Pfizer and Axitinib (AG-013736)

Pfizer is Announcing a New Phase 3 Trial for Axitinib (AG-013736)

Pfizer will soon announce the opening of a large scale, Phase 3 randomized trial in the U.S. and 20 other countries testing axitinib versus sorafenib (Nexavar) in patients who have previously failed a therapy, either cytokine (Interleukin-2 or Interferon) or a targeted therapy including Sutent. Pfizer expects to start the trial this summer and hopes to get the first IRB approval in June or July, 2008.

ACKC has been following the progress of axitinib in kidney cancer since the favorable results of an early Phase 2 trial were announced at the ASCO conference in the summer of 2005. At that time, Pfizer indicated that despite the favorable results, they were not prepared to continue testing the drug for kidney cancer (this was about the same time that Pfizer was developing Sutent for metastatic kidney cancer). We established a committee and have been meeting with Pfizer representatives regularly to encourage them to develop the drug for kidney cancer.

The Phase 3 trial seeks to demonstrate axitinib’s effectiveness as measured against a standard targeted therapy in current use, Nexavar. Secondly, if it is shown to be successful, Pfizer will have ample data to present to the FDA to seek official approval for the drug as another therapy against renal cell carcinoma. See ClinicalTrials.gov at http://tinyurl.com/63p93a for trial details.

For the latest trial results on axitinib, Olivier Rixe of Pitie-Salpetriere Hospital in Paris, the Principal Investigator, reported in an article in Lancet (Lancet Oncol. 2007 Nov;8(11):956-7), that in a Phase 2 trial for cytokine refractory patients, axitinib had an objective response rate of 44% including two complete responders (although half the responders progressed during the study). Another 42% showed stable disease for longer than 8 weeks. Median time to progression was 15.7 months. The most common grade 3 or 4 adverse events were diarrhea, hypertension, or fatigue, which were considered manageable. The results of this trial compare favorably to those of other targeted therapies including Sutent.

Axitinib Results in a Phase 2 Study[1]

Olivier Rixe, Ronald M Bukowski, M Dror Michaelson, George Wilding, Gary R Hudes, Oliver Bolte, Robert J Motzer, Paul Bycott, Katherine F Liau, Peter C Trask, Brian I Rini

The Trial and Results

On October 23, 2007, Doctor Olivier Rixe, from the Medical Oncology Department at Pitié-Salpêtrière Hospital of the University of Paris, and his research team published the results of the phase II clinical trial of axitinib, an oral medication for metastatic renal-cancer patients for whom immunological therapy had been unsuccessful. The results of the trial are quite promising, with 23 of 52 patients enrolled (44.2%) responding to the drug, following RECIST response criteria. Of the 23 objective responses recorded, two were complete, with disappearance of all tumors.[2]

The results of this trial are very encouraging following on the promising results of axitinib in earlier Phase 2 trials. Dr. Rixe points out in the introduction to his paper that only the healthiest renal-cell cancer sufferers tend to benefit from immunological treatments like interferon alpha and interleukin-2. When biological treatments are unsuccessful, the median survival is 12.7 months. In dramatic contrast, the median overall survival of patients in the axitinib trial was 29.9 months – two and a half times as long.[3] In trial patients, the median time to progression – the length of time between diagnosis and the disease beginning to worsen – was 15.7 months, and the one-year survival rate for the drug was 78.8%. In discussion of his findings, Dr. Rixe speculates that even if objective response is not met in all patients – if tumors do not noticeably regress – axitinib may still be beneficial in that it can help stabilize the patient’s condition and deter further tumor growth. Even if one’s health does not get appreciably better while on axitinib, Dr. Rixe points out that the drug may at least prevent it from getting worse, which is significant nonetheless.

How Axitinib Works – the VEGF Pathway

Axitinib is a selective inhibitor of the VEGF Receptors 1, 2, and 3. VEGF is an acronym for “Vascular Endothelial Growth Factor.” VEGF is a protein molecule secreted by cells in the human body to signal to blood vessel cells to grow and divide. VEGF molecules travel through body fluid to connect with receptors on the surface of vascular cells. Their arrival triggers a cascade of signals within the cell that leads to the activation of genes that prevent the cell from dying. The VEGF pathway is important to all blood vessel growth, but it is of particular significance in tumor growth and angiogenesis. Through this pathway tumors grow blood vessels, which provide them with nutrients to continue growing.

