This year’s American Society of Clinical Oncology (ASCO) annual meeting was held from June 2-6 in Atlanta. While few surprises were expected at the meeting, we have highlighted some of the more salient presentations below. In addition, we have summarized the changing treatment paradigm based on these presentations as well as our discussions with thought leaders.

To access other ASCO events not included in this report, please click here and search using the keyword "ASCO". Please note that we are still in the process of adding additional abstracts.

Breast cancer

Tykerb (Lapatinib; GlaxoSmithKline) – phase III study

This pivotal phase III study evaluated Tykerb, a novel EGFR tyrosine kinase inhibitor that also inhibits Her2/neu, in women with Her2-positive metastatic breast cancer who have failed Herceptin or other therapies. Herceptin is the standard of care for patients with Her2-positive breast cancer. This study met its primary endpoint of time-to-disease progression (TTP), with the results demonstrating that the addition of Tykerb to Xeloda (capecitabine) increased the TTP from 19.7 weeks (with Xeloda given alone) to 36.9 weeks (for the combination regimen). The effects of Tykerb on overall survival (OS) did not appear to be significant, but these results are still premature.

These results show that Tykerb, in combination with Xeloda, is an effective regimen and is significantly superior to Xeloda monotherapy in women with Her-2 positive breast cancer. Following the presentation of these results, it was recommended that this new treatment regimen form the new standard of care in women with Her2-positive breast cancer who are either intolerant of, or who have progressed on, Herceptin.

Interestingly, Tykerb appears to reduce the occurrence of brain metastases. The CNS is a common site for metastasis in patients with breast cancer and a reduction in this event may improve patient quality of life and survival. Herceptin has little effect on brain metastases since it is a monoclonal antibody that cannot cross the blood-brain barrier, whereas Tykerb, a small molecule, is thought to be able to penetrate the blood-brain barrier. Results from this phase III study showed that Tykerb did appear to reduce the risk of brain metastases (11 patients with CNS relapse in the Xeloda group compared to 4 patients in the combination group), although the results were not statistically significant. Further studies are being carried out to investigate the effects of Tykerb on the risk of brain metastases. This drug combination addresses an important disease event in breast cancer and will likely be considered for patients with Her2-positive breast cancer at risk of brain metastases.

Since Tykerb inhibits the Her2 pathway (the same target of Herceptin), it is probable that Tykerb will also be useful in earlier disease. However, these studies still need to be carried out. In the interim, we foresee Tykerb being primarily used in Herceptin-refractory patients. However, we speculate that two patient populations in particular will find Tykerb more attractive than Herceptin (and may use Tykerb off-label in earlier settings): those at risk of developing brain metastases and those at risk of cardiotoxicity. While some cardiac adverse events were seen in the Tykerb arm in this phase III study, these were not as frequent as those seen with Herceptin (especially when Herceptin is given with an anthracycline), making Tykerb a more attractive option for patients at risk of cardiovascular events.

Renal Cell Cancer

Targeted therapies in renal cell cancer (RCC) were again the hot topic at this year’s meeting. We outline here some of the important data, our conversations with genitourinary (GU) oncology specialists, and the implications for the RCC market in the summary at the end of this section.

Tykerb in second-line RCC – phase III data

This phase III study evaluated Tykerb monotherapy against hormone therapy. The investigators chose hormone therapy because at the time of study initiation, a standard of care in second-line was not established and hormone treatment was deemed at the time to be the most consistent and acceptable approach across Europe, where the study was conducted. The study enrolled 417 previously treated patients with tumors expressing EGFR (ErbB1) or Her2/neu (ErbB2) as identified by immunohistochemistry. The results showed that Tykerb had comparable efficacy with respect to TTP and OS to hormone therapy. TTP was 15.4 and 15.3 weeks and OS was 43.1 and 46.9 weeks for the hormone therapy and Tykerb arms, respectively. However, Tykerb was associated with markedly more toxicity than hormone therapy.

