With the craziness of the 41st annual American Society of Clinical Oncology (ASCO) meeting over, we have combed through the multitude of data to highlight some of the many interesting presentations that we attended. As we predicted, Avastin and Revlimid were the big stars of the meeting, however, the debate surrounding Sorafenib and Sutent for renal cell cancer also featured prominently. To wrap up the meeting, we have summarized some of the pertinent studies below.

Revlimid (Lenalidomide; Celgene)
Surprisingly for ASCO, hematologic cancers took center stage at this year’s meeting. Data of Revlimid in three different diseases were presented at ASCO: chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS). The results from the MDS and the MM studies were particularly important with both studies suggesting a dominant role for Revlimid in the treatment of these diseases.

Revlimid in myelodysplastic syndrome (MDS)
Eagerly awaited data from the pivotal phase II MDS-003 study of Revlimid in 5q deletion MDS patients were presented at ASCO. Very early preliminary data were presented at the American Society of Hematology meeting in December 2004. At ASCO, more mature interim data were presented which confirmed the earlier findings. In contrast to clinical studies with Vidaza (Azacitidine; Pharmion) and Dacogen (Decitabine; SuperGen), which focused on high risk MDS patients, Revlimid is being studied in low to intermediate risk patients. Approximately 90% of these patients are anemic and require blood transfusions to survive. Thus, the study endpoint of MDS-003 is an erythroid response, which when sufficient, can lead to independence from blood transfusions.

In these low to intermediate risk patients, a total of 75% of patients responded (overall response) to Revlimid therapy. Revlimid was shown to increase blood hemoglobin levels by a median of 5.3g/dl in these patients which resulted in a total of 66% of patients becoming transfusion independent, meaning that they no longer required blood transfusions. Revlimid also produced a cytogenetic response in 71% of patients, with 36% of patients achieving a complete cytogenetic response resulting in the restoration of bone marrow histology. The response to Revlimid was also durable with median duration of treatment not yet reached at 58 weeks post treatment initiation.

Toxicity of Revlimid in MDS patients have been a concern, however as reported at ASH 2004, only 2 patients (1%) have died as a result of Revlimid treatment which were related to neutropenia. Since MDS patients have an annual mortality rate of 10%, the 1% treatment-related death seen in this study is well within the acceptable range. Most of the adverse events related to Revlimid (myelosuppression in particular) were manageable with dose reductions or treatment interruptions.

Given the acceptable safety profile presented and the high rate of transfusion independence achieved, we believe that Revlimid will become the gold standard of treatment in low to intermediate risk MDS patients with 5q deletion. Revlimid is currently in an ongoing phase II study evaluating its efficacy in patients with non-5q deletion MDS, however, early data suggests that it is more efficacious in 5q deletion patients. We expect Revlimid to gain FDA approval for MDS in October 2005.

Revlimid in multiple myeloma (MM)
Revlimid is currently in pivotal phase III studies for the treatment of relapsed/refractory multiple myeloma. Results from the two special protocol assessments (SPA) trials, MM009 and MM010, were presented at ASCO. The trials were identical in design except MM009 was carried out in the U.S. while MM010 was international. Both trials evaluated Revlimid in combination with Dexamethasone compared to Dexamethasone alone. On March 7, 2005, it was announced that the Independent Data Monitoring Committee recommended halting both trials due to the interim results meeting the studies’ endpoint of time to disease progression. The results presented at ASCO showed that the addition of Revlimid to Dexamethasone prolonged progression-free survival from 5.1 months to 15 months and 13.3 months for MM009 and MM010, respectively (with a p<0.000001 for both studies). Time to disease progression is thought to be a good surrogate marker for overall survival and was the endpoint used for Velcade’s approval in multiple myeloma.

Based on the results presented here, we believe that Revlimid will gain FDA approval for this indication by the end of 2005 or early 2006 and for Revlimid to become the gold standard treatment for second-line multiple myeloma patients. Due to its more favorable safety profile, we expect Revlimid to erode Velcade’s market share once it comes onto the market. It will be interesting to see how efficacious Revlimid is in the first-line setting and whether it can displace Thalomid’s (Thalidomide; Celgene) dominance in this indication.

Avastin (Bevacizumab; Genentech)
While multiple trials of Avastin were presented at ASCO, the two studies that generated the most interest were in non-small cell lung cancer (NSCLC) and breast cancer.

