Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

ABSTRACTS IN PERSPECTIVE based on presentations from the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO)

Chicago, Illinois / May 30-June 3, 2008

EDITORIAL OVERVIEW:

Mary MacKenzie, MD, FRCPC Division of Medical Oncology, London Health Sciences Centre, Assistant Professor of Medicine, University of Western Ontario, London, Ontario

Activation of the PI3/akt/mTOR (mammalian target of rapamycin) signalling pathway occurs in a majority of cancers and contributes to the deregulation of proliferation, resistance to apoptosis and changes in metabolism characteristic of transformed cells. Study of the motor pathway has led to the prediction that inhibition of the mTOR pathways may be a promising new option in cancer treatment.

Much interest was generated by a number of presentations at this year’s ASCO meeting in which mTOR inhibition therapy alone or with other targeted therapies was found to have considerable activity in a number of advanced, recurrent or metastatic solid and hematologic malignancies.

Beyond First-line Treatment Failure in Metastatic Renal Cell Carcinoma

Currently, sunitinib and sorafenib, both oral antiangiogenic vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), are commonly used in the treatment of patients with metastatic renal cell carcinoma (RCC). However, nearly all patients eventually progress on TKIs and there is presently no standard treatment after failure of sunitinib or sorafenib in the first-line setting.

In a study by Dr. Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, New York, and colleagues, 272 relatively heavily pretreated patients with metastatic RCC who had progressed on sunitinib or sorafenib or both received the mTOR inhibitor everolimus 10 mg q.d. until progression or unacceptable toxicity. The primary end point of the study was progression-free survival (PFS) as determined by independent central review. Patients (n=138) who were initially randomized to placebo were permitted to cross over to active therapy offered on a compassionate basis at the time of progression.

Findings showed that patients receiving the mTOR inhibitor had a median PFS of four months compared with only 1.9 months for placebo patients, i.e. a 70% reduction in the risk of progression or death (P<0.001). At six months, 26% of patients on active treatment were still free of progressive disease compared with 2% of patients on placebo. Benefit for everolimus was also seen across all risk groups and treatment was mostly well-tolerated, with no worsening in quality of life compared with placebo.

Grades 3 and 4 stomatitis occurred in 3% of patients as did asthenia/fatigue (3%), pneumonitis (3%) and infections (3%) but both the safety of and patient-reported outcomes for the active treatment arm were judged to be acceptable. The investigators concluded that everolimus is the first and only agent now shown to have clinical benefit for the treatment of patients with RCC following progression on VEGF TKI therapy and that it should become standard-of-care in this setting.

Findings from a second, smaller phase II study provided further evidence that mTOR inhibition is an active and welltolerated strategy in the setting of metastatic RCC following VEGF TKI failure. According to Dr. Jaroslaw Jac, Methodist Hospital, Houston, Texas, and colleagues, in a group of 26 RCC patients who also received everolimus following failure on either sunitinib or sorafenib, disease stabilized for greater than three months in close to 85% of the group. Median PFS was 6.5 months, while median overall survival (OS) was 16.3 months.

Further data from a previously published, large randomized phase III trial of another mTOR inhibitor, temsirolimus, vs. interferon vs. the combination in poor-prognosis metastatic renal cancer was presented at ASCO 2008. In a subanalysis of the ARCC (Advanced Renal Cell Carcinoma) trial in which patients were treated with temsirolimus, Dr. Theodore Logan, Indiana University Cancer center, Indianapolis, and colleagues noted that response did not appear to be affected by nephrectomy status, as patients with no prior nephrectomy had responses similar to the group overall.

Activity in Relapsed or Refractory MCL

There is currently no accepted standard of care for patients with relapsed or refractory mantle cell lymphoma (MCL). Previous studies demonstrated anti-tumour activity with the mTOR inhibitor temsirolimus, in this setting. To that end, Dr. Georg Hess, Johannes Gutenberg University, Mainz, Germany, and colleagues set out to investigate two different weekly regimens of temsirolimus vs. investigators’ choice (IC) of single-agent therapy, usually gemcitabine or fludarabine.

Treatment consisted of initial temsirolimus 175 mg weekly for three weeks, then either 75 mg or 25 mg a week until progression. Patients had received between two and seven prior therapies, including stem-cell transplantation, and had measurable disease. At baseline, approximately half in the temsirolimus arms had stage IV disease, as did 44% of those treated with IC therapy. In patients who continued on the higher 75-mg dose, there was a 22% response rate, consisting of one complete response (CR) and 11 partial responses (PRs) compared to a 6% remission rate in the 25-mg arm (all PRs). Median duration of response was 7.1 months for the 75-mg group vs. 3.6 months for the 25-mg group.

One patient in the IC arm had a CR with gemcitabine (P=0.0019 for the 75-mg arm vs. the IC arm) (duration of response was not available for the IC arm). Median PFS was 4.8, 3.4 and 1.9 months for the 75 mg, 25 mg and IC arms, respectively (P=0.0009 for the 75-mg arm vs. the IC arm). The 75-mg dose treatment arm of temsirolimus also prolonged OS to a median of 13.6 months compared to a median of 10 months in the 25-mg arm and 9.7 months for the IC arm, but this difference was not statistically significant.

Grade 3 and 4 thrombocytopenia was the most common hematologic toxicity seen, occurring in 63% of the 75-mg arm and in 52% of the 25-mg arm, while grade 3 and 4 asthenia was the most common non-hematologic toxicity, occurring in 13% of those in the 75-mg arm and in 19% of those in the 25-mg arm. Generally speaking, toxicities with temsirolimus were mild and manageable relative to IC therapy. Investigators concluded that temsirolimus represents an attractive therapeutic option for relapsed or refractory MCL and further evaluation of its activity in earlier treatment is highly warranted.

Dr. Sonali Smith, University of Chicago, Illinois, and colleagues believe that there is a clear signal that mTOR inhibitors are active in other types of lymphoma as well, notably follicular lymphoma (FL). In a phase II study, weekly intravenous infusions over 30 minutes of temsirolimus 25 mg were administered to patients with diffuse large-cell lymphoma (DLCL), transformed or indolent FL, or chronic lymphocytic leukemia (CLL). The researchers observed an overall response rate in the DLCL and the FL patient cohorts of 49%, of which 20% were CRs. However, no treatment activity was observed in the CLL patient subgroup.

