Action to Cure Kidney Cancer

The American Society of Clinical Oncology (ASCO) conference was held in Atlanta this year from June 2-6. There were 29,000 attendees from throughout the world, and, for the first time, kidney cancer topics were presented at plenary sessions of the conference. Dr. Gary Hudes, from the Fox Chase Cancer Center, presented results for the targeted therapy, temsirolimus (CCI-779), which will likely be approved by the FDA for treatment of advanced metastatic patients. Dr. Robert Motzer talked about the use of sunitinib (Sutent) as a first line (initial) therapy for metastatic kidney cancer.

Unfortunately, there were no major breakthroughs of new drugs similar to the announcements last year of sunitinib and sorafenib (Nexavar), which both won FDA approval earlier this year. The drug companies seem to be in a "me too" mode, having witnessed the success of sunitinib and sorafenib. These drugs are tyrosine kinase inhibitors, which inhibit blood vessel and tumor growth factors, and the drugs in the pipeline are targeting similar mechanisms. However, the targeting of the growth factor EGFR, (by the drug Tarceva) was, by common consensus after several failed trials, felt to be not useful in the treatment of kidney cancer patients. There was also no progress announced in the immunotherapeutic approach to the treatment of metastatic kidney cancer.

Dr. Michael Atkins of Beth Israel Deaconess, in his role as a discussant to these presentations, mentioned a number of promising future trials which will combine targeted therapies, albeit at lower doses since adding one agent to another often increases the toxicity. It remains to be seen if the efficacy of treatment is lessened due to decreased dosages of each agent. Hodgkin's Disease, which has an 80% survival rate, has had great success with combination therapy, but, that hasn't yet been true for other cancer types, including RCC.

At one point, Dr. Atkins stated that "This is a banner day for kidney cancer", in reference to the presentations on sunitinib and temsirolimus by Doctors Motzer and Hudes. This quote was picked up by several newspapers in their headlines. However, if we look at the data more closely, we are a long way from a banner day. The targeted therapies do increase time to progression and overall survival. However, after a time, usually less than one year, they stop working, and have not as yet shown a durable response. As kidney cancer survivors and caregivers, we are seeking therapies that provide durable long-term response without severe toxicity.

What follows are reports on specific presentations delivered at ASCO this year.

Sunitinib versus Interferon-alpha

Phase III randomized trial of sunitinib (Sutent) versus interferon-alpha (IFN-alpha) to determine if sunitinib is effective as a first-line, systemic therapy for patients with metastatic renal cell carcinoma. This is a multi-center trial presented by Robert Motzer of Memorial Sloan-Kettering in New York.

Sunitinib is a multi-targeted, tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR), both factors having shown activation in kidney cancer. Last year, Dr. Motzer presented trial results showing kidney tumors having a 40% response rate to this drug, and, as a result, the FDA, in January 2006, approved the drug as a second line therapy (after previous use of cytokine drugs such as Interleukin-2 or interferon-alpha), for treatment of metastatic kidney cancer. This year's trial was designed to examine the benefits and risks of sunitinib vs. an established first line therapy, i.e., interferon-alpha.

Patients were accrued during the period August 2004 - October 2005. The primary endpoint was established as progression free survival with secondary endpoints of response rate, overall survival, and safety.

750 patients were accrued for this trial with 375 split among each arm. Among the requirements for entry onto the trial were clear cell pathology, no prior treatment, and metastatic disease. The breakdown of metastatic sites were as follows:

The patient population consisted of mostly low and intermediate risk patients based on the MSKCC risk factor categories.

As of November 2005, 66% of the patients remained on treatment on the sunitinib arm, while 34% remained on treatment on the interferon-alpha arm. 25% stopped sunitinib due to progressive disease and 8% due to adverse effects. For the interferon-alpha are, 45% stopped due to progressive disease and 13% due to adverse effects.