A subset analysis found that Tykerb appeared to improve OS in patients that strongly overexpress EGFR (ErbB1 3+). Approximately half of the patients in each treatment arm strongly express EGFR and in these patients, an increase in OS was seen in patients given Tykerb (39 weeks for hormone therapy versus 46 weeks for Tykerb). This survival benefit in EGFR-overexpressing patients need to be verified by a prospective trial. Overall, the results show that Tykerb has limited utility in the general RCC patient population.

Avastin (Bevacizumab; Genentech) and Tarceva (Erlotinib; OSI) in first-line RCC – phase II data

Updated 2-year results from this phase II study, which evaluated Avastin given alone against Avastin given in combination with Tarceva, showed that the addition of Tarceva to Avastin provides little in the way of added benefit to the patient. Results from this study showed that Avastin monotherapy resulted in an objective response rate of 13% and a progression-free survival (PFS) of 8.5 months compared to an objective response rate of 14% and PFS of 9.9 months for Avastin plus Tarceva. The OS for the combination arm was 20 months while the OS has not yet been reached in the Avastin arm. The shorter survival in the Avastin and Tarceva arm is perhaps attributable to an increase in toxicity that may have resulted in a shorter OS (indeed, there 23 deaths to date in the combination arm and 20 deaths in the Avastin arm). However, the OS data is still immature.

Avastin monotherapy shows good activity in first-line metastatic RCC, with the results comparing favorably with the standard front-line therapies for RCC (high dose IL-2 and IFN yield a median PFS of 3.1 months and 4.7 months, respectively). Further studies of Avastin monotherapy in first-line RCC are warranted, but these results do show that the addition of Tarceva does not enhance the efficacy of Avastin.

Nexavar (Sorafenib; Onyx) in second-line RCC – phase III data

Updated survival data from the pivotal phase III study (TARGETs) in second-line RCC showed that Nexavar increased OS from 15.9 months for the placebo group (best supportive care) to 19.3 months. These results were not as statistically significant as expected given the crossover of patients from the placebo group to Nexavar treatment in 2005. Despite the lack of significance, these results are the first to show a survival benefit in second-line patients with metastatic RCC and provide further support for the use of Nexavar in these patients.

Nexavar in first-line RCC – phase II data

Interim efficacy data on the randomized phase II trial evaluating the efficacy and tolerability of Nexavar against interferon alpha (IFNa) in first-line therapy of patients with clear-cell RCC were expected at this year’s meeting, because an interim analysis of the study was expected when 99 PFS events had occurred. However, during the slotted presentation, the presenter noted that the independent data committee that conducted the interim analysis recommended that the number of PFS events increase from 99 to 140 due to the high number of censored patients (at the time of data cut-off on March 15, 2006, only 87 PFS events have occurred as deemed by the data safety monitoring board). Consequently, no efficacy data was available at the meeting. The presenter noted that 140 events are expected to occur by the end of 2006.

While results from this study are still immature, insight into the efficacy of Nexavar in first-line metastatic RCC may be gleaned from the RDT discontinuation trial. The discontinuation trial evaluated Nexavar in 502 patients. Of these patients, 202 had metastatic RCC and of these 202 patients, 32 had no prior systemic therapy. In this 32 first-line patient subgroup, Nexavar produced a median PFS of 40 weeks (9.3 months). Since IFNa has shown a PFS of 4.7 months in previous studies, it is very likely that Nexavar can improve PFS, although the extent of this improvement is not yet known.

Sutent (Sunitinib; Pfizer) in first-line RCC – phase III data

Following the approval of Sutent in second-line RCC based on positive data from two small phase II studies, top-line phase III data in first-line metastatic RCC was presented at this year’s meeting. This phase III study, in 750 previously untreated patients, affirmed that Sutent monotherapy is superior to IFNa monotherapy, the current standard of care for the first-line treatment of metastatic RCC. Sutent resulted in a significantly higher response rate than IFNa, although no complete responses were observed (as assessed by the independent central review, although one complete response was seen in the investigator review). Sutent also significantly prolonged the PFS, the primary endpoint of the study, with patients treated with Sutent achieving a PFS of 11 months compared to 5 months with IFNa treatment. The 5 month PFS seen with IFNa is similar to prior studies evaluating IFNa. Sutent was associated with some serious adverse events, but these were deemed to be acceptable and manageable.