Duration of response was short-lived in the DLCL subset at only 2.5 months vs. 9.3 months for FL patients, suggesting that temsirolimus has activity across a number of lymphoma subtypes and is not limited to MC histologies.

Exploring mTOR Treatment in Other Advanced Malignancies

Since mTOR regulates protein synthesis and ultimately cell growth, cell proliferation and angiogenesis, abnormally activated mTOR may play a role in many cancer types. Preliminary evidence of two separate studies found signs of modest activity with mTOR inhibitor treatment in advanced endometrial cancer refractory to standard chemotherapy.

In a NCIC study led by Dr. Amit Oza, Professor of Medicine, University of Toronto, Ontario, 27 patients with recurrent or metastatic endometrial cancer were treated with temsirolimus 25 mg/week. Almost half of the group received over 90% of the planned dose. No CRs were seen but two patients (7%) achieved a PR and disease stabilized in 12 others (44%). Expected toxicities did occur; these included fatigue, mucositis, and pneumonitis. Findings indicate that temsirolimus has modest activity in previously treated women with recurrent or metastatic endometrial cancer, and that the majority of this activity comes in the form of stable disease.

Similar conclusions were reached by Dr. Brian Slomovitz, Weill Medical College of Cornell University, New York, and colleagues, who treated 35 patients with recurrent/metastatic endometrial cancer with everolimus 10 mg q.d. At a mean of 4.6 cycles, a clinical benefit response was seen in 43% or 12 patients, although four went off study due to progression. Treatment was well-tolerated, fatigue and nausea being the most common grade 3 adverse events but only grade 1 and 2 stomatitis and mucositis were observed.

A study of the combination of an mTOR inhibitor with another targeted agent in the treatment of advanced, refractory nonsmall cell lung cancer (NSCLC) was presented at ASCO 2008. Ninety-two patients with advanced NSCLC were enrolled. Seventy-two patients received daily full-dose erlotinib plus fulldose everolimus while 20 received a weekly regimen of everolimus 50 mg plus erlotinib 150 mg q.d. Among the daily regimens tested, there was one CR, 10 PRs and disease stabilized in 34 patients, as reported by Dr. Vassiliki Papadimitrakopoulou, M.D. Anderson Cancer Center, Houston, and colleagues. The daily regimen was felt promising enough to advance to a phase II study.

Lastly, Dr. John Hainsworth, Sarah Cannon Cancer Center, Nashville, Tennessee, and colleagues evaluated a combination of the intravenous VEGF inhibitor bevacizumab with everolimus in patients with advanced clear cell RCC. Half of 59 patients receiving the combination had received prior VEGF TKI therapy. No CRs were seen in either untreated or previously treated patients, but PRs were achieved in 23% vs. 17% and stable disease in 53% vs. 59% in untreated vs. treated patients, respectively.

With the bevacizumab/everolimus combination, median PFS was 12 months in untreated patients and 11 months in prior VEGF TKI patients, while median OS was 17 months vs. 12 months in untreated vs. treated patients, respectively.

Unlike many targeted agents when combined, full doses of both bevacizumab and everolimus could be given in most patients, suggesting tolerability and activity of the combination.

LBA5026 RAD001 vs. Placebo in Patients with Metastatic Renal Cell Carcinoma (RCC) After Progression on VEGFr-TKI Therapy: Results from a Randomized, Double-blind, Multicenter Phase-III Study R. J. Motzer, B. Escudier, S. Oudard, C. Porta, T. E. Hutson, S. Bracarda, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud

Background: RAD001 (everolimus) is an oral inhibitor of mTOR, an intracellular kinase that regulates cell proliferation and angiogenesis. Antitumour activity has been shown in a single-arm Phase-II trial in pretreated mRCC with continuous daily therapy ( JCO 2007;25[18S]:261S, Abs 5107).

Methods: Pts with RCC with a clear-cell component progressing on or <6 months (mo) after VEGFr-TKI therapy (sorafenib, sunitinib, or both) were randomized 2:1 to RAD001 (10 mg/d po) or placebo, both with best supportive care. Patients were stratified by MSKCC risk criteria and prior VEGFr-TKI therapy (1 vs 2). Progression-free survival (PFS), documented using RECIST and assessed via blinded, independent review, was the primary endpoint. At progression, treatment was unblinded and pts on placebo offered open-label RAD001. Based on a sample size of 362 pts, the trial had 90% power to detect a 33% risk reduction (HR 0.67), with a median exponential PFS improvement from 3.0 to 4.5 mo (stratified log-rank test). Results of a planned interim analysis are presented - as these met prespecified criteria for a positive trial, the Independent Data Monitoring Committee stopped the study to allow remaining patients on placebo to receive RAD001.

Results: From 9/06-10/07, 272 pts were randomized to RAD001 and 138 to placebo. Demographics were well balanced (pooled median age 60y) as was prior VEGFr-TKI therapy (sunitinib 71%, sorafenib 55%, sunitinib+sorafenib 26%). 191 PFS events (47% of 410 pts) were reported by central review: 101 (37%) and 90 pts (65%) on RAD001 and placebo, respectively. Most common AEs (all grades/grade 3-4) were stomatitis (RAD001 36/4%, placebo 7/0%), anemia (28/7% vs 15/5%), and asthenia (28/2% vs 20/4%). 10% of pts had AEs leading to discontinuation with RAD001 vs 4% with placebo whereas dose reductions were required by 4% vs <1%. 68 deaths were observed, and study followup is ongoing to assess the secondary endpoint of overall survival.

Conclusion: RAD001 resulted in a statistically and clinically significant improvement in PFS over placebo with a favorable safety profile in pts with mRCC after progression on other targeted therapies.

Commentary on abstract LBA5026

Historically, RCC was considered to be one of the least treatable malignancies. Treatment was limited to cytokine therapy which had limited efficacy and poor tolerability. Over the past few years, there has been a dramatic change in RCC treatment as the novel targeted agents became available, including sunitinib, sorafenib and temsirolimus. However, when patients invariably develop resistance to the VEGF TKIs, there has been no concensus regarding standard treatment. Early phase II trials suggested activity of an oral mTOR inhibitor following progression on VEGF TKI therapy. In this landmark study by Motzer et al., 272 patients with metastatic RCC who had progressed on sunitinib or sorafenib or both received the mTOR inhibitor everolimus 10 mg until progression or unacceptable toxicity while 138 received placebo. Median PFS was four months in the mTOR inhibitor arm vs. 1.9 months for placebo (P<0.001) for a 70% reduction in the risk of progression or death while on everolimus. The safety profile of active therapy was acceptable. Investigators concluded that everolimus is the first and only agent to have demonstrated clinical benefit in the post-VEGF TKI setting and should become standard-of-care.