Grade 3/4 laboratory abnormalities reported for sunitinib patients were neutropenia¹ in 12% of the patients and lymphopenia², also in 12% of patients. Lymphopemia showed up in 22% of the interferon-alpha patients. There were no grades 3/4, treatment-related adverse effects among the sunitinib arm of the study amounting to more than 10% of the patients. 8% were reported as suffering from hypertension, 7% fatigue, and 5% each for diarrhea and hand-foot syndrome. 11% of the interferon-alpha patients suffered from grade 3/4 level fatigue.

The results of the trial, as verified by independent central review, are:

(* 88 patients not yet assessed by central review)

The median progression free survival was 11 months for sunitinib and 5 months for interferon-alpha. Interestingly, Dr. Motzer stratified progression free survival by risk factor, giving the following results.

Median Progression Free Survival by MSKCC Risk Status

The median overall survival has not yet been reached for either sunitinib or interferon-alpha.

Comment: This trial demonstrates that sunitinib is indeed effective as a first line agent in the treatment of metastatic kidney cancer and is certainly more effective than interferon-alpha. Sunitinib's side effects seem to be well tolerated. However, as with the other targeted therapies, there is something in the cancer that eventually overcomes the effect of the therapy, as we see that the progression free survival is less than one year. Therefore, this is not the drug that will turn kidney cancer into a chronic disease. Note also that this drug, unlike the cytokine drugs, must be taken continuously to be effective, as once it is discontinued the cancer will return.

Robert Motzer said that "Sunitinib is the new reference standard for first line treatment of metastatic renal cell carcinoma". Bernard Escudier made a presentation at ASCO of sorafenib (Nexavar) versus interferon-alpha in a first line setting, but he didn't have progression free survival data available. So, Dr. Motzer is correct, and Pfizer will undoubtedly apply to the FDA for re-labeling of the drug to include it as first line treatment in metastatic RCC.

¹Abnormal low count of neutrophils, a type of white blood cells, which are a defense against acute bacterial and certain fungal infections.

²Abnormal low count of lymphocytes in the blood, notably T-cells.

Temsirolimus (T) vs. Interferon-alpha (Inf-A) vs. Both T & Inf-A

Phase III randomized, 3-arm study of temsirolimus (Torisel / CCI-779) vs. interferon-alpha vs. the combination of the two in the treatment of first-line, poor prognosis patients with advanced renal cell carcinoma. This is a multi-center trial presented by Gary Hudes of Fox Chase Cancer Center in Philadelphia.

Temsirolimus is an inhibitor of mTOR, which is involved in kidney cancer cell proliferation and angiogenesis.

A total of 626 advanced metastatic patients with poor risk features were entered into this trial with 207 taking interferon-alpha, 209 taking temsirolimus alone, and another 210 taking a combination of temsirolimus and interferon-alpha, with the latter taking lower doses of both T & Inf-A than in the T alone arm or in the Inf-A alone arm. 67% of the patients had a prior nephrectomy, and 80% had clear cell pathology. Requirements for entry in the trial included, among other things, stage IV or recurrent disease and at least three of six poor-risk factors of the Memorial Sloan-Kettering Cancer Center risk factor categories. The primary endpoint of the trial was overall survival, with secondary endpoints being progression free survival and objective response. The accrual period was July 2003 - April 2005.

One of the significant grade 3/4 side effects was asthenia¹, reported in 12% of the temsirolimus arm, 30% of the temsirolimus/interferon-alpha combination, and 27% of the interferon-alpha alone arm. Another significant side effect was dyspnea², reported in 9% of the temsirolimus patients, 11% of the temsirolimus/interferon-alpha patients, and 8% of the interferon-alpha patients. The significant grade 3/4 laboratory side effects reported were anemia in 21% of the temsirolimus patients, 39% of the temsirolimus/interferon-alpha patients, and 24% of the interferon-alpha patients; hyperglycemia in 10% of the temsirolimus patients; and neutropenia³ in 14% of the temsirolimus/interferon-alpha combination group.

As of the data cutoff for evaluation date, March 15, 2006, most patients had discontinued treatment, the majority due to disease progression. Specifically, the temsirolimus, temsirolimus/interferon-alpha, and interferon-alpha arms saw discontinuance rates of 93%, 92%, and 94%, respectively. The following chart lists the reasons for those patients who discontinued treatment.