Axitinib works by blocking the VEGF pathway, so blood vessels sprouted by tumors are never signaled to divide. Thus, theoretically, tumor growth can be limited or eliminated entirely. Essentially, axitinib combats tumors through attrition. The drug fits into the receptors that would normally house VEGF molecules, but does so without turning on protective genes that the normal VEGF signal would. As a result, the tumor’s vascular cells cannot proliferate and the tumor has a much harder time obtaining nutrients by which to grow. Alternatively, antibody drugs like bevacizumab work by targeting the VEGF signaling molecules themselves, binding to them in a way that makes them unable to bind to their receptors; so the growth signal is interrupted.

The VEGF pathway is targeted in part by several other anti-tumor drugs, including sunitinib (Sutent) and sorafenib (Nexavar). The dosage for axitinib in this trials was 5 mg given twice a day. By contrast, the standard dosage for the other targeted oral therapies are: sunitinib 50 mg/day, two weeks on one week off, and sorafenib 400 mg given twice a day continuously. Dr. Rixe speculates in his paper that the success of axitinib compared to these drugs may be a matter of depth versus breadth: whereas sunitinib and sorafenib target many pathways employed by growing tumors, axitinib focuses specifically on VEGFR, and delivers a more concentrated and powerful dose of medicine to that specific process of tumor growth.

Tumor necrosis was even noted in several study patients, even in some with progressive disease, a response that Dr. Rixe notes demands further consideration.

Adverse Events

Almost every patient, 48 of them, had a treatment-related adverse event. 28 had a grade 3 or grade 4 treatment-related adverse event.[4] The most common side effects recorded in the trial were diarrhea, hypertension (high blood pressure), nausea and fatigue.

Hypertension is a common side effect of anti-VEGF medications and was expected as a result of axitinib. It was recorded in 30 of the 53 patients tested, with 8 experiencing it at grades 3 or 4. However, in most patients hypertension was easily managed with one or more standard blood pressure medications and the trial was able to continue safely. After going off the drug, hypertension generally dissipated. Hematological toxicity – decreased production of blood cells or platelets that can occur as a result of many different cancer treatments – was not recorded. Overall, the toxicity from treatment with axitinib was well within safe levels and could easily be controlled with additional medication.

Diarrhea was associated with positive response to the treatment and non-responders generally recorded no increase in gastrointestinal distress. As patients acclimated to the drug, diarrhea generally stabilized. The point about the diarrhea aside, there was no data available to do analysis of which base line markers could be prognostic for patient response to treatment.

Discontinuance of Treatment

Patient accrual for this trial was conducted from October 2003 to April 2004. At the time of the report preparation, April 2007, 50 of the 52 patients were off treatment. 25 patients had progressive disease or had absence of efficacy, and another 10 were removed due to adverse events. Two were still on treatment with CRs.

Conclusions

The results reported in the study are encouraging. However, Dr. Rixe cautions that the drug’s apparent success could be the product in part of patient selection bias. Among the 52 patients enrolled in the study, 22 had no unfavorable prognostic risk factors[5] in addition to their illness. Further studies would benefit from a better representation of risk factors in patient samples.

Nevertheless, the results of Dr. Rixe’s phase II trial of axitinib are encouraging and warrants a Phase 3 trial.. Axitinib could become a powerful agent in the fight against renal-cell cancer, if not in achieving tumor regression then at least in contributing to patient stabilization.


[1] See full article Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study by Olivier Rixe, Lancet Oncology2007;8:975-984

[2] Note that with respect to the response statistics presented for this trial, there was no independent radiographical review to confirm the results.

[3] One caveat is that data on later lines of treatment were not available for analysis, which could have an impact on the median survival statistic.

[4] Adverse Events: Grade 1- Mild; Grade 2 – Moderate; Grade 3 – Severe; Grade 4 – Life-threatening or disabling.

[5] Risk factor refers to the Memorial Sloan-Kettering three risk factor categories: low Karnofsky performance status (<80%), low serum hemoglobin, and high corrected calcium.

September 2007 Update

In the last couple of years, ACKC has conducted a campaign to convince Pfizer to continue the development of its targeted therapy drug axitinib, which showed very promising results in early trials against kidney cancer – see AG-01376 vs Sutent and Report from ASCO 2007 for trial results for axitinib (AG-013736). Our letter writing campaign to Pfizer’s Executive Staff led to a request from Pfizer for us to meet with their director of advocacy affairs for pipeline drugs and one of their medical directors at the 2006 ASCO Conference in Atlanta. We invited other kidney cancer advocates attending the conference to join us.