Avastin in non-small cell lung cancer
In the pivotal ECOG 4599 phase III study evaluating Avastin in combination with paclitaxel and carboplatin, the addition of Avastin to chemotherapy improved the response rate, the median time to disease progression and median overall survival over chemotherapy alone. Toxicity with Avastin is a concern since it can induce life-threatening bleeding, and in this study, 4.5% of grade 3 or 4 hemorrhages were reported. While still higher than for other therapies, the hemorrhagic adverse event rate is lower in this study than in earlier studies of Avastin in NSCLC, most likely due to the exclusion of patients with hemoptysis or squamous NSCLC. Thus, when patients with a high risk of bleeding were excluded, Avastin appears to be relatively well tolerated.

While survival results from this study were announced previously, the demonstration that Avastin significantly prolonged overall survival in front-line NSCLC from 10.2 months to 12.5 months is of great importance. This is the first study in which a targeted therapy has been shown to improve overall survival in NSCLC, which is a very difficult to treat and aggressive disease. Therefore, these results suggest that Avastin will become the most important targeted therapy in front-line non-squamous NSCLC.

While the results are impressive, there was much concern and debate regarding the cost of Avastin at ASCO, which muted some of the enthusiasm over the positive results. Given the current pricing of Avastin in colorectal cancer and the higher dosages used in NSCLC, Avastin will cost approximately $100,000 per patient for this indication. Many physicians felt that the debate will not be whether Avastin will benefit these patients, but rather these patients will spend that much money for an additional 2 months of survival. We believe the most important factor in this debate is whether the cost of Avastin will be subsidized.

Avastin in breast cancer
At a special late-breaking session at ASCO, results of Avastin and Herceptin in breast cancer were presented and commented on. The ECOG 2100 study of Avastin (in combination with paclitaxel) in front-line, mostly HER-2 negative, breast cancer showed that the addition of Avastin to paclitaxel significantly improved progression-free survival from 6.1 months to 11 months. Avastin also showed a trend towards improving overall survival although the data is yet too immature to tell.

This study is significant in being the first large study of Avastin in breast cancer that demonstrated a significant survival benefit. The first phase III study of Avastin in breast cancer failed to meet its primary endpoint of improving progression free survival, however, in that study, Avastin was used in combination with Xeloda (Capecitabine; Roche) and the study also enrolled HER-2 positive breast cancer patients. While we don’t know why Avastin worked in this setting but not in the previous setting (see event for more details), the results from ECOG 2100 suggests that Avastin will become a major therapeutic option in front-line metastatic breast cancer in HER-2 negative patients.

Herceptin (Trastuzumab; Genentech)
As mentioned above, Herceptin in breast cancer was featured at a special late-breaking session at ASCO. While Herceptin has already been approved as a front-line therapy for HER-2 positive metastatic breast cancer, compelling data from 3 studies were presented at ASCO that suggests Herceptin should be used in women with HER-2 positive earlier breast cancer in the adjuvant setting. The 3 trials were the NSABP-B31, NCCTG-N9831, and HERA studies. While the studies are still ongoing and data is maturing, the interim data presented at ASCO were highly compelling.

The first two studies (NSABP and NCCTG) were initiated separately but were combined for data analysis. In the analysis of these 2 studies on 3,351 patients, Herceptin improved disease-free survival with a hazard ratio of 0.48, meaning that there was a 52% reduction in risk of disease progression in patients given Herceptin. Herceptin also reduced the risk of developing a distant metastasis (HR=0.47) in these patients. In a separate study, the HERA study, which enrolled 5090 women with HER-2 positive breast cancer, Herceptin again showed that it prolongs disease-free survival (HR=0.54) and slow the time to developing a distant metastasis (HR=0.51).

While both studies are still too early for survival analyses, they both show a trend towards improving overall survival in patients given Herceptin. Given the size of these trials and the overwhelming positive data that were consistent between the studies, we believe that Herceptin will now be advocated in the adjuvant setting in HER-2 positive cancer, expanding it’s use considerably.

Sutent (SU-11248; Pfizer)
Sutent is a tyrosine kinase inhibitor inhibits the VEGF and PDGF pathways. It is currently in phase III studies for gastrointestinal stromal tumors (GIST) and renal cell carcinoma (RCC).

Sutent for Gastrointestinal Stromal Tumors (GIST)
The phase III study of Sutent in Gleevec (Imatinib)-resistant GIST was halted early as recommended by the study’s independent data monitoring board due to the study meeting its primary endpoint. Data presented at ASCO showed that Sutent significantly prolonged time to disease progression (6.3 months compared to 1.5 months for placebo control). While survival evaluation is still ongoing, patients given Sutent are showing a trend towards improved survival as well. Based on this positive data, Sutent is expected to receive FDA approval for this indication in early 2006.