Reasons for Treatment Discontinuation

The overall survival results for the three-arm trial are as follows.

Overall Survival by Treatment Arm

A secondary endpoint was progression free survival. The progression free survival for the temsirolimus and temsirolimus/interferon-alpha arms was identical at 3.7 months, while that for the interferon-alpha was 1.9 months. Another secondary endpoint was objective response, or tumor shrinkage, which was: temsirolimus 9%, temsirolimus/interferon-alpha 11%, and interferon-alpha 7%. Finally, Dr. Hudes posited the variable 'clinical benefit', which he defined as tumor shrinkage plus stable disease for more than 16 weeks. The figures for clinical benefit are: temsirolimus 46%, temsirolimus/interferon-alpha 41%, and interferon-alpha 29%.

Dr. Hudes' concluded that there was a significant increase in both survival, by 3.6 months, and progression free survival, by 1.8 months, of the temsirolimus arm over the interferon-alpha arm. However, there was no statistically significant difference in median survival for the patients on the temsirolimus/interferon-alpha arm versus the interferon-alpha arm alone. Given the survival benefit of temsirolimus over interferon-alpha and the fewer grade 3/4 toxic side effects, Dr. Hudes concluded that temsirolimus "can be considered standard first-line therapy for patients with metastatic RCC and poor-risk features" and that "mTOR is an important therapeutic target in renal cell carcinoma".

Michael Atkins from Beth Israel Deaconess Medical Center in Boston commented on Gary Hudes' presentation as well as Robert Motzer's sunitinib presentation. He remarked that the dosage of temsirolimus had to be reduced due to increased side effects on the combined temsirolimus/interferon-alpha arm of the trial, which might have accounted for the reduced efficacy of the combination. If true, this may not bode well for a number of future trials that are combining targeted drugs with cytokines. He also stated that the side effect profile of temsirolimus and sunitinib are different, "suggesting they may have at least partially non-overlapping mechanisms of action". Since they each have different targets, it might be interesting to test whether they can be used in combination.

Finally, it would be useful to see what effect temsirolimus would have on patients who do not have such a poor prognosis.

¹ Asthenia is weakness or lack of energy and strength.

² Dyspnea is shortness of breath.

³ Neutropenia is an abnormally low count of neutrophils, a type of white blood cells, which are a defense against acute bacterial and certain fungal infections.

Dr. Michael Atkin's Comments at the Plenary Session

Dr. Michael Atkins of Beth Israel Deaconess Medical Center in Boston was a discussant at the Plenary Session for the Motzer and Hudes presentations. In addition to his comments regarding the Motzer and Hudes trials, Dr. Atkins made some useful general observations. Dr. Atkins is the only recipient of a kidney cancer SPORE grant from the National Cancer Institute. SPORE grants are 5-year, $2.5 million per year research grants, awarded by the NCI to move laboratory discoveries to clinical settings. Dr. Atkins' observations are as follows. The first few comments refer to sunitinib and temsirolimus; however, they can be generalized to include all the current targeted therapies.

• Activity is robust, but there are few, if any, complete responses.

  Note that the only medical therapies that provide complete responses to metastatic kidney cancer have been Interleukin-2, which has an 8-10% complete response rate, INF, or the combination of Interleukin and interferon, and, allogeneic stem cell transplants, which have also shown a small percentage of complete responses. None of the targeted therapies have shown a durable, complete response.

• Continued treatment appears required to maintain efficacy.

  In other words, if the use of the targeted therapy is stopped, the cancer starts spreading again. The immunotherapy drugs Interleukin-2 and interferon-alpha (INF) are administered for a specified duration and then stopped, say a 12-week cycle, which may or may not be repeated. They either work or they don't, but they are not given continuously. The targeted therapies, which may also be given in cycles say 4 weeks on and 2 weeks off, are given in continuous cycles until they stop working.

• Disease resistance usually develops within 6-12 months.

  This is the major point. These drugs not only do not have complete responses, they only prevent the disease from advancing for less than one year. There is some anecdotal evidence that once a single drug stops working, a patient can switch to another drug and still receive benefit. But we are a long way from turning kidney cancer into a chronic disease.