At the meeting, the Pfizer officials told us that they had fulfilled one of our requests by expanding the then current AG-013736 sorafenib-refractory trial from 32 patients to 66 patients. We discussed a number of issues but emphasized our concern that the AG drug continue to be developed and tested in kidney cancer. The meeting was cordial and all parties agreed to keep an open dialogue and meet again, which we did in the fall of 2006 and again at the 2007 ASCO Conference in Chicago.

At the Chicago meeting, we were advised that Pfizer intends to initiate a Phase 3 trial for axitinib in kidney cancer within the next 6-9 months. We are hopeful, especially given Pfizer’s financial problems with some of the other drugs in their portfolio, that we will see them devote more research money on cancer drugs. In 2006, 12% of their research effort went into cancer drugs. For 2007, the figure is expected to be 20%.

Anyone who wishes to be kept informed of developments with the Pfizer drug or wants to help with our campaign can join our Pfizer Working Group by submitting an Advocacy form http://www.ackc.org/advocate and entering “Pfizer Working Group” in the Other box.

What follows is a record of the history of our Pfizer campaign.

September 2006 Update

The preliminary results from a phase 2 AG-013736 trial conducted last year, showed partial response of 46% and stable disease of 40%, giving it an overall response rate of 86% – this compared to 63% for the latest Sutent trial, for which Pfizer received FDA approval in January 2006. The AG drug is also thought to have fewer toxic side effects than Sutent.

But instead of developing AG-013736 in a Phase 3 trial and preparing it for the priority FDA approval process, Pfizer initiated a 32-patient trial for sorafenib resistant patients. Another concern was that despite the fact that the results of the Phase 2 trial for the AG drug were announced at last year’s (2005) American Society for Clinical Oncology (ASCO) conference in Orlando, there were still no updated results for this trial.

Based on this, ACKC initiated a letter-writing campaign to Henry McKinnell, Pfizer’s Chief Executive Officer, and William Schlichenmyer, Pfizer’s VP of Oncology Drug Development, asking them to increase the number of patients in the current sorafenib resistant trial, to release updated trial data, and to seek FA approval for the drug if the trial results prove favorable.

When jay Bitkower, the President of ACKC, was in Atlanta attending the ASCO conference, he received a call from Pfizer’s director of advocacy affairs for pipeline drugs. She requested that he meet with her and one of Pfizer’s Medical Directors. Jay invited three other patient advocates to join the meeting.

At the meeting, Pfizer said that it decided to open the sorafenib refractory trial to an additional 34 patients, totaling 66 patients. Pfizer also stated that it has submitted a manuscript with the results of the Phase 2 trial of AG-013736 to the Journal of Clinical Oncology (JCO) and expects the article to be published later this year. They did not agree to embark on a Phase 3 trial at this time, but did agree to revisit that issue. They also indicated their desire to maintain an open dialogue with us and suggested that we meet again at their headquarters in New York City in 2-3 months to continue discussing the development of AG-013736.

All four of us advocates felt that the meeting was very encouraging. It was cordial and non-confrontational, and we agreed that it is important to maintain a dialogue with Pfizer as long as the AG drug is showing efficacy in fighting kidney cancer. ACKC also recognizes that the people who wrote letters to Pfizer’s management were instrumental in helping Pfizer realize the importance of AG-013736 to the kidney cancer survivorship community.

Anyone who wants to participate in future actions with regard to this drug, should contact us.


What follows is a synopsis of Pfizer’s initial clinical testing of their AG13736 drug and the cessation of that testing in kidney cancer. Following the synopsis are ACKC’s responses to the discontinuance of testing and Pfizer’s reply.

At the American Society of Clinical Oncologists (ASCO) conference in May 2005, Dr. Brian Rini, then of UCSF, presented the results of a Phase II kidney cancer trial which tested the results of Pfizer’s investigational drug AG13736 in a Phase II trial for kidney cancer. The drug showed very promising results especially compared to the other targeted therapies under investigation at the time. The trial was open to patients who were “refractory to cytokine therapy”, that is, they had previously failed Interleukin-2 or Interferon therapy. Similar to other drugs that are being tested for kidney cancer, AG13736 targets what are called tyrosine kinase receptors, those proteins that contribute to tumor and blood vessel growth, in this case VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β. At the time of the ASCO report in May, the median time-to-progression (TTP) was not yet reached but was greater than 12 months. The 46% partial response and 40% stable disease (90% of whom had some tumor shrinkage) rank AG13736 very high among its targeted therapy competitors. When questioned from the floor about a future Phase II or Phase III trials for this drug, Dr. Rini indicated, to the astonishment of the few hundred oncologists and researchers who were in the audience, that Pfizer had no plans to continue testing AG-13736 drug any further in KIDNEY CANCER! But Pfizer will test it in breast cancer, melanoma, thyroid cancer, and lung cancer – (see image of brochure below). He offered no reason as to why Pfizer made this decision.