Sutent for Renal Cell Cancer (RCC)
While a phase III study of Sutent in front-line RCC has been initiated, phase II results in second-line RCC were presented at ASCO. In two sequentially conducted phase II studies in metastatic second-line RCC, treatment with Sutent resulted in an overall response rate of 40% and 39% in trial 1 and 2, respectively. While progression-free survival is not yet available for Study 2, in the first study, treatment with Sutent resulted in a progression-free survival of 8.7 months, which compares favorably to Onyx’s Sorafenib. The studies are ongoing for overall survival analysis. Sorafenib (BAY 43-9006; Onyx)
Sorafenib is a tyrosine kinase inhibitor that has activity against the RAF kinase pathway as well as VEGF and PDGF pathways. It is currently in phase III studies in second-line metastatic renal cell cancer (RCC) and on March 21, 2005, the pivotal phase III study was halted due to the study meeting its primary endpoint. The interim results presented at ASCO showed that Sorafenib doubled progression-free survival to 24 weeks (6 months) from the 12 weeks observed in the placebo arm. Based on this positive data, an NDA is expected to be submitted in the coming months and Sorafenib is expected to receive FDA approval for metastatic RCC in early 2006.

While Sorafenib has definite first-to-market advantage for RCC, it would appear that from the phase II studies of Sutent in RCC that Sutent is more efficacious than Sorafenib. Patients given Sutent achieved a median time to disease progression of 8.7 months compared to 6 months with Sorafenib treatment. However, it must be cautioned that Sorafenib was evaluated in a phase III placebo-controlled study that included analyses on 769 patients. In the case for Sutent, it has only been evaluated in small phase II studies that enrolled a total of 169 patients. More importantly, these phase II studies of Sutent were not placebo-controlled. While a direct comparison between the 2 drugs is not possible without a head-to-head study or at least a placebo-controlled study for Sutent, the more impressive time to disease progression seen with Sutent does suggest that Sutent will be used off-label for RCC once it gets approved for GIST. However, we believe that there is room in the RCC market for both drugs and that Sorafenib should get a sizeable market share with it’s first-to-market advantage. We also believe that the final overall survival analyses of both drugs will play heavily on how these two drugs will compete in this market.

Early drugs to keep an eye on
AP23573 (Ariad)
Early data from three studies of Ariad’s mTOR inhibitor, AP23573, were presented at ASCO, with the most compelling data coming from the study in sarcoma. In the phase II study in 4 different types of sarcomas, AP23573 demonstrated clinical efficacy in 3 types of sarcomas (bone sarcoma, leiomyosarcoma, and other soft tissue sarcomas) with some patients achieving stable disease and partial responses. Due to the positive results, the study is recruiting more patients to allow for a better evaluation of clinical efficacy. While the study is ongoing and these results are still early, given the lack of effective therapy for sarcoma, AP23573’s positive data places it in a competitive position for this difficult to treat disease.

Perifosine (KRX-0401; AEterna Zentaris and Keryx)
Results from a phase II study of Perifosine in androgen-dependent (hormone sensitive) prostate cancer was presented at ASCO. The study’s primary endpoint was PSA response, defined as a greater than 50% reduction in PSA levels from baseline, with a secondary endpoint of PSA doubling time. The study did not meet its primary endpoint with none of the patients demonstrating a greater than 50% reduction in PSA levels. Moreover, Perifosine did not modulate PSA doubling time. While the company is trying to determine how best to carry the Perifosine in prostate cancer program forward, these results were disappointing and does not bode well for the drug.

Telcyta (TLK286; Telik)
Telik presented positive interim data from its phase I/II study of Telcyta in front-line non-small cell lung cancer (NSCLC). In this study Telcyta, given in combination with cisplatin, resulted in a 36% objective response rate and an 86% disease stabilization rate. Responses were seen in all NSCLC subtypes including squamous cell carcinoma. At the time of analysis, median survival had not yet been reached. While the studies are early, these results are encouraging and should bode well for the ongoing phase III study.

Vitaxin (MEDI-522; MedImmune)
Vitaxin is a monoclonal antibody directed against alpha-V-beta-3 integrin that is currently in phase II studies for melanoma and prostate cancer. Results from the melanoma study were presented at ASCO. In this study, Vitaxin was given alone or in combination with DTIC (the standard treatment for metastatic melanoma) in patients with end-stage (Stage IV) metastatic melanoma. Interim data demonstrated that the addition of DTIC to Vitaxin improved progression-free survival to 78 days compared to the 42 days with Vitaxin alone. In contrast, Vitaxin alone yielded a better overall survival of 12.7 months compared to the 9.4 months seen with the combination of Vitaxin and DTIC. The results were rather confusing in that Vitaxin alone was better for overall survival but Vitaxin in combination with DTIC yielded better progression-free survival. However, while the results are very preliminary, it suggests that Vitaxin has clinical efficacy in metastatic melanoma.