Dr. Atkins then proposed an "algorithm" to select the proper therapy for metastatic renal cell cancer patients. For first-line therapy for good and intermediate risk patients, Dr. Atkins recommends the use of High Dose Interleukin-2 for "select" patients, that is, those patients who display a certain marker that may indicate that IL-2 will be successful. There is a trial planned to test for this marker - see Glossary below for an explanation of the marker. For those patients not in the "select" group, Dr. Atkins recommends the use of sunitinib. Sunitinib (Sutent) will be approved as a first-line drug (treatment naÔve) by the FDA based on the results of the phase III trial presented by Dr. Motzer.

Continuing, as first-line therapy, for poor risk patients, Dr. Atkins recommends, when it is FDA approved, temsirolimus (Torisel / CCI-779), based on the trial results announced at this year's ASCO where temsirolimus added 3‡ months to overall survival vis-ý-vis interferon-alpha and produced fewer side effects than interferon-alpha.

For second-line therapy, for those patients who were prescribed cytokine therapy (IL-2 or INF) and failed, Dr. Atkins recommends sorafenib (Nexavar). Note that Dr. Atkins did not mention sorafenib's use as a first-line therapy, possibly because Bayer has not announced test results for the drug in a first-line clinical trial setting yet.

Finally, Dr. Atkins has no recommendation for VEGFR or TOR inhibitor failures, sunitinib/sorafenib and temsirolimus, respectively (sorafenib is also a VEGFR inhibitor). That's because nothing exists as a backup to these drugs. The fact that Dr. Atkins has no recommendation doesn't mean that he wouldn't personally prescribe a treatment for one of his patients who failed a VEGFR inhibitor. It just means, at that point, there is no proven standard treatment, so whatever one gives it is just an educated guess as to its potential efficacy.

Finally, Pfizer, with sunitinib and Bayer, with sorafenib, have a head start on the other drug companies with respect to targeted therapies for kidney cancer treatment, but by next year's ASCO, there will be several more targeted therapies ready for prime time as the other companies are scrambling to catch up. In addition, investigators will be combining therapies to test their efficacy - see the following Atkins' trials to watch for 2007 and beyond.

Glossary:
IFN = Interferon-alpha
Sorafenib = Nexavar
Bevacizumab = Avastin
HD IL-2 = high dose Interleukin-2
BeST = BeST stands for bevacizumab (Avastin), erlotinib (Tarceva), sorafenib (Nexavar) and temsirolimus (Torisel / CCI-779), the 4 drugs in this ECOG trial where every patient gets 2 of these drugs at a time, and then "crosses over" to another 2 drug combination at some point. However, given the poor results of erlotinib reported at ASCO 2006, it will probably be dropped from the BeST Trial.
CWG = Cytokine Working Group
TKI = tyrosine kinase inhibitors, e.g. suntinib and sorafenib
ECOG = Eastern Cooperative Oncology Group
EORTC = European Organisation for Research and Treatment of Cancer

HD Il-2 Select Trial will prospectively test two markers as predictive values for the success of HD Il-2 treatment of metastatic renal cell cancer. The markers are Carbonic Anhydrase IX (CA9) and the tumor histology, specifically, the amount of alveolar and granular features present in the tumor. This trial will probably only include clear cell patients since IL-2 has usually not to have elicited responses in patients exhibiting other types of renal cell histologies.

Sorafenib and Interferon-alpha (Two Studies)

The following reviews the results of two separate trials, both testing the combination of sorafenib and interferon-alpha in metastatic renal cell patients. The first trial results were presented orally by Dr. Christopher Ryan, and the second study was offered by Dr. Jared Gollob as a poster presentation.

Sorafenib and Interferon-alpha (Ryan)

Sorafenib (Nexavar) plus interferon-alpha (IFN) as first-line therapy for advanced renal cell carcinoma. Reporting on the trial is Dr. Christopher Ryan from the Oregon Health & Science University in Portland.