Questions and answers with Dr. Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, New York, New York

Q: Do we know the mechanism by which patients develop resistance to the TKIs?

A: The small-molecule TKIs improve response and PFS but at some point, all patients progress and we don’t know why. One of the attractive features of mTOR inhibitors is that they have a different mechanism of action from TKIs—it’s a central mechanism on the tumour cell itself—and they seem to be particularly effective in tumours that have developed resistance to the other agents. So when a tumour becomes resistant, we like to switch over to a different type of compound and that is why this was an attractive treatment strategy in this group of patients.

Q: What do you think this trial has brought to the management of metastatic RCC?

A: The highest level of evidence comes from phase III randomized trials and this trial has shown us that treatment with an mTOR inhibitor was associated with a significant benefit in PFS, so I think that in secondline therapy after sunitinib and sorafenib, the standard of care should be everolimus.

5113 A Phase II Study with a Daily Regimen of the Oral mTOR Inhibitor RAD001 (Everolimus) in Patients with Metastatic Renal Cell Carcinoma Which Has Progressed on Tyrosine Kinase Inhibition Therapy J. Jac, R. J. Amato, S. Giessinger, S. Saxena, J. P. Willis

Background: Everolimus, an oral mTOR inhibitor, affects tumour growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have shown efficacy in renal cell cancer (RCC). Reported at ASCO 2007, everolimus has promising anti-tumour activity in patients with MRCC demonstrated by 32% partial response (PR) and stable disease (SD) for >6 months in 38% of patients. This phase II study assessed the efficacy of daily oral dosing with everolimus in MRCC patients who have failed no more than 2 prior therapies one of which was a tyrosine kinase inhibitor (sorafenib or sunitinib).

Methods: Patients had confirmed predominantly clear cell RCC, progressive measurable metastatic disease, adequate organ/marrow function, good performance status and no active CNS involvement. Everolimus was given (10 mg daily, p.o.) without an interruption (28-day cycle), with dose modifications for toxicity per NCI-CTC, version 3.0. Patients were evaluated every 2 cycles (8 weeks) using RECIST.

Results: Among the first 22 enrolled patients, 22 were treated and evaluable for safety, 19 for response after withdrawal of 2 patients following the first 4 weeks of therapy, and 1 too early. Patients were mostly male (68%) with a median age 57 years, 100% Zubrod Performance Status 0-1. PR were seen in 3(16%) and SD for >3 months in 14 (74%). Median PFS was 5.5+ months (1-12+ months), median OS was 8+ months (1-14+). The most common treatment related adverse events were Grade 1/2: hypertriglyceridemia (73%), hyperglycemia (59%). hypercholesterolemia (64%), stomatitis (45%), rash (32%), nausea (27%), and diarrhea (18%); Grade 3/4 adverse events included pneumonitis (27%).

Conclusions: Everolimus shows encouraging antitumour activity against MRCC patients who have had prior exposure to sorafenib or sunitinib as indicated by the tumour responses and progression-free survival. Anti-tumour activity and toxicity will be presented in addition an update of the ASCO 2007 data.

Commentary on abstract 5113

Given the findings from the landmark study of mTOR inhibition in metastatic RCC following VEGF TKI failure, investigators have solid evidence to meet the needs after TKI failures. Updated findings from an earlier phase II study add further weight to the results from the phase III trial reported here this year. In an earlier cohort of 41 patients treated with everolimus, median PFS was 11.1 months, while median OS was 22 months. Updated information on this initial group of patients (n=37) indicated that PRs were seen in five patients while disease remained stable for greater than three months in 72.9% of the group. An independent third party assessment observed a lower rate (two patients with PR) but rates of stable disease were virtually identical, regardless of whether investigators or the independent third party carried out the assessment. In a further 26 patients treated with the same oral daily protocol, five of whom had received prior sunitinib and 21 of whom had received prior sorafenib, investigators observed no CRs or PRs, but disease stabilized for greater than three months in 84.6% of the group (n=25). Median PFS and OS in this group of TKI failures were 6.5 months and 16.3 months, respectively. Thus, this trial provides further evidence that mTOR inhibition is an appropriate therapeutic target for metastatic RCC following VEGF TKI failure.

Questions and answers with Dr. Sarah Giessinger, The Methodist Hospital Research Institute, Houston, Texas

Q: Where are we in the treatment of RCC right now?

A: Because of all the up-and-coming [treatments], there are multiple new agents that people can go to now for treatment—some first-line, some second-line, but there are endless possibilities now for RCC as single agents and as possible combinations, including the mTOR inhibitors. So it’s a promising time for treatment of RCC.

Q: What makes the mTOR inhibitors an attractive therapeutic option for the treatment of many cancers, including metastatic RCC?

A: They have a low side-effect profile and they are relatively slow-acting so treatment is not as aggressive as with some other agents. Response is not immediate, but treatment with the mTOR inhibitors leads to stable disease in many patients. So patients tolerate the treatment well and it is effective. In our second group of 26 patients, 22 of them achieved stable disease on [everolimus] and a PR is not out of the question yet, as response takes time.

Q. How would you characterize treatment efficacy so far in your experience?

A: In our initial 41 patients, our median OS is 22 months, almost two years, while PFS is almost a year, and for metastatic RCC, these are great numbers. We are also using [everolimus] in combination with sorafenib because they each work on different pathways, so we might expect synergy between the two drugs as well.

5050 Exploratory Analysis of the Influence of Nephrectomy Status on Temsirolimus Efficacy in Patients with Advanced Renal Cell Carcinoma and Poor-risk Features T. Logan, D. F. McDermott, J. P. Dutcher, A. Makhson, J. Mikulas, A. Berkenblit, L. Galand, M. Krygowski, G. R. Hudes

Background: Temsirolimus (TEMSR), a novel inhibitor of the mammalian target of rapamycin, has demonstrated significantly longer overall survival (OS) (P=.008) and progression-free survival (PFS) (P<.001) vs interferon alfa (IFN) in patients with previously untreated advanced renal cell carcinoma (RCC) and poor-risk features (Hudes et al., NEJM 2007;356:2271). In poor-risk populations, a high percentage of patients do not have nephrectomy prior to systemic treatment. This retrospective subgroup analysis evaluated the influence of prior nephrectomy on outcomes in patients treated with TEMSR or IFN.

