Update on Targeted Therapies

Elisabeth Heath, who is from the Karmanos Cancer Institute at Wayne State University in Detroit, made an oral presentation entitled “Update on Renal Cell Carcinoma Treatment Options for the Practicing Oncologist”. Many of the attendees are community oncologists, that is, they are not connected with the major teaching hospitals. They also probably do not have much experience treating mRCC patients. Dr. Heath presented a survey of the current FDA-approved treatments for mRCC, as related to clear cell patients. She advised her audience to seek out trials for the other RCC histologies, although certain targeted therapies, like temisrolimus, have shown some efficacy in non-clear cell patients. Dr. Heath listed the six FDA-approved targeted therapies and the relevant trial data for each therapy, but she didn’t recommend one over another. She also listed the adjuvant therapy trials. Following below is her list. The generic name is used for each therapy. A glossary of generic name and brand name is included after Dr. Heath’s list.

For reference, the following is a list of all targeted therapies that have been approved by the FDA for treatment for kidney cancer, by order of approval.

Many of these therapies were tested against interferon-alpha, an immunotherapy that was a standard of care for mRCC before the targeted therapy era. For reference, front/first line refers to treatment of patients who had no prior treatment for mRCC. Second line refers to patients treated with one prior therapy. Standard measures of treatment on a trial are median progression-free survival, or PFS, and median overall survival (OS). PFS refers to the inception of treatment on the therapy until the tumor(s) begin to grow or death occurs from any cause. OS is the time interval from inception of treatment until death occurs. Cytokine therapy is treatment with INF or Interleukin-2 (IL-2). Refractory means failure of treatment, e.g., cytokine refractory refers to patients who failed treatment with INF or IL-2.

Sorafenib is an oral tyrosine kinase inhibitor given at 400 mg, twice a day. A Phase II trial of sorafenib versus INF showed a PFS for sorafenib at 5.7 months and INF 5.6 months. In a Phase II trial of sorafenib versus placebo in cytokine-refractory patients, the PFS was 5.5 months (sorafenib) and 2.8 months (placebo). OS was 17.8 months versus 14.3 months. [Ed. Note: Sorafenib, the first targeted therapy to win FDA approval, is considered the least effective of the targeted therapies, although many patients have done well on sorafenib and it has provided long-term stable disease with few side effects. Nevertheless, sorafenib has now replaced INF, in randomized trials, as the standard of care that the newer therapy is compared against.]

Sunitinib is an oral tyrosine kinase inhibitor given at a 50 mg dose, daily for 4 weeks with a 2-week break and then continuing the next cycle. It is also given at 37.5 mg daily, continuous treatment. In a Phase III front line trial of sunitinib versus INF, the PFS was 11 months versus 5 months, respectively. The OS was 26.4 months versus 21.8 months, however 60% of the INF patients were crossed over to sunitinib after failure on INF, contaminating the OS results. In Phase II and Expanded Access trials, sunitinib, as a second line therapy for cytokine refractory patients, demonstrated a PFS range of 8-11 months. With respect to targeted therapy resistant patients, sunitinib given to bevacizumab refractory patients yielded a PFS equal to 7 months. In a sorafenib – sunitinib and sunitinib – sorafenib setting, sunitinib has consistently done better than sorafenib, as noted in several studies, when used as a follow-up to failure of the first drug. Sunitinib, although FDA-approved only a month after sorafenib, is today considered the standard front line therapy of mRCC. [Ed. Note: That may change by next year when the results of a head-to-head trial of pazopanib versus sunitinib is reported on and when two new drugs, axitinib and tivozanib will probably gain FDA approval for treatment of mRCC.]

Pazopanib is also an oral tyrosine kinase inhibitor given at 800 mg daily. In the landmark Phase III trial where patients were randomized to pazopanib or a placebo, the median PFS for treatment naïve patients was 11.1 months versus 2.8 months, respectively. In the same trial, about half the patients were cytokine refractory, and the results for this group were PFS equal to 7.4 months versus 4.2 months for pazopanib and placebo, respectively. [See http://tinyurl.com/5rccx5y for a complete write-up of this trial on ACKC’s website]. There are ongoing studies of pazopanib in targeted therapy refractory patients but no data are as yet available. [Ed. Note: As mentioned above, the results of the pazopanib versus sunitinib trial are not yet available. Dr. Heath’s talk did not cover adverse events, but we should mention that pazopanib tends to raise liver enzyme levels so should probably not be given to people with liver problems.]