These results are the first ever demonstrating a targeted therapy to be efficacious in first-line metastatic RCC. These results also justify the expedited FDA approval of Sutent in January this year for the treatment of second-line RCC .

Temsirolimus (Wyeth) in first-line RCC – phase III data

The efficacy and safety of Temsirolimus were evaluated in a randomized phase III study in first-line patients with a poor prognosis (Karnofsky performance status of 60 or greater). This was a three-arm study that evaluated Temsirolimus given alone, Temsirolimus given in combination with IFNa, and IFNa given alone.

Temsirolimus monotherapy was not only better tolerated than IFNa, but was also more efficacious than IFNa: Temsirolimus monotherapy improved the objective response rate and significantly increased both the PFS and OS compared to IFNa. Patients given Temsirolimus monotherapy experienced a 3.6 months improvement in OS when compared to IFNa monotherapy (10.9 months versus 7.3 months). This result was statistically significant and corresponds to a 49% decrease in the risk of death.

Interestingly, the combination of Temsirolimus plus IFNa did not fare better than Temsirolimus monotherapy with regards to OS (1.1 month improvement over IFNa) although it did produce similar PFS data to those seen with Temsirolimus monotherapy. This may be due to the lower dose of Temsirolimus used in this combination arm, which may have compromised efficacy.

These results make Temsirolimus the first agent to show a statistically significant increase in OS in first-line RCC (IFNa has only demonstrated a small survival advantage, which is seen primarily in good prognosis patients). Note that while the PFS data in the Sutent phase III study is impressive, Sutent has yet to demonstrate a significant overall survival advantage. Based on these results, Temsirolimus will likely become the treatment of choice for treatment-naive RCC patients with a poor prognosis.

Comments for the changing RCC market

This is a very exciting time for the treatment of metastatic RCC. Metastatic RCC is a notoriously difficult disease to treat and is associated with a poor prognosis, with only a quarter of patients surviving one year. Until recently, the mainstay therapy for RCC was either high dose IL-2 or IFNa, both of which are used in the front-line setting and both of which are associated with serious toxicity. While IFNa is not FDA approved in the US, it is the reference standard for clinical trials since it is the only drug (until now) to have shown a survival benefit in a phase III study (high-dose IL-2 has not demonstrated a survival benefit in the overall patient population). Clinical studies have shown IFNa to produce a response rate ranging from 7.5% to 15% and a median PFS of 4.7 months. High dose IL-2 produces a median PFS of 3.1 months.

Until recently, there was little recourse for patients who failed IFNa or IL-2. Apart from these two cytokines, all other agents tested including chemotherapy have failed to show a benefit in patients with metastatic RCC. However, data from the last few ASCO meetings are set to change the way metastatic clear-cell RCC will be treated. Note that all these studies have been carried out in clear cell RCC, the most common type of RCC, accounting for 70-80% of RCC. It is too early to tell whether these agents are also effective in the other RCC subtypes.

At ASCO last year, data presented on Sutent and Nexavar showed that these two tyrosine kinase inhibitors (TKIs) have activity in second-line RCC. Indeed, Nexavar was the first agent to show an improvement in PFS in a placebo-controlled study. These results led to the approval of both Nexavar and Sutent for second-line RCC (in patients who have already failed cytokine therapy). Sutent’s approval was based on data from two small uncontrolled phase II trials.

Following their approval for second-line therapy, the emphasis now is whether these new targeted therapies have a role in the first-line treatment setting. Three important talks on clinical trials in first-line RCC were given at ASCO this year (the Avastin study was first presented two years ago): Nexavar phase II, Sutent phase III and Temsirolimus phase III. All three studies were carried out in patients with clear cell metastatic RCC, and all three studies compared the active drug to IFNa.