Methods: Patients received IFN 3 million units [MU] subcutaneously 3x weekly, escalating to 18 MU, or TEMSR 25-mg intravenous infusion weekly. Kaplan- Meier analysis and a Cox proportional hazards model were used to analyze OS and PFS for the 2 patient subsets (no nephrectomy vs nephrectomy).

Results: In each treatment arm, 33% of patients did not receive nephrectomy prior to treatment (IFN, 68/207; TEMSR, 70/209). There was no association between risk factors and nephrectomy status within the 2 treatment arms. Median OS was longer for TEMSR vs IFN (Table), resulting in reduced hazard ratios (HR) for death in both patient subsets (no nephrectomy, HR=0.61 [95% CI, 0.41, 0.91]; nephrectomy, HR=0.84 [95% CI, 0.63, 1.11]). In both subsets, median PFS was longer when treated with TEMSR (no nephrectomy, HR=0.62 [95% CI, 0.43, 0.88]; nephrectomy, HR=0.72 [95% CI, 0.55, 0.93]). Nephrectomy status did not affect temsirolimus efficacy with respect to either OS (P=.20) or PFS (P=.47). Among non-nephrectomized patients, more patients treated with TEMSR showed reductions in primary kidney tumour size than did those treated with IFN (TEMSR, 37/64 [58%]; IFN, 18/59 [31%]).

Conclusion: Temsirolimus benefits patients with advanced RCC and poor-prognostic features, regardless of nephrectomy status, and displays
mary kidney tumours.

<img1953|center>

Commentary on abstract 5050

Pooled results from previously published, randomized trials have suggested a survival benefit for cytoreductive nephrectomy in patients with metastatic renal cancer. However, not all patients are medically fit for surgery for reasons of metastatic disease burden or comorbid illness. In this retrospective analysis of the phase III global ARCC trial, investigators evaluated the influence of prior nephrectomy on outcomes in patients with poor prognostic features treated with either temsirolimus or interferon (IFN). One-third of patients in each treatment arm had not undergone nephrectomy prior to receiving systemic therapy. Regardless of nephrectomy status, patients receiving temsirolimus had longer PFS and OS rates than those receiving IFN. For non-nephrectomized patients, median PFS and OS were 5.7 months and 11.5 months in the temsirolimus arm and two months and 6.2 months in the IFN arm. For those who had had a nephrectomy, median PFS and OS were 5.3 months and 10.4 months for the mTOR-treated patients and 3.5 months and 7.8 months for IFN-treated patients. The majority of primary RCC tumours also shrank in response to temsirolimus treatment. This analysis suggests that temsirolimus benefits RCC patients with poor-risk features, regardless of their nephrectomy status.

Questions and answers with Dr. Theodore Logan, Indiana University Cancer Center, Indianapolis

Q: What was the impetus for this retrospective analysis?

A: I had a patient in the ARCC [Advanced Renal Cell Carcinoma] trial that had quite an amazing response to treatment so I wanted to go back and look at data from this trial. The trial has already been published and it is a well-known paper showing that median PFS in the temsirolimus arm was 5.5 months vs. 3.1 months for IFN, while median OS was 10.9 months in the temsirolimus group vs. 7.3 months for the IFN. So we were trying to break down the data looking at patients who had had their kidney out vs. those who had not.

Q: What constituted poor-risk features in this patient group?

A: Poor prognostic features included less than one year from initial diagnosis to randomization in the ARCC trial, a Karnofsky PS of 60 or 70, and multiple organ sites of metastasis.

Q: What is the take-home message from this analysis?

A: There is really one take-home point and that is, in this retrospective preliminary analysis, having the kidney in or out did not seem to make a whole lot of difference in terms of the overall findings of the study. And those findings still stand in both groups: temsirolimus was better than IFN in terms of OS and PFS regardless of their nephrectomy status. So I don’t think you have to be as concerned about getting the kidney out in patients who are in bad shape and in whom you are considering temsirolimus.

8513 Phase III Study of Patients with Relapsed, Refractory Mantle Cell Lymphoma Treated with Temsirolimus Compared with Investigator’s Choice Therapy G. Hess, J. E. Romaguera, G. Verhoef, R. Herbrecht, M. Crump, A. Strahs, J. Clancy, B. Hewes, B. Coiffier

Background: Temsirolimus (TEMSR) is a specific inhibitor of mTOR, a kinase that regulates translation of key cell cycle proteins such as cyclin D1. Mantle cell lymphoma (MCL) is characterized by an 11;14 translocation that results in overexpression of cyclin D1 mRNA. In this phase 3, randomized, open-label study, we compared the antitumour activity of TEMSR with an investigator’s choice of therapy (IC) in patients (pts) with relapsed and/or refractory MCL.

Methods: To test the hypothesis that TEMSR would increase progression-free survival (PFS) compared with IC (assuming medians of 6.2 and 3.0 mo, respectively), accrual of 177 pts to achieve 105 PFS events was planned. Power was 80% and =0.025 comparing TEMSR with IC. Pts must have received 2-7 prior lines of therapy and received an alkylating agent, an anthracycline, and rituximab. Pts were randomly assigned (1:1:1) to 1 of 2 schedules of IV TEMSR, 175 mg 3x weekly followed by either 75 mg (175/75, arm 1) or 25 mg (175/25, arm 2) weekly, or to IC (arm 3) with the single agents gemcitabine (42%); fludarabine (26%); chlorambucil, cladribine, etoposide (6% ea); cyclophosphamide, thalidomide, vinblastine (4% ea); or alemtuzumab, lenalidomide (2% ea). The primary endpoint was PFS based on central independent review of radiologic and clinical data.

Results: We report final results for 162 pts (54 pts/arm, median age 67 y, 81% male, 50% >3 prior regimens, 32% prior stem cell transplant) after 105 PFS events. Treatment with TEMSR 175/75 mg resulted in significant improvement in PFS and objective response rate and a trend toward longer overall survival compared with IC (Table). The most frequently occurring adverse events >gr 3 were thrombocytopenia (arm 1: arm 2: arm 3, 59%: 52%: 36% pts), anemia (20%: 11%: 17%), neutropenia (15%: 22%: 26%), and asthenia (13%: 19%: 8%).

Conclusions: With an acceptable safety profile, TEMSR 175/75 mg significantly increased
ponse rate of pts with relapsed, refractory MCL compared with IC.