Sorafenib is a blocker of VEGFR, the vascular endothelial growth factor receptor and platelet derived growth factor receptor (PDGFR). Blocking VEGFR and PDGFR is thought to have an inhibitory effect on angiogenesis (growth of new blood vessels to the tumor) and tumor cell proliferation. Interferon-alpha, aside from having modest immunotherapeutic activity, also suppresses VEGF production (the growth factor itself). Therefore, it was hypothesized that Interferon-alpha might enhance the antiangiogenic effect of sorafenib.

This is a multi-center, phase II study. The accrual period was September 2004 - May 2005. The requirements for entry into the study were metastatic, clear cell pathology and no prior treatment. The sorafenib dosage was initially set at the standard 800 mg per day. The primary endpoint of the study was response rate, which in previous trials was shown to be low (<10%).

Of the 61 patients who were evaluated, only 26% remain on the trial. 46% discontinued treatment due to disease progression and 21% due to toxic side effects. With respect to grade 3/4 events, fatigue was reported by 30% of patients, diarrhea by 11% and leukopenia¹ by 11%. 64% of the patients required dose reductions of INF, while 26% required dose reductions of sorafenib. Interestingly, 30% of patients in the phase III study of the single agent sorafenib reported hand-foot syndrome problems, while in this study, only 13% of patients had that problem. The INF may have counteracted the effect of the sorafenib, in this case.

There was one complete responder and 10 partial responders giving a total of 18% response rate (note that another 12% were unconfirmed partial responders). The response duration varied from 8 to 62+ weeks. 38% showed stable disease. The median progression free survival (PFS) was 6.5 months. Dr. Ryan compared the PFS obtained from this trial with that of sorafenib and INF each used as single agents in previous trials. The comparison is as follows.

Median Progression-Free Survival

The median overall survival has not yet been reached. The 6-month overall survival rate is 89%.

Here we see a significant increase in response rate for the combination of sorafenib and INF over the single agent sorafenib. The median progression-free survival (PFS) only increased by one month, but there was a wide range in the 95% confidence interval, i.e. 3.7 months to 12.1 months. It will be interesting to compare the median overall survival of the combination with that of the single agent sorafenib.

¹Leukopenia is a decrease in the white blood cells.

Sorafenib and Interferon-alpha (Gollob)

Phase II trial of sorafenib (Nexavar) plus interferon-alpha 2b (IFN-α2b) as first or second-line therapy in patients with metastatic renal cell cancer (RCC). The trial results were presented by Dr. Jared Gollob from Duke University. This was a poster presentation.

Interferon-alpha is an immune system booster, but it also suppresses VEGF production (the growth factor itself). Therefore, it was hypothesized that Interferon-alpha might enhance the antiangiogenic effect of sorafenib.

This was a single-center trial. 39 patients, about 80% of whom had clear cell pathology, were accrued to this trial during the period November 2004 - May 2006. The dosage for sorafenib was the standard 800 mg per day, although there were dose reductions for over half the patients due mostly to rash, neutropenia , fatigue, or anorexia. 29 of the patients were evaluated. The overall response rate (RR) was 36% with a complete response rate (CR) of 6%. The median response duration was 6 months. The median progression free survival figure is 10 months.

One of the patients, who has collecting duct type of kidney cancer, probably the most resistant to therapy, had stable disease for 14 months before being taken off therapy for side effect problems.

Ryan and Gollob

These are the results of the two trials side-by-side.

There is a significant difference in the trial results. Dr. Ryan's trial was a multi-center trial sponsored by the Southwest Oncology Group (SWOG), while Dr. Gollob's trial was a single center trial at Duke University. Data from multi-institution trials are generally more reliable than data from a single institution, however, it is clear, that we will have to await the results of a future phase III trial to determine the efficacy of this combination.

² Neutropenia is an abnormally low count of neutrophils, a type of white blood cells, which are a defense against acute bacterial and certain fungal infections.

Sorafenib plus Bevacizumab

A phase I/II trial of sorafenib (Nexavar) with bevacizumab (Avastin) in metastatic renal cell cancer (mRCC) patients. The trial results were presented by Dr. Jeffrey Sosman, Vanderbilt University Medical Center, Nashville, TN. This was a poster presentation.