While the phase II data of Nexavar in the front-line setting is still too immature, data from the discontinuation trial suggests that Nexavar may improve PFS. Both Sutent and Temsirolimus clearly demonstrated a significant improvement in PFS compared to IFNa in their phase III studies. Sutent has yet to show a benefit on OS (data still too immature) although a trend towards a survival benefit was noted. In contrast, Temsirolimus clearly demonstrated an improvement in OS over IFNa, making Temsirolimus the first drug since IFNa to demonstrate a significant OS benefit.

Interestingly, these results indicate that TKIs targeting angiogenesis (Sutent and Nexavar) are efficacious in RCC while TKIs targeting the EGFR pathways (Tykerb and Tarceva) are not. The anti-angiogenic properties of Sutent and Nexavar are thought to be an important mechanism for the effects seen in RCC since the monoclonal antibody Avastin, which directly targets angiogenesis by binding to VEGF, has good activity in RCC. Indeed, the anti-angiogenic properties of Temsirolimus may also account for its effect in RCC. Temsirolimus inhibits mTOR (mammalian target of rapamycin), a signaling protein involved in cell division and angiogenesis. Based on the limited activity seen with Tarceva and Tykerb, it can be assumed that targeting the EGFR pathway is not clinically useful in RCC.

Taken together, these results suggest a paradigm shift in the way metastatic RCC will be treated. Following the multiple presentations on RCC at ASCO, genitourinary (GU) oncology specialists all appeared to agree on the following for the treatment of first-line metastatic RCC patients:

• IFNa should no longer be considered, given the superior efficacy of Sutent and Temsirolimus and the high toxicity burden of IFNa;
• In patients with good to intermediate prognosis, Sutent or high dose IL-2 (in appropriate patients) should be utilized; and
• In patients with poor prognosis, Temsirolimus should be prescribed.

High-dose IL-2 still has a place in the treatment of RCC since it can produce a durable response (equating to remission) in a small percentage of patients (these responsive patients may be identified by assays for proteins such as carbonic anhydrase IX). For patients who are unlikely to respond to high-dose IL-2, Sutent or Temsirolimus should be encouraged depending on the patient’s performance status. Thus, Sutent and Temsirolimus are set to become the new standard of care for first-line RCC patients.

While these new recommendations bring welcomed changes to the way RCC will be treated, more research is still needed to determine which targeted therapy is best for which patient subgroups and the best order in which to give these drugs. These drugs do not cure RCC but merely prolong PFS or OS. Accordingly, patients will eventually progress on these therapies and more studies are needed to determine the sequence of drugs for patients who have progressed. For example, in patients who have failed Sutent in the front-line setting, should Avastin or Nexavar be tried next? Or if patients used Avastin first, which TKI should be followed or whether a TKI will work after a patient has already failed Avastin (results from the Sutent in Avastin-refractory patients suggest that indeed they can). These are some of the many questions raised from these presentations and we look forward to new research that may address them at future ASCO meetings.

Conversations with GU specialists

Despite a lack of data in the first-line setting, after speaking to a number of GU specialists at the meeting, we believe that Nexavar will also likely to be used in the first-line setting. These specialists indicated that while both Sutent and Nexavar have toxicities, Sutent is associated with severe fatigue that leads to many patients discontinuing the drug. Many of these physicians believe that Sutent and Nexavar are probably equivalent in their efficacy and that fatigue is a big consideration since it can severely negatively impact the patient’s quality of life. These specialists indicated that they would not hesitate to prescribe Nexavar for first-line patients instead of Sutent if they consider fatigue to significantly impact their patient’s quality of life. Thus, while data for Nexavar in the front-line setting is still immature, the positive data from Sutent is likely only to boost the use of Nexavar in the first-line setting.

Moreover, Pfizer lacks a sales force that is specifically responsible for Sutent for RCC and many physicians have indicated that Onyx’s Nexavar sales force is doing a good job at educating physicians. In addition, many of the GU thought leaders indicated that they have a better relationship with Onyx since the company has willingly distributed all clinical data (for detailed scrutiny) while the same cannot be said about Pfizer. Taken together, these factors suggest that there will be significant off-label use of Nexavar in the first-line setting.