<img1954|center>

Commentary on abstract 8513

Mantle cell lymphoma (MCL) is a highly refractory disease with a five-year survival rate of 27%. Currently, there is no accepted standard of care in relapsed disease. With earlier studies demonstrating anti-tumour activity with temsirolimus in this setting, investigators compared two different weekly regimens of temsirolimus vs. investigators’ choice (IC) of single-agent therapy (gemcitabine or fludarabine). In the temsirolimus 175/75 mg arm, there was a 22% response rate, consisting of one CR and 11 PRs, compared to a 6% response rate in the 175/25 mg per week arm (all PRs). One patient had a CR with gemcitabine in the IC arm. Median duration of response was 7.1 months for the 175/75 mg group vs. 3.6 months for the 175/25 mg group, while median PFS was 4.8 months for the 175/75 mg arm, 3.4 months for the 175/25 mg arm, and 1.9 months for the IC arm. Temsirolimus 175/75 mg also prolonged OS to a median of 13.6 months compared to a median of 10 months in the 175/25 mg arm and 9.7 months for the IC arm, but not significantly so. Toxicities were mild and manageable relative to IC therapy. Temsirolimus therefore represents an attractive option for relapsed or refractory MCL.

Questions and answers with Dr. Georg Hess, Johannes Gutenberg University, Mainz, Germany

Q: You had no patients with blastoid features in the high-dose arm. Do the results still hold when you remove patients with the blastoid variant of the disease?

A: Yes, after exclusion of these patients, results still hold, so I think temsirolimus makes sense in this patient population as well.

Q: What kind of toxicities did you see with temsirolimus?

A: The 175/75 mg arm was associated with a higher incidence of grade 3 and 4 thrombocytopenia at 63% compared with the IC arm at 40%, but a lower incidence of grade 3 to 4 neutropenia at 24% vs. 45% for the comparator arm. Rates of grades 3 and 4 infection were also higher at 9% for the high-dose temsirolimus arm vs. 4% for the IC arm. Hyperglycemia rates were, however, relatively low at 7% for the high-dose temsirolimus arm and 6% for both the 175/25 mg arm and the IC arm.

8514 Activity of Single Agent Temsirolimus (CCI-779) in Non-mantle Cell Non-Hodgkin Lymphoma Subtypes S. M. Smith, B. Pro, A. Cisneros, S. Smith, P. Stiff, E. Lester, S. Modi, J. E. Dancey, E. E. Vokes, K. van Besien

Background: Mammalian target of rapamycin (mTOR) is a critical mediator of mRNA translational initiation. Many mRNA transcripts under mTOR regulation contribute to lymphomagenesis, providing rationale for testing mTOR inhibition (MTI) in NHL. The success of MTI in mantle cell lymphoma is well-established, but there is limited data in other NHL subtypes.

Methods: Temsirolimus (CCI-779) is a rapamycin ester derivative. We conducted a multicenter phase II study of temsirolimus 25 mg IV over 30 minutes weekly with 8 planned weeks of therapy (2 cycles) in pts with relapsed/refractory diffuse large B-cell lymphoma (DLCL), follicular lymphoma (FL), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and other indolent B-NHL.

Results: 82 pts with a median age of 62 yrs (range, 30-88 yrs) enrolled; 4 pts refused treatment and 4 pts are too early for eval. Pts had median 2 prior regimens (range, 1-7), and all but 9 had prior rituximab. Of 74 pts, 56 received > 2 cycles of temsirolimus; 18 pts received < 2 cycles due to rapid PD (n=6) or toxicity (n=12). ORR in pts completing > 2 cycles of temsirolimus is 46% (26/56). ORR in pts receiving at least one dose of temsirolimus is 35% (26/74) with 25 pts maintaining SD. Response by histology is in Table 1. Median PFS of all pts is 123d, with 60% 100- day PFS. Median PFS of pts completing > 2 cycles is 156d, with 79% 100-day PFS. Median PFS of pts with PR/CR is 215d, with 96% 100-day PFS. Median DR of pts with PR/CR is 116d. Most nonhematologic toxicities were grade 1/2 (stomatitis, rash, and metabolic deregulation) but 12 pts were removed from study due to pneumonitis (n=5), pneumonia/stomatitis (n=2), infection (n=2), or cytopenias (n=3).

Conclusion: The ability of temsirolimus, a presumably cytostatic compound, to induce a 46% ORR (35% ITT ORR) suggests an activity signal that should be pursued further. The heterogeneity of response implies that the
more likely to benefit from MTI; identifying this population will be key to future development of MTI in NHL.

<img1955|center>

Commentary on abstract 8514

In a previous study ( JCO 2005;23:5347-56), an overall response rate of 38% and a median time to progression (TTP) of 6.5 months was reported in patients with relapsed/refractory MCL given temsirolimus 250 mg. However, most patients required a dose reduction because of toxicity and a subsequent study was carried out using 10% of the dose without compromising response rate or duration of response. The current study explored whether temsirolimus at the same lower dose also has activity in non-MCL histologies. Patients had either aggressive disease (DLCL, transformed FL) or indolent FL or CLL. Out of 82 evaluable patients, two with DLCL achieved a CR and six achieved a PR. Ten FL patients had a CR and 13 a PR, for an overall response rate in DLCL and FL patients of 49%, 20% being a CR. Only two CLL patients responded to mTOR inhibition for an overall response rate of 11%. Median duration of response was 9.3 months for FL patients vs. 2.5 months for DLCL patients. For patients completing at least two cycles of therapy, median PFS was 9.5 months. Thrombocytopenia was the most common hematologic toxicity, but few patients required a dose reduction. Investigators concluded that temsirolimus has activity across lymphoma subtypes not limited to MC histologies, although not CLL.

Questions and answers with Dr. Sonali Smith, University of Chicago, Illinois

Q: What happened in the CLL population and why was response so different than those with more aggressive lymphomas?

A: In the CLL population, we didn’t see anybody progressing but we just didn’t see the responses we needed to expand the study. For DLCL patients, we saw responses but they were very short-lived. But these are biologically two very different diseases and DLCL by nature has a much more aggressive course. In addition, many of the DLCL patients were autotransplant failures or were too old to go through a transplant, so it was a sicker population overall than the FL patients.

Q: Could you comment on mTOR inhibition in MCL?

