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Oncology Unplugged Podcast Interview Highlights From the ASCO

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Oncology Unplugged Podcast Interview Highlights From the ASCO Powered By Docstoc
					            Oncology Unplugged Podcast Interview: Highlights From the
                 ASCO 2009 Genitourinary Cancers Symposium

 An Interview With Thomas E. Hutson, DO, PharmD, FACP, and Robert J. Motzer, MD

Introduction
A number of recent studies have identified novel treatments that may improve the
outcomes of patients with genitourinary cancers including, among others, renal and
prostate cancers. Renal cell carcinoma (RCC) is the seventh most diagnosed cancer in
men and ninth most in women, and prostate cancer remains the most diagnosed cancer in
men.1 For more than 20 years, RCC was traditionally and usually unsuccessfully treated
with cytokine therapy.2 More recently, agents that target and inhibit key signaling
pathways involved in tumor growth have been shown to be more successful in prolonging
progression-free survival (PFS) and/or overall survival in these patients.3-11 In prostate
cancer, novel techniques are currently being developed to evaluate the efficacy of
systemic therapy and to assess disease prognosis.12,13 New treatments and potential
prostate cancer preventatives have also recently been examined.14,15 In this interview,
Robert Motzer, MD, and Thomas Hutson, MD, discuss current advances in both renal
and prostate cancer research as presented at the American Society of Clinical Oncology
2009 Genitourinary Cancers Symposium (2009 ASCO GU meeting).

Robert J. Motzer, MD: My name is Robert Motzer. I’m a medical oncologist
specializing in genitourinary oncology and an attending physician at Memorial Sloan-
Kettering Cancer Center. Today I will be bringing you highlights from the 2009 ASCO
GU meeting. I am joined by Thomas Hutson, Director of Genitourinary Oncology at
Texas Oncology PA at Baylor Sammons Cancer Center. We’re here to discuss key data
that were presented in RCC and in prostate cancer.

In RCC, the emphasis at the conference this year was on the new targeted therapies,
especially in following through with earlier American Society of Clinical Oncology
(ASCO) meetings that have shown promising outcome results for a number of different
targeted agents including sunitinib, sorafenib, and the mammalian target of rapamycin
(mTOR) inhibitor temsirolimus.3,4,7,8,16 So, at the 2009 ASCO GU meeting there was an
emphasis on trying to understand the drugs’ molecular mechanisms of action and
resistance to these agents. Additionally, there was the introduction of a new agent, AV-
951, which is a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor
receptor (VEGFR).17 Data for this compound used in RCC was first reported at the 2009
ASCO GU meeting. Tom, do you have any comments on the spectrum of data that was
reported?

Thomas E. Hutson, DO, PharmD, FACP: Yes. First of all, thank you Bob for having
me speak about this with you. I agree with you that it’s a very exciting meeting. We
heard about the final results from some older agents (ie, everolimus) that you presented,
as well as data on an exciting new agent, AV-951, which is a newer-generation
angiogenic inhibitor.17,18 Can you provide updated results on the everolimus phase III
trial?



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Robert J. Motzer, MD: Well, everolimus is an orally administered mTOR inhibitor that
was studied in a large pivotal trial in patients who had progressed on TKIs, which were
the new standard of care.9 The trial was designed as a randomized phase III trial with a 2
to 1 randomization of everolimus compared to placebo (Figure 1). The study drug was
given orally, and the patients receiving placebo were crossed over at progression to open-
label everolimus.




The initial data for the trial were presented at the 2008 ASCO Annual Meeting and
published in Lancet (Figure 2).9,19 Those results were based on a data cutoff of October
2007. Since that time, there has been additional follow-up because the trial continued to
enroll before the blind study was terminated. As the trial matured, the median PFS for
everolimus with longer follow-up was higher than that which we had originally reported.
By independent central review, the median PFS was 4.9 months compared to 1.9 months
with placebo.18 By investigator assessment, with the extended follow-up the median PFS
was 5.5 months (Figure 3).