After the session, a couple of kidney cancer advocates went to the Pfizer exhibition area and spoke with a Pfizer rep, who told them that “Pfizer had made a corporate decision not to continue testing AG13736 in kidney cancer but would proceed to test it in breast, lung, thyroid and melanoma”. She also offered no reason for this decision but took phone numbers and said that a Pfizer manager would get back to the advocates on this. However, no one ever did.

After the conference, ACKC asked its supporters and ACOR list members to write to Pfizer management asking them to reverse their decision. On May 27th, we wrote an official letter to Catherine Mackey, Pfizer’s Senior VP in charge of Global Research and Development. Ms. Mackey heads the lab in La Jolla, CA where AG13736 was developed – (see copy of letter below). Ms. Mackey’s response, dated June 21st, was typical of the responses to others who received answers from Pfizer, that is, it stated that AG13736 would continue to be tested, but carefully avoided mentioning whether testing would include KIDNEY CANCER. In other words, Pfizer did not intend to stop their current trials for these drugs, but Ms. Mackey did not address the issue of Pfizer’s decision not to continue testing AG13736 in a new Phase III trial for kidney cancer – (see response letter below).

In reply to Ms. Mackey’s letter, ACKC responded with an email that asked the specific question about continuing testing AG13736 beyond the current Phase II trial – (see copy of email below). Ms. Mackey has not responded to this email.

On August 9th, ACKC sent a letter to Henry McKinnell, Chief Executive Officer of Pfizer, requesting that Pfizer continue testing AG13736 in a Phase II trial for kidney cancer. Mr. McKinnell has not responded either.

Letters to Henry McKinnell can be addressed to:

Henry McKinnell, Chief Executive Officer
Pfizer Inc.
235 East 42nd Street
New York, NY 10017

If you want to be part of a committee to plan how to convince Pfizer to continue development of AG13736 in kidney cancer, then email Jay Bitkower at Jay.Bitkower@ackc.org with the subject Pfizer Campaign.

If you write to Pfizer, please let us know what their response is.

ACKC-Pfizer Correspondence

The following correspondence between ACKC and Pfizer reflects the suspension of testing the new targeted drug AG13736 by Pfizer. See “Cancer Drug Controversy: Pfizer’s AG-013736 vs. Sutent” elsewhere on this site for the full story.

The documents are:

  1. Letter to Catherine Mackey, Pfizer’s Senior VP in charge of Global Research and Development. Ms. Mackey heads the lab in La Jolla, CA where AG13736 was developed (May 27, 2005).
  2. Catherine Mackey’s response to ACKC (June 21, 2005).
  3. Email to Catherine Mackey in response to her letter (June 25, 2005). Note: There was no response to the email to Catherine Mackey.
  4. Letter to Henry McKinnell, Chief Executive Officer of Pfizer (August 9, 2005).

Email sent on 6/25/05 to Catherine.mackey@pfizer.com in response to her letter of 5/27/05.

Dr. Mackey,

Thank you very much for your response to my May 27th letter concerning AG13736.

I understand that the AG13736 Phase II study for mRCC is ongoing and has not been stopped. What I would like you to clarify for me is whether Pfizer intends to test AG13736 any further in kidney cancer beyond the current ongoing Phase II study.

When I visited Pfizer’s booth at ASCO and inquired about Pfizer’s future plans for testing AG13736, I was told by a rep that you do not plan to test AG13736 for kidney cancer any further beyond the current ongoing Phase II study. Other kidney cancer patients at ASCO were told the same thing by different Pfizer representatives.

Those of us at ASCO representing the kidney cancer community were very excited to hear Dr. Brian Rini’s presentation. AG13736 seems to be the most efficacious and least toxic therapy that has been tested in kidney cancer patients and we are extremely anxious that you continue the development of the drug specifically for kidney cancer as well as for other cancers.

Again, thank you for your attention and I look forward to your response.

Very truly yours,

Jay Bitkower, President
Action to Cure Kidney Cancer (ACKC)