A: MCL is the lymphoma subtype that is furthest along in development with mTOR inhibitors and there is very a clear pathway for them, as mTOR activates cyclin D1, which is part of the pathogenesis of MCL. In DLCL and FL, we don’t have that nice, straightforward pathway. We have conjectured about which downstream targets are important in DLCL and FL but we don’t have a nice clear pathway as we do in MCL.

Q: Where do you see the mTOR inhibitors contributing to the management of lymphomas?

A: Either this drug specifically or the class of drugs needs to be taken forward, as there is clearly an activity signal. And I think combination studies are the next logical step.

5516 A Phase II Study of Temsirolimus (CCI-779) in Patients with Metastatic and/or Locally Advanced Recurrent Endometrial Cancer Previously Treated with Chemotherapy: NCIC CTG IND 160b A. M. Oza, L. Elit, D. Provencher, J. J. Biagi, L. Panasci, J. Sederias, J. E. Dancey, M. S. Tsao, E. A. Eisenhauer, NCIC Clinical Trials Group

Background: Loss of PTEN function occurs in 26- 80% of endometrial carcinomas and leads to deregulated PI3K/Akt/mTOR signalling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR with temsirolimus, an ester derivative of rapamycin, has demonstrated promising activity, irrespective of PTEN loss, in chemotherapy naïve endometrial cancer with an objective response rate of 21% and prolonged stable disease in 48%. This trial was designed to assess the level of activity in patients who had previously received chemotherapy.

Methods: A single stage phase II study of temsirolimus in women with chemotherapy treated, recurrent or metastatic endometrial cancer has been completed, at a dose of 25mg i.v. weekly. 27 eligible patients have been enrolled and archival specimens of tumour have been collected for PTEN immunohistochemistry analysis. Thirteen had received prior radiation and 10 hormonal therapy. Twenty-five patients had adenocarcinoma (8 serous carcinoma) and 2 had adeno-squamous carcinoma; 20 patients had grade 2/3 disease, 5 unknown and 2 grade 1.

Results: Hematologic toxicity has been mild with 5 episodes of grade 3 lymphopenia and 2 of anemia; 8 patients had grade 3/4 non-hematologic adverse events [pneumonitis, mucositis, fatigue, GI, pain]. Grade 3/4 biochemical toxicities were hypokalemia, hyperglycemia, hypoalbuminemia and hypophosphatemia. Two patients have had a confirmed partial response (PR) (7.4%; 95% CI 0.9-24.3%) and 12 patients had stable disease (SD) (44%), median duration 3.5months (2.4-7.2m) and 10 patients had progressive disease (41.7%). Five of the 8 patients with serous disease had SD and of the 17 with Grade 3 disease, 1 was PR and 7 SD. PTEN assays are underway.

Conclusions: The results indicate modest activity for Temsirolimus in women with recurrent endometrial cancer previously treated with chemotherapy.

Commentary on abstract 5516

A high proportion of patients with endometrial cancer have PTEN mutations resulting in an aberrant molecular pathway which makes the disease more aggressive. mTOR inhibitors may inhibit this aberrant pathway, thus offering a potentially novel way to control the disease and effect responses in a proportion of patients. In this NCIC-based phase II study, temsirolimus 25 mg weekly was administered to 27 patients with recurrent or metastatic endometrial cancer. Seventeen patients had adenocarcinoma, eight had serrous histology and two had squamous histology. The actual dose received was 21.9 mg and 48.1% of patients received over 90% of the planned dose. No CRs were seen but two patients (7%) achieved a PR and disease stabilized in 12 others (44%). Responses were seen in both adenocarcinoma and serrous histologies but no response was seen in squamous cell disease. Grade 3 fatigue, dehydration, mucositis, cough and dyspnea were observed, as was grade 3 pneumonitis. One patient reported grade 3 pain as well. Neither PTEN, p56K, pATK nor pmTOR correlated with responses. Investigators concluded that temsirolimus has modest activity in women with previously treated endometrial cancer, although response rates were lower and duration of response shorter than in chemotherapy-naïve patients.

Questions and answers with Dr. Amit Oza, Professor of Medicine, University of Toronto, Ontario

Q: Why did you want to explore mTOR inhibition in advanced endometrial cancer?

A: We did a previous study in patients who had not had chemotherapy and had shown that mTOR inhibition was a very active strategy in that population. So this study was following up on that patient population to see if there was equal activity or not.

Q: You concluded that temsirolimus had modest activity in advanced disease. Would this indicate a first-line use for mTOR inhibition?

A: First-line would certainly seem to be more active as a strategy, but even in our recurrent population, it did have activity and so the next question is: Is this level of activity sufficient to develop this further in endometrial cancer? I think it is. There are very few treatment options in women who have endometrial cancer, particularly when they have had chemotherapy, and so if you do identify a drug that has some activity, then it is worth exploring further to see if we can define this level of activity. We could potentially combine it with hormonal or chemotherapy as well.

Q: Do we need new medications to treat all of the cancers that mTOR inhibitors are now being tested in, including endometrial cancer?

A: The option of using mTOR inhibitors is a welcome addition in oncology, and it is especially important to develop their use further in gynecologic cancer. Oftentimes, gynecologic cancer is at the back of the queue when it comes to new drug development and new options for treatment. So having mTOR inhibitors as an additional option and defining their use further in gynecologic cancer is really important.

5502 A Phase II Study of Oral Mammalian Target of Rapamycin (mTOR) Inhibitor, RAD001 (Everolimus), in Patients with Recurrent Endometrial Carcinoma (EC) B. M. Slomovitz, K. H. Lu, T. Johnston, M. Munsell, L. M. Ramondetta, R. R. Broaddus, R. L. Coleman, C. Walker, D. M. Gershenson, T. W. Burke, J. Wolf

Background: The finding of PTEN mutations in 40-60% of EC suggests this pathway is important in the pathogenesis of this disease. Loss of PTEN leads to constitutive activation of AKT, which leads to up-regulation of mTOR. RAD001 is an oral rapamycin analog that acts by selectively inhibiting mTOR.

Methods: A single institution, open-labeled, single arm, Phase II study in patients with recurrent EC who have failed at least one and no more than 2 prior chemotherapeutic regimens was performed. RAD001 was administered at a dose of 10 mg PO daily for 28 day cycles. One dose reduction (to 5 mg) was permitted. Patients were treated until progression or toxicity. The primary efficacy endpoint is Clinical Benefit Response (CBR), defined as a complete or partial response or prolonged stable disease (SD;>8 weeks) by RECIST criteria. Inclusion was limited to patients with endometrioid EC. Correlative studies evaluating PTEN were performed if tissue was available.