A multi-center trial is being conducted to determine the proper dosage level and the efficacy of the combination therapy of sorafenib and bevacizumab in metastatic renal cell cancer. The theoretical rationale for this combination is a follows. Sorafenib is a blocker of VEGFR, the vascular endothelial growth factor receptor, or it is an anti-angiogenic agent, that is, it prevents blood vessel growth that would feed nutrients to the tumor. However, sorafenib contains a poison pill in that it is also a promoter of VEGF itself, which promotes tumor growth and proliferation. So is this the reason why sorafenib does not have durable responses? Nobody knows! Bevacizumab, on the other hand, is a blocker of VEGF. So the hypothesis is that the combination of the two agents will both inhibit blood vessel growth and will not promote tumor growth. 24 patients have been enrolled so far in the phase I part of this test with the hope of enrolling 45 patients in the phase II trial. Given the toxicities of these individual drugs, dose limiting toxicities were expected. Sorafenib was started at half dose, that is, 400 mg per day. Even so, hand-foot syndrome, anorexia, fatigue, and stomatitis appear to limit the tolerable dosage for the phase II portion of the trial.

Of the 24 patients enrolled, 9 have shown partial response (38% response rate), with another 12 showing stable disease. Although preliminary, these are much better results that for sorafenib alone, which shows very low partial response rates. The toxicities have limited the dosage, and the full 800 mg dosage of sorafenib, for example, was found to be intolerable in combination with bevacizumab. The maximum dosage may, in fact, be limited to 200 mg. Will this limit the long term response rate? This is not yet known. But, with the favorable results so far in terms of response rate, it will be interesting to see the results of the phase II portion of the trial when the proper dosage is established, the number of patients is increased, and time to progression can be measured.

Bevacizumab plus Erlotinib

Bevacizumab (Avastin) with or without erlotinib (Tarceva) in metastatic renal cell carcinoma (RCC) in a multicenter, randomized, double-blind Phase 2 trial. The trial results were reported by Dr. Ronald Bukowski of the Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Ronald Bukowski of the Cleveland Clinic, presented the results of a multi-center, phase II trial testing the efficacy, in metastatic kidney cancer patients, of adding erlotinib to bevacizumab as a first line treatment (previously untreated patients). The patients had to have over 50% clear cell histology and be in good overall health but with measurable disease. The primary endpoints or objectives of the trial were the measurements of response rate (RR) and progression free survival (PFS). A previous second line trial (patients having had a prior therapy) showed bevacizumab at the current trial's dosage (10 mg/kg) exhibiting a PFS of 4.8 months versus 2.5 months for a placebo. Bevacizumab is a VEGF (vascular endothelial growth factor) inhibitor while erlotinib is an EGFR (epidermal growth factor receptor) inhibitor. VEGF promotes tumor growth and proliferation, and has been a somewhat successful target in kidney cancer therapy. EGFR also promotes tumor cell growth and the hypothesis for this study is that by targeting this receptor in kidney cancer, tumor growth will be suppressed.

104 patients were enrolled in the trial from March-October 2004, as follows: 53 patients bevacizumab and a placebo versus 51 bevacizumab + erlotinib.

Grade 3/4 toxicities were as follows: hypertension (bevacizumab 25%, + erlotinib 31%); bleeding (bevacizumab 4%, + erlotinib 6%); rash (bevacizumab 0%, +erlotinib 16%); diarrhea (bevacizumab 0%, + erlotinib 8%).

Trial results: median PFS (bevacizumab 8.5 months, + erlotinib 9.9 months; RR (complete and partial) (bevacizumab 13%, +erlotinib 14%), stable disease (SD) (bevacizumab 36%, +erlotinib 34%), disease progression (PD) (bevacizumab 17%, + erlotinib 16%); not determined 2%. Median survival (bevacizumab not yet reached, + erlotinib 20 months).

