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2006 ASCO Preview
May 30, 2006
This year’s American Society of Clinical Oncology (ASCO) meeting will be held in Atlanta, Georgia between June 2nd and 6th. As in previous years, this year’s meeting will also focus on targeted therapies, particularly kinase inhibitors. Of special interest this year is whether these targeted therapies can be safely combined and if these combinations lead to increased efficacy.
The majority of presentations this year are from smaller studies that either provide additional supportive data or early data in different oncology settings. However, there are a few major phase III presentations this year that should be interesting. We expect the subject of one of these presentations, GlaxoSmithKline’s tyrosine kinase inhibitor Tykerb, to be the star of ASCO this year. A special session has been convened to discuss the role of Tykerb in the treatment of breast cancer. Renal cell cancer will also remain an important topic this year with three presentations of top-line phase III data – for Tykerb, Sutent, and Temsirolimus – expected.
We have outlined some of the more interesting drugs below.
Tykerb (Lapatinib; GlaxoSmithKline)
Tykerb is a novel tyrosine kinase inhibitor however, unlike Tarceva, Sutent or Nexavar, Tykerb not only inhibits the epidermal growth factor receptor (EGFR) pathway, but also the Her2/Neu pathway. The Her2 pathway is upregulated in numerous tumors, including breast cancer and lung cancer, and is targeted by the monoclonal antibody Herceptin (Genentech). With its broader range of targets, Tykerb may offer additional efficacy or another treatment option for patients who have already failed an EGFR kinase inhibitor.
Tykerb is currently in phase III studies for breast cancer and renal cell cancer. In breast cancer, Tykerb is being evaluated in patients who have documented Her2 over expression and who have failed or experienced disease progression on Herceptin. The study to be presented is evaluating Tykerb given in combination with Xeloda (capacitabine) compared to Xeloda given alone. In April 2006, an independent monitoring board recommended that this study stop early due to the study exceeding its primary endpoint of time to disease progression. A special session has been convened at ASCO to discuss results from this study. We expect that this "Special Scientific Session of Lapatinib in Trastumumab Resistant Breast Cancer" will also address the use of Tykerb in breast cancer and the patient population most likely to benefit from Tykerb treatment. These sessions are valuable for educating physicians and thus this potentially helps the uptake of Tykerb should it receive FDA approval.
Tykerb is also being evaluated in other oncology settings, including RCC and hepatocellular cancer. Results from the phase II/III study of Tykerb in RCC will also be presented. Unlike the impressive results expected for breast cancer, the results for RCC are not expected to be so positive. In November 2005, GSK noted that this study did not yield statistically significant results in the overall patient population although a subgroup of patients were identified who did achieve a survival benefit with Tykerb treatment. These patients had EGFR overexpression and these results may help identify the appropriate patient population for Tykerb treatment (which may also be generalized to other cancer indications).
The much anticipated phase III data of Sutent in front-line RCC will be presented at a plenary session at ASCO. The big play at last year’s meeting were data from two tyrosine kinase inhibitors for the treatment of second-line RCC: Pfizer’s Sutent and Onyx’s Nexavar (Sorafenib). That Nexavar data showed that it doubled the progression free survival from 3 months (placebo group) to 6 months (Nexavar group) in a randomized, placebo-controlled study that enrolled over 800 patients. This result is impressive in light of the historically low median survival (6 months) in these cytokine-refractory patients. These results led to the FDA approval of Nexavar in 2005, which became the first drug approved for RCC in over a decade; Proleukin (IL-2; Novartis) was approved in 1992 and was the only drug approved for RCC until Nexavar.
Pfizer’s Sutent had lagged behind Nexavar in development, but it too received FDA approval, only one month after Nexavar. At ASCO last year, interim results from two small phase II studies of Sutent in cytokine refractory RCC were presented. Results from one of the studies (in 63 patients) showed that patients given Sutent achieved a time to disease progression of 8.7 months and median overall survival of 16.4 months. These impressive results led to an expedited FDA approval for Sutent in second-line RCC despite a lack of data from a phase III, placebo-controlled study.
Sutent is currently being evaluated in an open-label phase III study comparing Sutent to interferon-alpha in front-line RCC. Interferon-alpha, while not approved for RCC in the US (although it is in Europe), is often used in the front-line setting. This study being carried out in front-line RCC makes it difficult to compare the results between Sutent’s phase III study and Nexavar’s phase III study. However, Nexavar is currently also being evaluated in front-line RCC, though only in a phase II study. The results from these studies should provide another interesting battle between Sutent and Nexavar, this time in first-line RCC. Should the results of Sutent’s phase III study show that Sutent compares favorably with interferon-alpha, then we expect these results to enhance Sutent's uptake and perhaps expand its off-label use in front-line RCC. If Nexavar’s phase II data looks better, then we can expect Nexavar to enjoy a significant boost.
Sutent is also being evaluated in other oncology settings and data from some of these studies will be presented at ASCO. Of particular interest is preliminary phase II data for the treatment of second-line NSCLC. Given Tarceva's success in NSCLC, there is a good possibility that Sutent may also be efficacious in this setting. This may help expand Sutent's use to a much larger (though more competitive) market.
As mentioned above, interim phase III RCC data was presented at ASCO last year. At this year’s meeting we expect more mature data from this study, particularly overall survival data. While we expect a trend of Nexavar improving overall survival, we do not expect the results to be statistically significant due to the crossover of patients. Following the early cessation of the study in 2005 due to the study meeting its primary endpoint of progression free survival, patients in the placebo arm were allowed to crossover to the treatment group and start Nexavar treatment. This crossover will most negatively impact any survival benefit seen with Nexavar treatment since the placebo group will also have received Nexavar. While we do not expect the survival results to be significant, we feel that a trend is enough to suggest that Nexavar prolongs overall survival.