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In addition, the safety information was updated (Table 1). Overall, the reports about
everolimus show that it was a well-tolerated agent, with the most common side effect
being stomatitis.18 The one serious side effect that has been associated with this drug is
pneumonitis. An update on the pneumonitis data was provided along with a review of the
findings by an external panel of pulmonologists. They highlighted that this toxicity is an
adverse event that we need to watch for in patients treated with this class of drugs.
Overall, the grade III toxicity associated with everolimus was about 3%.




The outcome data were also reported for the group that was initially randomized to
receive the placebo and was then crossed over (Figure 4). In that group, the median PFS
was 5.1 months as well, which is consistent with the other data.18 And finally, the
survival data for the study was reported all the way out to a follow-up of November 2008,
where the median survival for the everolimus-treated patients was 14.8 months (Figure
5). There wasn’t a difference, however, in the survival between the 2 arms because about
80% of the patients crossed over from everolimus to placebo. I think that this
presentation was significant because of the excitement around this agent and the fact that
it’s being viewed as a potential candidate for registration.




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5
Thomas E. Hutson, DO, PharmD, FACP: Another exciting 2009 ASCO GU oral
presentation was about the novel new agent, AV-951, which is a potent selective
VEGFR1-3 kinase inhibitor.17 The results that were presented were from a large,
randomized phase II discontinuation trial (Figure 6). The authors reported the results
from 272 patients in the first 16-week lead-in to the randomized discontinuation trial.
Surprisingly, we saw a drug that was fairly well tolerated and had a side effect profile
(Table 2) that may make it a little more amenable than the currently available kinase
inhibitors, with a response rate (RR) that is in the same ballpark of what we see with
similarly targeted agents like sunitinib, pazopanib, and axitinib (Table 3).7,17,20,21




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7
In the discussion, Dr Escudier mentioned that we’re at a point now where we have
multiple similar targeted agents, and it’s unclear how much benefit the newer agents will
add over the drugs that are currently available.22 A discussion ensued about the
development of drugs that provide a meaningful benefit such as improved RR, prolonged
survival, or an improved side effect profile. So it was encouraging to see yet another drug
that looks like it may be at least as good as the currently available therapies but may have
a more favorable side effect profile. Did you have any specific comments about AV-951
or the presentation?

Robert J. Motzer, MD: I found that to be the other presentation that was very important
at the 2009 ASCO GU meeting. The trial design was a randomized discontinuation trial
where patients were treated for a lead-in of 16 weeks and were then assessed for response
(Figure 6).17 If they had a response, defined as greater than a 25% reduction in tumor
size, they were continued on AV-951. If the patients progressed they were taken off the
study drug, and if they had stable disease they were randomized to placebo versus
continued AV-951 in a blinded fashion. At the 2009 ASCO GU meeting, the outcome
data at 16 weeks were reported to us. The data showed that the drug was active and could
produce responses (Table 3). I think the data were too immature to really help us
compare AV-951 to the activity of other agents, other than to say that it is indeed active.

Additionally, there were safety data from the entire cohort showing that AV-951 was
quite tolerable and had a favorable toxicity profile (Table 2).17 The targeting profile is
another thing that is exciting about this agent. Of the different agents that have been
studied, AV-951 seems to hit the VEGFR target the hardest. It’s really a super binder to
VEGFR. I think it’s the targeting profile that most of us find the most intriguing, and we
look forward to hearing more about this compound. The presenter indicated that there
would be more mature data that may be presented at the 2009 ASCO Annual Meeting.

Thomas E. Hutson, DO, PharmD, FACP: As I look through the RCC program, there
were several educational sessions where it seemed like the focus was on moving toward
individualizing patient care. We’re seeing a lot of research investigating mechanisms so
that physicians in the clinic can begin to select particular agents for particular patients by
identifying characteristics like histologic subtype or by evaluating different mechanisms
of resistance. What are your thoughts in that regard?