Temsirolimus should also compete effectively in this first-line RCC market. While we initially thought that the IV administration could hamper the drug’s uptake, it became clear at ASCO that many physicians believe that this once weekly administration was not viewed unfavorably by many of their patients. Moreover, in the US, physicians are reimbursed for IV procedures and not for prescribing pills (such as Sutent or Nexavar). These considerations lead us to believe that Temsirolimus may enjoy a better uptake than previously expected.

We are in the process of updating our RCC drug revenue models.

Non-small cell lung cancer (NSCLC)

Tarceva in first-line NSCLC in patients with good performance status – phase II study

In this study, first-line patients with a good performance status (ECOG 0-1) were given Tarceva until disease progression, upon which they received chemotherapy. This treatment regimen resulted in a PFS of 28.6 weeks (6.6 months) and a median survival of 49 weeks (11.3 months). These results compare well with doublet chemotherapy and suggest Tarceva monotherapy should be further explored in this patient setting.

Tarceva in first-line patients with performance status of 2 – phase II study

A phase II study was carried out to evaluate Tarceva in front-line patients with a poorer prognosis (ECOG PS 2). This randomized phase II study compared Tarceva monotherapy to the widely used chemotherapy doublet carboplatin and paclitaxel (CP). While the results indicate that Tarceva monotherapy produced results comparable to that of single agent chemotherapy, Tarceva monotherapy was inferior to CP doublet with respect to PFS and OS.

Avastin and Tarceva in second-line NSCLC - phase II study

This 3-arm phase II study compared Avastin given in combination with Tarceva, Avastin given in combination with chemotherapy, or chemotherapy alone in second-line NSCLC patients. The data showed that the combination of Avastin and Tarceva was equivalent to the combination of Avastin plus chemotherapy in refractory NSCLC patients. While the results of Avastin plus Tarceva were not statistically superior to Avastin plus chemotherapy, the Avastin plus Tarceva arm appeared to be better tolerated.

These results show that Tarceva can be safely combined with Avastin and that this combination may provide an alternative to chemotherapy based-regimens in NSCLC. While chemotherapy is likely to remain a mainstay therapy in NSCLC, given the toxicity of chemotherapy and the better toxicity profile of the Avastin plus Tarceva combination, this drug combination may become an important treatment option for patients who cannot tolerate chemotherapy. However, this study evaluated this drug combination in second-line patients who have failed chemotherapy. Given that Avastin (in combination with chemotherapy) is set to become the new standard of care in first-line non-squamous NSCLC, further studies are required to see how this drug combination fits into the new treatment paradigm (in patients who have failed Avastin in the front-line setting).

Zactima (AstraZeneca) in second- and third-line NSCLC - phase II study

Zactima is a novel tyrosine kinase inhibitor that blocks both the EGFR and the VEGF signaling pathways. A phase II crossover study in second- and third-line NSCLC was presented in which patients were first randomized to receive either Iressa or Zactima. After disease progression, patients had a 4-week washout period and were then eligible for the alternative treatment. The first part of this study showed that single agent Zactima exhibits activity in NSCLC, with a PFS of 11 weeks (compared to 8.1 weeks with Iressa). In a subset analysis, adenocarcinoma patients had better PFS than other histologies though this did not translate into better OS.

After patients were crossed over to the alternative treatment, it appeared that post-crossover, no additional responses were seen. OS was not significantly different between the two treatment groups, though it appears that patients who were given Iressa first and Zactima second did better than patients who started on Zactima first. However, the OS data is likely to have been confounded by the crossover design.

These results warrant further investigation. While Zactima monotherapy appears to possess activity in NSCLC, this activity may be improved if the drug is combined with either chemotherapy or another targeted agent. The 11 week PFS seen with Zactima treatment compares favorably with other targeted agents (11.3 weeks with Sutent and 11.9 weeks with Nexavar in small phase II studies). However, single agent chemotherapy (docetaxel and premetrexed) has demonstrated a PFS of 12.6 weeks in a similar patient population. Given the slightly better PFS with chemotherapy, it is likely that Zactima will need to be given as a combination therapy. Encouragingly, no hemorrhage was seen in this study with Zactima treatment (hemorrhage is a serious adverse event seen with other VEGF inhibitors including Avastin and Nexavar). Overall, we are encouraged by the PFS data and the lack of hemorrhage.