Results: Twenty-nine patients were enrolled (median age 58; range: 38-81). A total of 74 cycles have been administered. 11 of 25 (44%) evaluable patients for response had CBRs. All of these patients had SD (median: 4 cycles; range 2- 10). One patient achieving CBR is still on treatment. Patients with CBR discontinued treatment because of toxicity (6), progression (3), and noncompliance (1). 14 of the 25 patients discontinued treatment after receiving <2 cycles because of progressive disease (13) and toxicity (1). Four patients were unevaluable after receiving <1 cycle because of toxicity (3) or noncompliance (1). The most common adverse events were abdominal pain (28%), nausea/vomiting (21%), low-grade fever (21%), and anemia (17%). 12 patients required a dose reduction. Fifteen of 25 evaluable patients had tissue available from the original hysterectomy. Loss of PTEN expression was predictive of CBR with a sensitivity of 88%, specificity of 57%, positive predictive value of 70% and negative predictive value of 80% (P=0.10).

Conclusion: RAD001 shows encouraging single agent clinical benefit in pretreated patients with recurrent EC. Loss of PTEN may predict CBR. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy.

Commentary on abstract 5502

Over 40,000 new cases of endometrial cancer are expected to be diagnosed in the US this year. Both hormonal and chemotherapy regimens are used to treat recurrent or metastatic disease but with very limited success. PTEN is a tumour suppressor gene and up to 60% of endometrial cancers have PTEN mutations. Loss of PTEN activates AKT and activated AKT upregulates mTOR, suggesting a rationale for mTOR inhibition in endometrial cancer. This study included 35 patients with recurrent/metastatic endometrial cancer who had had two or fewer prior chemotherapy regimens. Patients received everolimus 10 mg/day. All 35 were evaluable for toxicity, while 28 were evaluable for efficacy. Two patients were removed from study due to clinical deterioration and five due to toxicity. At a mean of 4.6 cycles, a clinical benefit response was seen in 43% or 12 patients, four of whom went off study due to progression. Treatment was well tolerated; fatigue and nausea were the most common grade 3 adverse events. No grade 3 stomatitis or mucositis was reported but they did occur in lesser grades. Investigators concluded that everolimus shows encouraging single-agent clinical benefit responses in pretreated patients with recurrent endometrial cancer.

Questions and answers with Dr. Brian Slomovitz, Weill Medical College of Cornell University, New York

Q: Could you comment on the translational component of the study?

A: We looked at several markers involved with the PTEN pathway and the only marker that we saw a slight trend towards predicting response was PTEN. So loss of PTEN would upregulate mTOR, and the study showed that loss of PTEN had a high positive predictive value for response to therapy but that the other markers did not.

Q: Could you comment on what constituted a clinical benefit response?

A: One of the things that was interesting in our trial is that while the tumours did not shrink, patients had stable disease. Most of the time, all we can offer patients at this stage of the disease is palliative care, so the fact they had stable disease was a sign of activity. What we need to do now is combine mTOR inhibitors with either hormonal or cytotoxic agents and in a follow-up trial, we will be looking to do just that: we will be combining everolimus with the hormonal agent letrozole in a similar population of patients. We will also be looking to give the same agent in combination with chemotherapy for first-line endometrial cancer.

8051 A Phase 1/2 Study Investigating the Combination of RAD001 (R) (Everolimus) and Erlotinib (E) as 2nd and 3rd Line Therapy in Patients (Pts) with Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated with Chemotherapy (C): Phase 1 Results V. Papadimitrakopoulou, G. R. Blumenschein, N. B. Leighl, J. Bennouna, J. C. Soria, H. A. Burris, III, S. Dimitrijevic, T. Kunz, L. Di Scala, B. E. Johnson

Background: R is an oral inhibitor of the mammalian target of rapamycin (mTOR) in clinical development as an anticancer agent. Clinical benefit including objective tumour responses were observed in pts with NSCLC receiving R. E is an oral epidermal growth factor receptor inhibitor (EGFRI) approved for the treatment of NSCLC pts failing C. Preclinical evidence suggests that R may enhance EGFRI anti-tumour activity and reduce resistance to EGFRI.

Methods: Patients with advanced NSCLC, failing <2 prior C regimens, ECOG PS <2, adequate bone marrow and liver function were eligible. Phase 1 part assessed the combination of R and E using a standard “6+6” dose-escalation design based on the rate of dose-limiting toxicity (DLT) and pharmacokinetic (PK) drug- drug interaction (DDI) during the first 28 days of combined treatment. A range of R doses administered in either a daily (qd) or a weekly (qw) schedule were evaluated in combination with different daily doses of E. Results: 61 pts treated in 7 cohorts: Male/Female 32/29, ever smoker/never smoker 49/12, prior therapies 1/2 31/30. Doses and schedules evaluated: R 2.5mg qd, 5mg qd, 30mg qw, 50mg qw in combination with qd doses of E 75mg, 100mg, and 150mg. R 2.5mg qd + E 150mg qd, R 5mg qd + E 75mg qd, and R 50mg qw + E 150 mg qd, were established as feasible dose regimens. DLTs observed were: mucositis (5), rash (4), diarrhea (4), vomiting (1) and neutropenia (1). Available duration of exposure of the combination was 0.2-25.8 months in daily cohorts and 0.1-2.9 months in weekly cohorts. Preliminary best overall response based on RECIST as per Investigator lesion assessment was: CR (1), PR (3), SD (17), PD (18).

Conclusions: Phase 1 part of the study established feasible doses of R in combination with E with promising early indication of clinical efficacy. Phase 2 of the study will evaluate the efficacy of dose regimens established in the phase 1 part.

Commentary on abstract 8051

The only molecularly targeted agent approved for advanced NSCLC is erlotinib, an inhibitor of EGFR TKI. Preclinical observations suggested additive or synergistic interactions with the combination of EGFR and mTOR inhibitors in NSCLC, and investigators established modest activity for everolimus given as a single agent in advanced NSCLC in an earlier study. In this study, the same investigators evaluated a combined daily or weekly regimen of mTOR inhibition plus daily erlotinib in a total of 92 patients, 72 in the daily cohort and 20 on the weekly regimen. Over half of all patients had received one prior line of chemotherapy and over 45% had received two. Doses were sequentially escalated and decisions to escalate were based on dose-limiting toxicity (DLT). Out of all daily regimens tested, there was one CR, 10 PRs and stable disease in 34 others. In contrast, the weekly regimen of everolimus 50 mg plus erlotinib 150 mg/day was largely inactive and was subsequently discontinued. Main DLTs included rash, stomatitis/mucositis and diarrhea. Otherwise, the daily schedule of full-dose everolimus 5 mg plus full-dose erlotinib 150 mg was deemed promising and will be taken forward in a phase II study.