Robert J. Motzer, MD: I think there was some mention of predictive factors and
mechanisms of resistance that I think are extremely important aspects of kidney cancer
work at this point. We now have multiple agents that have activity and are changing the
outlook for our patients, but we are lacking information regarding why they’re working,
why the tumors become resistant, and whether some tumors respond better to VEGFR
inhibitors compared to mTOR inhibitors. Preliminary information regarding these topics
was another particular focus at the 2009 ASCO GU meeting, for example, George
Thomas’s report on the mTOR pathway and Jim Mier’s presentation on the molecular
basis for these targeted therapies.23,24 The Cleveland Clinic group also gave a very nice
presentation regarding some factors that go into safety, particularly why some patients
develop more toxicity with one agent than with another.25



                                              8
For the most part, these presentations indicated that we don’t yet have all the answers. I
think that they emphasize the approach that is taken and that it is something that we need
to work very hard at. Hopefully, this will allow us to make progress in our understanding
of the mechanisms of response and of resistance. It will also help better individualize
treatment for patients and potentially identify some drugs that may be safer and more
effective in treating tumors.

Thomas E. Hutson, DO, PharmD, FACP: I agree. It was a very exciting group of
presentations. I had the privilege of attending the prostate sessions where several notable
trials were presented, including the results of the very large SELECT trial, which was a
prostate cancer prevention trial.26 It involved 35,533 men that, at the time of enrollment,
did not have prostate cancer. Subjects were randomized to receive either oral selenium
with a vitamin E placebo, vitamin E with a selenium placebo, or the combination of
selenium and vitamin E (Figure 7). That trial was launched on the basis of
epidemiological studies suggesting that dietary supplementation with these agents could
lower one’s risk of developing prostate cancer. The results were presented after a 7-year
interim analysis and demonstrated absolutely no benefit from supplementation with either
selenium or vitamin E. So this was a very large, major chemoprevention trial that
unfortunately did not show any benefit.




There was an interesting phase III trial in the metastatic setting that was looking at the
GVAX immunotherapy.27 This was a trial that randomized patients to receive either
docetaxel/prednisone, which is the current standard of care in the frontline setting, or


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docetaxel/GVAX, the experimental arm (Figure 8). This was a large trial that involved
408 patients and unfortunately did not demonstrate a benefit. Docetaxel/prednisone
actually was proven to be better than docetaxel/GVAX.




A third abstract that was of interest presented work that looked at the oral bisphosphonate
clodronate (Figure 9).28 In the United States, the standard of care has been to use
intravenous bisphosphonates, but we certainly recognize that oral bisphosphonates are
also of value.29-31 This was a large trial done in metastatic prostate cancer, and the results
demonstrated that using clodronate provides a survival benefit and may decrease skeletal-
related events.




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Finally, one of the other interesting parts of the prostate cancer session was looking at
circulating tumor cells.32 The underlying theme that Howard Scher discussed was that
prostate cancer is heterogeneous, so our treatments are likely going to have to be directed
with this in mind. The evaluation of circulating tumor cells could be one mechanism by
which the response to therapy could be gauged and the benefit of chemotherapy or other
agents being used could be assessed. There were data presented from ongoing studies on
circulating tumor cells.

I think there’s clearly been significant drug development in RCC, and in prostate cancer
we’re certainly trying to do the same thing by evaluating novel drugs. I think the most
exciting information was about circulating tumor cells. Bob, do you have any comments?

Robert J. Motzer, MD: I agree with that. I think another emphasis of the session in
terms of more cutting-edge work was the analysis of circulating tumor cells. There was a
keynote lecture that was provided by Daniel Haber from Massachusetts General Hospital
Cancer Center that really reviewed this and showed some of the most recent data in
prostate cancer and lung cancer.33 This has potential for study in other gastrointestinal
malignancies, including RCC.

Thomas E. Hutson, DO, PharmD, FACP: I think this was a very exciting meeting, and
we look forward to seeing some of these topics presented at the 2009 ASCO GU meeting
being expanded upon at the 2009 ASCO Annual Meeting, which is going to be at the end
of May this year.



                                            11
Robert J. Motzer, MD: I agree. I’d like to take this opportunity to thank Tom Hutson
for joining me in this session and providing information and his opinions on the
important aspects of this exciting meeting.