Dr. Bukowski concluded that although bevacizumab has an effect as a mono-therapy, this trial demonstrated no clinical benefit of adding erlotinib in combination. In response to a question from the audience about the failure of EGFR inhibitors such as erlotinib (Tarceva) to have an effect on metastatic kidney cancer, Dr. Bukowski said that there are no data to support further studies of EGFR inhibitors in RCC.

This is the trial which prompted the October 2005 press release from Genentech, the manufacturer of bevacizumab (Avastin) and erlotinib (Tarceva), when it said that "At this time we do not believe further studies of this particular combination in kidney cancer are warranted". So this trial is old news and the results are expected - a modest benefit of the use of bevacizumab in RCC, that is PFS of 8.5 months. More interestingly, it seems that everyone now agrees that, contrary to the original hypothesis, EGFR inhibitors don't work for kidney cancer. Researchers will have to look for other receptors and find new drugs to attack them if we are to see significant improvement in survival for patients with metastatic kidney cancer. With 59% of the patients in this trial on the bevacizumab/placebo arm having some grade 3/4 toxicity, it may not be a pleasant ride when it's combined with other targeted and immunotherapies.

RAD001

A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). The trial results were presented by Dr. Robert Amato, Methodist Hospital Research Institute, Houston, TX. This was a poster presentation.

Robert Amato of the Methodist Hospital in Houston presented the results of a phase II trial of RAD001, an inhibitor of mTOR, which is another cell cycle pathway to attack besides the ones that sunitinib and sorafenib inhibit. There is speculation that the drug also blocks VEGF (is anti-angiogenic). The primary endpoint that Dr Amato wanted to evaluate in his trial was time to progression with a secondary endpoint of overall survival. Of the 28 patients on the trial, 26 had clear cell histology. The metastatic sites were distributed among lung, bone and liver but predominantly lung (65%). A number of toxic side effects were reported, but aside from laboratory abnormalities, such as hyperglycemia and anemia, the extent of the physical toxicities such as skin rash, diarrhea, etc. were not reported.

The results were, for the 25 patients that were evaluated: 9 partial responders (PR) (1 for 6-9 months, 4 for 9-12 months, and 4 for over 12 months). 11 patients had stable disease (SD) and 5 had progressive disease. The time to progression is 6+ months. Median overall survival has not been reached.

At first glance, the results for RAD001 appear to be promising with 36% PR and another 44% SD. However, it is still early in the trial, with a median duration of only 8 months of therapy. Furthermore, the results have not been verified by an independent radiologist, which often reduces the response rate from the one reported by the principal investigator.

Inhaled Interleukin-2

Observational study in patients with pulmonary metastases of renal cell carcinoma receiving inhaled recombinant interleukin-2. Trial results reported by Dr. Antonia Garcia from Hospital Reina Sofia, Cordoba, Spain. This was a poster presentation.

Interleukin-2 is usually administered intravenously or subcutaneously, however, in an observational study conducted at 54 facilities in Spain and Portugal between 2000 and 2005, Dr. Garcia reported on of the use of inhaled Interleukin-2 in kidney cancer patients with pulmonary metastases. Specifically, 107 patients were treated with inhaled IL-2 with progression free survival (PFS) and overall survival (OS) as the primary endpoints. 50% of the patients had metastases to other organs in addition to the lungs. The overall treatment period was 12 weeks (3 weeks on, 1 week off per cycle for three cycles of treatment).

The results were a response rate of 12% and stable disease rate of 22%. Median PFS was 3.7 months, while overall survival was 18.5 months. The major toxicity was mild coughing, considered grade 1/2.

These results are not very impressive. The pioneer in using inhaled IL-2 is Dr. Edith Huland of Germany and her studies show that the response to the drug is lessened when there are metastases to other organs besides the lungs. Dr. Garcia didn't stratify his results by site of metastasis, which would have been instructive. It should be noted that of the responders, 2.8% were complete responders. This method of treatment should be used in those patients who have metastases to the lungs only. With this select group, the number of responders might significantly increase. It is puzzling that the use of inhaled IL-2 for treatment of metastatic kidney cancer is not used in the United States. American oncologists have not attempted to duplicate the results of seemingly successful trials conducted mostly in Germany and Israel.