Sutent in second- and third-line NSCLC - phase II study

Sutent is currently being investigated in phase II studies in both first-line and refractory NSCLC patients. Results from the study in refractory NSCLC were presented at this year’s meeting. Top-line data from this open-label study showed that Sutent has single-agent activity in previously treated patients with recurrent and advanced NSCLC (who have not had prior antiangiogenic therapy). Sutent administration resulted in an objective response rate of 9.5% and a PFS of 11.3 weeks. These results are comparable to other studies of single agents in this patient population. Sutent was generally well tolerated although three patients had hemorrhage-related deaths (given the increase in hemorrhage seen with Avastin treatment, hemorrhage may be a class effect with VEGF inhibitors). Overall, the results were encouraging.

Nexavar in second- and third-line NSCLC - phase II study

Updated results from the ongoing single-arm phase II study of Nexavar in previously treated patients with recurrent and advanced NSCLC showed that Nexavar treatment resulted in a PFS of 11.9 weeks and an OS of 29.3 weeks. Nexavar was well tolerated although three patients had epistaxis and one patient died of pulmonary hemorrhage. Given the tumor cavitation and hemorrhage seen with Avastin and Sutent in NSCLC patients, it would appear that hemorrhage is a class effect with VEGF inhibitors. Therefore, the issue of cavitation and bleeding requires further evaluation and careful monitoring during treatment.

Summary of NSCLC presentations

In studies attempting to assess the utility of Tarceva in the first-line setting, the results show that Tarceva monotherapy appears to have activity in patients with good prognosis with performance status of 0-1. Patients with a performance status of 2 did not appear to respond as well to Tarceva monotherapy. Further studies of Tarceva in first-line patients with good prognosis are warranted and suggest a role for Tarceva in these patients (particularly in patients who are ineligible for Avastin). Since the study in good performance patients followed Tarceva treatment with chemotherapy, and since the Tarceva monotherapy study in PS 2 patients yielded negative results, Tarceva is unlikely to supplant chemotherapy. However, the combination of Avastin and Tarceva does appear to be active in second-line patients and this combination was shown to be better tolerated than chemotherapy, suggesting a role for this drug regimen in patients who cannot tolerate chemotherapy. Further studies are required to determine whether this Avastin plus Tarceva combination is also effective in first-line patients.

The newer targeted therapies that are now in early studies in NSCLC are also showing activity in this disease. Presentations on Zactima, Sutent and Nexavar showed that these agents are fairly comparable. Zactima produced a PFS of 11.0 weeks, Sutent resulted in a PFS of 11.3 weeks and an OS of 23.9 weeks and Nexavar produced a PFS of 11.9 weeks and an OS of 29.3 weeks. Zactima's OS was questionable due to the crossover study design. Note that in a similar patient population, Tarceva also demonstrated a PFS of 11.7 weeks and 29.5 weeks OS. Therefore, it appears that Zactima, Sutent and Nexavar possess comparable efficacy to Tarceva. However, the efficacy of these agents does not appear to be greater than that with chemotherapy and thus, further evaluations of these agents in a combination setting (perhaps in combination with chemotherapy) are warranted. Tarceva did not show a benefit when combined with chemotherapy and the question of whether these agents can be combined with chemotherapy (or each other) requires further research.

Of concern with these TKIs are the bleeding events. Avastin is associated with hemorrhage-related deaths, which were also seen in these phase II studies with Sutent and Nexavar. Zactima thus far has not been shown to cause hemorrhage-related death. Based on these observations, it would appear that hemorrhage is a class effect and these bleeding events will need to be carefully monitored in future studies. The bleeding events seen with Sutent and Nexavar also suggest that, like Avastin, these drugs should be avoided in patients with squamous NSCLC.