References
1.    American Cancer Society. Cancer Facts and Figures 2008. Atlanta, GA:
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2.    Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell
      cancer. Cochrane Database Syst Rev. 2005(1):CD001425.
3.    Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both
      for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281.
4.    Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-
      cell carcinoma. N Engl J Med. 2007;356(2):125-134.
5.    Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-
      2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind
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6.    Bukowski RM, Eisen T, Szczylik C, et al. Final results of the randomized phase
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7.    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in
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8.    Figlin R, Hutson T, Tomczak P, et al. Overall survival with sunitinib versus
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9.    Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal
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10.   Motzer RJ, Escudier B, Oudard S, et al. RAD001 vs placebo in patients with
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11.   Dutcher J, de Souza P, Figlin R, et al. Effect of temsirolimus versus interferon-α
      on survival of patients with advanced renal cell carcinoma of different tumor
      histologies. ASCO 2008 Genitourinary Cancers Symposium. 2008 (abstr 384).
12.   Georgiou HD, Namdarian B, Corcoran NM, et al. Circulating endothelial cells as
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13.   Morgan TM, Lange PH, Vessella RL. Detection and characterization of
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14.   Harzstark AL, Ryan CJ. Novel therapeutic strategies in development for prostate
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15.   Sarvis JA, Thompson IM. Prostate cancer chemoprevention: update of the
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      Curr Oncol Rep. 2008;10(6):529-532.
16.   Motzer R, Figlin R, Hutson T, et al. Sunitinib versus interferon-alfa (IFN-α) as
      first-line treatment of metastatic renal cell carcinoma (mRCC): updated results
      and analysis of prognostic factors. J Clin Oncol 2007 ASCO Annual Meeting Proc
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17.   Bhargava P, Esteves B, Lipatov O, et al. Activity and safety of AV-951, a potent
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18.   Kay A, Motzer R, Figlin R, et al. Updated data from a phase III randomized trial
      of everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC).
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19.   Motzer R, Escudier B, Oudard S, et al. RAD001 vs placebo in patients with
      metastatic renal cell carcinoma (RCC) after progression on VEGFr-TKI therapy:
      Results from a randomized, double-blind, multicenter Phase-III study. J Clin
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20.   Hutson T, Davis I, Machiels J, et al. Pazopanib (GW786034) is active in
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21.   Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with
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22.   Escudier B. In discussion of: Bhargava P, Esteves B, Lipatov ON, et al. Activity
      and safety of AV-951, a potent and selective VEGFR1, 2 and 3 kinase inhibitor,
      in patients with renal cell carcinoma (RCC): interim results of a phase II
      randomized discontinuation trial. ASCO 2009 Genitourinary Cancers Symposium.
      2009 (abstr 283).
23.   Thomas G. mTOR pathway: biologic rationale for targeting in renal cell cancer.
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24.   Mier J, Kumar M, Bhatt R, et al. Mechanisms of acquired resistance to VEGF
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25.   Ganapathi R. Pharmacogenetics/polymorphism: side effects and comorbidity, and
      predisposition to toxicity. ASCO 2009 Genitourinary Cancers Symposium. 2009
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26.   Klein E, Lippman S, Goodman P, et al. The Selenium and Vitamin E Cancer
      Prevention Trial (SELECT): Southwest Oncology Group Study S0000. ASCO
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27.   Small E, Demkow T, Gerritsen W, et al. A phase III trial of GVAX
      immunotherapy for prostate cancer in combination with docetaxel versus
      docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer
      (CRPC). ASCO 2009 Genitourinary Cancers Symposium. 2009 (abstr 7).




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28.   Dearnaley D, Mason M, Parmar M, et al. Survival benefit with oral sodium
      clodronate in metastatic but not localised prostate cancer: long-term results of
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29.   Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical
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30.   Lacerna L, Hohneker J. Zoledronic acid for the treatment of bone metastases in
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31.   Polascik TJ. Bone health in prostate cancer patients receiving androgen-
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32.   Scher H, Fleisher M, Heller G. Use of circulating tumor cells to guide individual
      patient management. ASCO 2009 Genitourinary Cancers Symposium. 2009
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33.   Haber D. Microfluidic isolation and molecular analysis of circulating tumor cells.
      ASCO 2009 Genitourinary Cancers Symposium. 2009 [keynote lecture].




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