events were fatigue (7%) and asthenia (6%), which is a lack of energy and strength. Only one RCC patient with brain metastases experienced treatment-related cerebral hemorrhage, of grade 2 severity. Four patients experienced treatment-related convulsions (two at grade 2 severity, two at grade 4), and one patient experienced a treatment-related seizure. None of these events were fatal, and the researchers speculate that they may be linked not to the patients' brain conditions but to reversible posterior leukoencephalopathy, a rare degenerative brain condition observed in patients in prior sunitinib trials and other anti-cancer treatments. That these events occurred during the sunitinib trial is a by-product of anti-cancer treatment and not necessarily linked to the presence of brain metastases.

Response

The response rates for patients with brain metastases were lower than those for patients without. However, they were still encouragingly strong, with 65% of patients with brain metastases experiencing some degree of clinical benefit from sunitinib. The table below lists the observed responses, using RECIST criteria, in all evaluated patients:

Dr. Hariharan stratified the responses by patients receiving prior cytokine therapy. This analysis follows.

The above tables show mixed results. The author didn't comment on the overall survival statistics that were stratified by prior cytokine treatment, and we don't know if they are statistically significant. No other prior treatment was included in this study so we have nothing to compare these figures with. The investigators could have done a better job here.

Discussion

First, note that Dr. Hariharan is an employee of Pfizer, the manufacturer of sunitinib, so, we have to take that fact into account when we evaluate his conclusions.

The author states that "the safety profile for sunitinib in patients with mRCC (metastatic RCC) and brain metastases mirrored that for the overall patient population". That's true and there were no significant cases of brain hemorrhages or convulsions. This study answers the question of whether suntinib can be safely taken by patients with brain metastases.

The second issue is survival since, ultimately, the most important statistic related to a given drug's effectiveness is the overall survival rate. In this trial, the median overall survival in patients with brain metastases was 9.5 months. Dr. Hariharan compared this rate to the survival rate in a study[1] done by Stéphane Culine at the Institut Gustave Roussy, Villejuif, France. In a retrospective, single institution study, Culine reported a median overall survival (OS) of 7 months. However, the purpose of Culine's study was to identify risk factors that affect survival. Based on the risk factors he studied, Culine separated patients into two categories, intermediate risk and poor risk. The intermediate risk patients had an 8 month median OS, while the poor risk patients had a 3-month median OS. Data describing Culine's risk factors, such as sedimentation rate and location of the metastases, were obviously not collected in the sunitinib open-access trial, so no comparisons can be made. However, on the face of it, the 9.5 months looks good compared to historical survival data, which Curine quotes as 4-6 months overall.

Dr. Hariharan also compares sunitinib to sorafenib's (Nexavar) results with patients with brain metastases, specifically, with the open-access trial run for sorafenib and reported on by CA Henderson at the ASCO 2007 Conference in an abstract (15506). They didn't report survival data, only tumor response, which was low for sorafenib at 4%, which it usually is. However, there was 70% stable disease for a total of 74% clinical benefit compared to 65% for sunitinib. Dr. Hariharan said that the "objective response rate (for sunitnib) was considerably higher than that reported recently for mRCC patients with brain metastases receiving the targeted therapy sorafenib in an expanded access study". He is saying that the 12% partial response rate for sunitinib is significantly higher than the 4% for sorafenib. On the other hand, sorafenib showed 70% stable disease versus 53% for sunitinib. As one can see, this piece of Dr. Hariharan's analysis may have more to do with the competition between Pfizer and Bayer/Onyx than scientific objectivity.

In any case, initial tumor progression is no substitute for survival data when it comes to analyzing a drug's efficacy. One final note: in the sorafenib open-access trial, 6.2% of the patients had grade 3 seizures.

Dr.Hariharan mentions that the tumor response in the sunitinib open-access trial was lower than that reported in previous clinical trials using sunitinib in rcc. He also didn't have access to OS data for sunitinib, which was just released at the ASCO 2008 Conference. The median OS for the sunitnib open-access trial for all patients was 19.8 months (4185 patients). The median OS, as reported by Dr. Robert Figlin at ASCO from a Phase III randomized trial, was 26.4 months for sunitnib and 21.8 months for interferon-alpha. Dr. Hariharan didn't comment on why normal trial data for sunitinib are superior to the open-access trial results. One can speculate that the patient selection process for the early trials was more rigorous than the patient enrolment procedures for the open-access trial. In fact, if one analyzes the data that Dr. Hariharan presents for risk categories breakdown, it is likely that the open-access trial contained twice as many patients in the poor prognosis category than did the seminal sunitinib trials that he uses as a comparison. An even greater proportion of the patients with brain metastases fell into the poor prognosis category. One could also speculate that this is reason enough to account for the lower survival time for patients with brain metastases than those patients without and for lower survival times for patients on open-access trials than patients on highly structured clinical trials that have the objective of proving the efficacy of the drug for eventual FDA approval.

The open-access trial would more likely mirror the "real world" mRCC patient population that seeks sunitinib treatment. We would like to see clinical trials established that have as their objective the study of the effect of targeted therapies on patients with brain metastases.

[1] "Prognostic factors for survival in patients with brain metastases from renal cell carcinoma", Culine, Bekradda, etal, Cancer 1998, vol.83, n^o12, pp.2548-2553