Questions and answers with Dr. Vassiliki Papadimitrakopoulou, M.D. Anderson Cancer Center, Houston, Texas

Q: Why did you choose to explore this particular combination in advanced NSCLC?

A: This is a group of patients who have failed front-line therapy and for whom options for further treatment are very limited. So the goal for this study was primarily to explore other options for this group of patients and secondarily, to explore the potential synergy or additivity between the two agents, as laboratory data suggested there was a rationale for this combination.

Q: It is interesting that you were able to use full doses of both agents, as others have not been able to use full doses of other targeted agents when used together in combination.

A: We did have some difficulties to get there because we had to redefine our DLTs, but I think if you have experience with the drugs, most of the adverse events were very short-lived, so you can overcome toxicity and continue with the full dose.

Q: Why do you think the mTOR inhibitors are showing activity in so many different types of cancer, including NSCLC?

A: I think the mTOR pathway lies at the convergence of many growth factor signalling pathways downstream and there are multiple mechanisms for mTOR inhibitors, including signalling effects and antiangiogenic effects. So I think some of the tumours that are being targeted with mTOR inhibitors are being targeted through their antiangiogenic mechanisms. In the setting of NSCLC, however, we are targeting the signalling pathways more than antiangiogenesis.

Q. Would that not argue in favour of mTOR inhibition on its own?

A: We already did that study and presented it last year. Everolimus has modest activity as a single agent— it has about a 4% response rate and 56% disease stabilization in advanced NSCLC—but I think the value of these agents is going to be in combination, they are just much more potent in combination.

5010 Phase II Study of Bevacizumab and Everolimus (RAD001) in the Treatment of Advanced Renal Cell Carcinoma (RCC) R. C. Whorf, J. D. Hainsworth, D. R. Spigel, D. A. Yardley, H. A. Burris, III, D. M. Waterhouse, E. R. Vazquez, F. A. Greco

Background: Recent use of anti-angiogenesis agents and m-TOR inhibitors has improved the treatment of patients (pts) with advanced RCC. In this multicenter phase II trial, we evaluated the efficacy and safety of a combination of bevacizumab (VEGF inhibitor) and RAD001 (m- TOR inhibitor) in pts with metastatic RCC.

Methods: Pts with metastatic or unresectable locally recurrent clear cell RCC, ECOG PS 0 or 1, were eligible. 2 groups of pts were enrolled, based on previous treatment: Group A, no previous treatment with sorafenib or sunitinib; Group B, previous treatment with sorafenib and/or sunitinib. All pts received bevacizumab 10mg/kg IV every 2 weeks and RAD001 10mg PO daily. Pts were reevaluated after 8 weeks of treatment; pts with objective response/stable disease continued treatment with reevaluations every 8 weeks until progression.

Results: Between July 2006 and November 2007, 59 pts (30 Group A, 29 Group B) were enrolled. The median age was 65 years; 76% had intermediate Motzer prognostic scores, and 43 pts (73%) had undergone previous nephrectomy. 42 pts (71%) received at least 8 weeks of treatment and were reevaluated; 6 pts were inevaluable (toxicity, 4; rapid progression, 1; intercurrent illness) and 11 are too early. 90% of pts who completed 8 weeks of treatment had objective response (21%) or minor response/stable disease (69%). Efficacy in Groups A and B is compared in the table below. Grade 3/4 proteinuria occurred in 10 pts (19%); other grade 3/4 toxicity was uncommon (fatigue 9%, stomatitis 8%). Grade 1/2 toxicities were common including fatigue (68%), skin rash/pruritus (55%), mucositis/stomatitis (49%), hyperlipidemia (45%), nausea (40%), hypertension (25%).

Conclusions: The combination of bevacizumab + RAD001 is active and tolerable treatment for metastatic clear cell RCC. The combination has a
sly treated with sorafenib and/or sunitinib. Better definition of the efficacy of this combination versus single-agent therapy requires comparative trials.

<img1956|center>

Commentary on abstract 5010

Inhibitors of the VEGF and mTOR pathways have shown single-agent activity in advanced RCC. Investigators therefore combined bevacizumab, a VEGF inhibitor, and everolimus, an mTOR inhibitor, to improve efficacy in patients with advanced clear cell RCC. Half of 59 patients had no previous targeted therapy, the remainder having received either sunitinib or sorafenib. The majority received at least eight weeks of bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day. Median length of treatment was six months. No CRs were seen in either untreated or previously treated patients. PRs were achieved in 23% vs. 17% and stable disease in 53% vs. 59% of untreated vs. treated patients, respectively. Patients with no prior nephrectomy had similar responses to the group overall. PFS was again similar in untreated patients at 12 months vs. 11 months in previously treated patients, as was OS at a median of 17 months in the untreated group and 12 months in the treated group. Mucositis and stomatitis were the most troublesome adverse events for patients, as was proteinuria. Unlike most targeted agents when combined, full doses of both drugs could be given in most patients, suggesting the combination was well tolerated as well as active.

Questions and answers with Dr. John Hainsworth, Sarah Cannon Cancer Center, Nashville, Tennessee

Q: How would you compare your responses to other treatment strategies in previously untreated RCC patients?

A: If you look at response rates to sunitinib, studies indicate that in previously untreated patients, there is a 31% response rate and a median PFS of 11 months. Response to the combination of bevacizumab plus IFN, again in previously untreated patients, was 31% in another study, with a median PFS of 10 months. Our response rate in previously untreated patients was 23% with a median PFS of 12 months. So compared to other results, ours look reasonably good in a relatively small number of patients.

Q: Did you observe much hematologic toxicity?

A: No, not surprisingly, there was not much hematological toxicity with these two agents and there was no febrile neutropenia. Of the nine patients that had to discontinue treatment because of toxicity, five discontinued treatment because of proteinuria, so this seems to be somewhat more common than has been previously reported with bevacizumab alone, and as this combination goes forward, this is something we need to continue to watch.