Bevacizumab is a monoclonal antibody that targets VEGF itself rather than the receptor, the objective of the other TKIs. Bevacizumab was paired with INF in its seminal trial testing this combination vesus patients on INF alone, for treatment naïve patients. Bevacizumab is given as an infusion, 10 mg/kg, once every two weeks. INF was administered subcutaneously, three times per week. The trial results favored the bevacizumab arm, PFS equal to 10.2 months versus 5.4 months for INF alone. The OS was 23.3 months versus 21.3 months, with the INF refractory patients being crossed over to the bevacizumab arm. In a 2003 Phase II trial for cytokine refractory patients who were randomized to bevacizumab or a placebo, the resultant PFSs were 4.8 months versus 2.5 months, respectively. There is an ongoing trial for sunitnib refractory patients.

Temsirolimus is an mTOR inhibitor given as an infusion at 25 mg weekly. In the seminal Phase III front line trial, patients were randomized to three arms: temsirolimus alone, temsirolimus in combination with INF, or INF alone. The results were PFS equal to 10.9 months, 8.4 months, and 7.3 months, respectively. In a cytokine refractory Phase II trial, patients, who were given various doses of temsirolimus, had a median PFS of 5.8 months. Temsirolimus is currently being tested against sorafenib. [Ed. Note: It is difficult to compare the response results for multiple therapies over different trials since the patient population is not the same. For temsirolimus, it is even more difficult since this agent is usually given to poor risk patients rather than the more common mix of intermediate and good risk (risk being a predictor of survival for patients taking a given therapy). Secondly, in the seminal trial, a small subset of the trial population, who had non-clear cell disease, seemed to respond better to the therapy than the clear cell patients did. However, follow-up with trials that test m-TOR inhibitors in non-clear cell patients is sparse. There are a handful of current trials that test temsirolimus and everolimus, but the response data are not yet available.]

Everolimus is the second mTOR inhibitor that has been approved for treatment of mRCC patients. It is an oral tablet given at 10 mg daily. The seminal second line Phase III trial randomized mostly targeted therapy refractory patients to everolimus or placebo. The PFS was 4.9 months for everolimus versus 1.9 months for placebo and the OS was 14.8 months and 14.1 months, respectively, with 80% of patients on the placebo arm crossing over to everolimus. [Ed. Note: Everolimus is only approved for second line treatment as no data are available on first line activity. The current trials are mostly testing everolimus in combination with other therapies, although one is testing it serially versus sunitinib. Everolimus is the only kidney cancer therapy that the NCCN does not recommend for front-line treatment.]

Editor’s Comments:
Combination therapies using the above agents have been tried, but in most of them the combination proved too toxic and not even more effective than monotherapy. More combinations are being tested as well as serial application of two therapies. Except for bevacizumab/INF, there is no FDA approval for any combination therapy. There are also current trials testing targeted therapies in the adjuvant setting for patients at high risk of recurrence. No data are available but there are indications that many of the patients taking the therapies have dropped out of the trials due to toxicity of the therapy.

Dr. Heath mentioned three novel agents in her talk: AGS-003, AGS-16M8F, and SGN-75. The first one, AGS-003, is a dendritic cell therapy, which looks promising. It is currently being tested in combination with sunitinib for which a Phase III trial is in the planning stages. The results of a Phase II trial using this combination are reviewed on our website at http://tinyurl.com/4garrea. AGS-16M8F and SGN-75 are biologics that are in Phase I trials and are still in the recruitment stage.

Dr. Heath presented a good overview of the targeted therapies that have been FDA approved for treatment of mRCC. However, she didn’t talk about toxicities or biomarkers. It is also disappointing that she never even mentioned two immunotherapies, Interleukin-2 (IL-2) and MDX-1106. IL-2 was the first drug approved, in 1992, to treat mRCC patients and is still being used. Its downside is that it is highly toxic and must be administered in a hospital setting in order to deal with adverse events. Due to its toxicity, it can only be administered to patients who, other from their cancer, are in good physical condition with few in any co-morbidities. Also, it has also proven to be effective in only clear cell patients. The upside is that it has been shown to have a complete response in a small minority of patients (6-8%). That’s pretty low, but these patients may be cured of their disease, which one cannot say about any of the targeted therapies. Secondly, IL-2 treatment is administered in cycles, lasting up to two weeks. Once a cycle has been completed, the patient is put under observation to see if there is a response, that is, tumor shrinkage. If so, they may undergo another treatment cycle in six months or so. But in between, there is no treatment, and the adverse effects that have occurred usually dissipate. In a trial reported on at the ASCO 2010 Meeting, the overall response rate was 28%. So, even if not curative, it gives patients time and does not preclude one from switching to a targeted therapy when IL-2 becomes ineffective. IL-2 may not be a drug of choice for a community oncologist, however, there is no reason that a patient could be referred to a center that does treat mRCC patients with the drug.

A second immunotherapy that looks promising is MDX-1106. It has shown promise for mRCC patients in a Phase I trial, see http://tinyurl.com/6ahmc9z and is currently in a Phase II trial for kidney cancer patients.