Nexavar is also being investigated in front-line RCC. Preliminary data from a phase II study evaluating Nexavar in combination with interferon-alpha in first-line and second-line RCC are expected at this year’s meeting, and should the drug combination show activity, it may expand the off-label use of Nexavar in front-line RCC. Moreover, this phase II data will also allow further comparisons between Nexavar and Sutent, albeit this time in front-line RCC patients.
Much like Sutent, Nexavar is also being investigated in other cancer settings, and preliminary data from early phase II studies are expected in NSCLC, hormone refractory prostate cancer (HRPC), ovarian cancer, and breast cancer.
Wyeth’s Temsirolimus is a second generation rapamune, an immunosuppressive drug, used in transplant rejection. Temsirolimus inhibits mTOR kinase, an enzyme involved in cell cycle regulation, and is currently being investigated in several cancer indications including RCC. Results from a phase III study in RCC will be presented at plenary session at ASCO this year. This study is a three-arm study evaluating Temsirolimus given alone against Temsirolimus given in combination with interferon-alpha or interferon-alpha alone. Patients recruited in this study are front-line patients who have a poor prognosis. We expect positive data from this study based on data from a dose-finding phase II study of Temsirolimus in cytokine-refractory patients which showed that patients given Temsirolimus survived for an average of 13.8 to 17.5 months. Despite impressive phase II data, we believe that the use of Temsirolimus may be hampered by the drug’s mode of delivery -- weekly IV infusions. However, if the phase III data looks impressive, we expect Temsirolimus to still be competitive in this market, though it may be more likely to be adopted in patients with a poor prognosis.
A discussion session will follow the presentations of phase III data from Sutent and Temsirolimus in RCC. We believe that this discussion session will reveal more insights into the changing treatment paradigm for RCC. We presume that this session will be valuable in shedding light on the competitive landscape of the RCC market and provide a useful debate on which patients are likely to benefit from these newer agents and how these drugs are likely to be utilized.
Avastin (Bevacizumab; Genentech)
While Avastin is awaiting FDA approval for non-small cell lung cancer (NSCLC) based on positive phase III data presented at ASCO last year, we do not expect any major phase III data of Avastin at this year’s event. However, Avastin is being widely evaluated in numerous oncology settings and we expect data from these early studies at this year’s meeting. These include data for pancreatic cancer, hepatocellular (liver) cancer, and brain cancer (malignant gliomas).
Data of Avastin in renal cell cancer (RCC) are also expected, though these are probably more mature data from the exploratory phase II study comparing Avastin alone or in combination with Tarceva. Preliminary results from this study presented in 2005 showed that the addition of Tarceva did not enhance the efficacy over Avastin given alone. However, there is a small possibility that preliminary data from the phase III study of Avastin in front-line RCC (CALGB 90206) may be a late breaking abstract at ASCO. This study is evaluating the addition of Avastin to interferon alpha compared to interferon alpha alone. Since this study completed enrollment in July 2005 there is a possibility that preliminary data from this study (which is event driven) may be ready in time for ASCO (though the company has not indicated this to be the case). Based on positive phase II data, we predict that the results from this study, whether or not they will be presented at ASCO, will be positive.
One of the focuses at this year’s meeting is the combination of targeted therapies. These tend to revolve around the use of Avastin with a tyrosine kinase inhibitor. There are several presentations of the combination of Avastin plus Tarceva and these have been evaluated for the treatment of colorectal cancer, ovarian cancer and RCC. One of the most interesting presentations, in our view, is the combination of Avastin and Tarceva in the treatment of NSCLC. This study compares the efficacy of Avastin when given in combination with chemotherapy to that of Avastin given with Tarceva. Data from this phase II study is likely to shed light on whether patients can take these two targeted therapies together, and potentially bypass chemotherapy, or whether chemotherapy is still required for Avastin’s efficacy. If the combination of Avastin and Tarceva can demonstrate equivalent efficacy to the Avastin/chemotherapy combination, this may potentially alter the treatment paradigm for NSCLC (since we believe that Avastin plus chemotherapy is set to become the standard of care for front-line non-squamous NSCLC).
Tarceva (Erlotinib; OSI Pharmaceuticals)
The majority of presentations on Tarceva will focus on identifying the appropriate patient population likely to benefit from Tarceva treatment. However, a few presentations on Tarceva may help to address Tarceva’s potential benefit in front-line NSCLC patients. As mentioned above, we expect top line data from the phase II study of Tarceva plus Avastin in front-line NSCLC patients. There is much hope that these new targeted therapies may allow patients to avoid toxic chemotherapy. If the results of this study are positive, we expect some off-label use of Tarceva in front-line NSCLC as a result. The use of Tarceva in front-line NSCLC is also being addressed in other presentations that do not include the use of Avastin. These studies will help to determine the role of Tarceva in front-line patients, perhaps in those not eligible for Avastin (such as those with Squamous NSCLC).
At last year’s meeting, Tarceva demonstrated that it can improve survival in patients with pancreatic cancer. The drug was approved for this disease in late 2005. Tarceva represents the first drug to show a survival benefit in this disease since Gemzar (Gemcitabine; Eli Lilly). At this year’s meeting, preliminary results from a phase II study evaluating the combination of Tarceva and Avastin will be presented. This study will also help to address the issue of whether these two targeted therapies can be combined for increased effectiveness.
While results from Amgen’s RANK ligand inhibitor for osteoporosis are not expected until 2008, early results from the phase II bone metastases studies will be presented at ASCO. The study was only designed to be a dose-finding study, but Amgen has indicated that some efficacy (on bone turnover and skeletal-related events) has also been seen in this study. These results may give important insights into the ongoing phase III studies of Denosumab in bone metastases.