The OBR Blog

February 24, 2011 - 10:02 am Posted in Featured comments0 Comments

By Julie Moloney, IntrinsiQ, LLC

Since Avastin’s 2008 FDA approval for breast cancer, IntrinsiQ data—which tracks use of all drugs for the treatment of cancer, both on- and off-label—have shown the lackluster penetration of Avastin within its indicated metastatic breast cancer market. This lack of use in the indicated market illustrates the fact that physicians do not rely solely on FDA approvals; and, in this case, the agency seemed to realize what most physicians already knew—Avastin was not providing value in the first-line setting for breast.

According to the IntrinsiQ data, physicians are more often using Avastin in breast cancer off-label. More importantly, this use is defensible given the extended time to progression the drug provides over non-Avastin therapy in the metastatic setting.

In July ’10, when an FDA advisory panel voted in favor of removing breast cancer as an approved indication for Avastin, our data tracking was already showing that Avastin was not performing as expected in Met 1. Therefore, the FDA’s December ’10 ruling to remove Avastin‘s breast cancer labeling came as no surprise.

The question now is what does the future hold for Avastin? Clues to Avastin’s fate, like the evidence found in the IntrinsiQ data supporting the FDA decision, can be found in its past usage.

In February ’08, Avastin was granted accelerated approval by the FDA for use in combination with paclitaxel to treat HER2-negative metastatic breast cancer patients receiving initial therapy. The FDA approved the combination with the condition that additional studies be performed. However, the approval did not translate into a strong willingness by physicians to use the combination in metastatic first-line therapy.

Our data on Avastin’s penetration into front-line HER-2 negative metastatic breast cancer typically remained under 10% from approval in February ’08 through December ’10. Shares hit a peak of 11% at the beginning of 2010 so physicians, obviously, did not adopt the combination therapy in this patient population as hoped. Possibly, due to the lack of compelling evidence.

Through December ’10, only about 10% of patients receiving Avastin in the metastatic breast setting are receiving it according to the first-line setting labeling. Even when loosening the definition to include combinations with any taxane, only about 20% is on-label use. While more than half of Avastin use is with a taxane, the vast majority of the time, the off-label use is with patients who previously received chemotherapy for metastatic disease. Additionally, after initial therapy fails, Avastin is not only being paired with paclitaxel, but also with agents such as Celgene’s Abraxane and other typically monotherapeutic treatments such as gemcitabine and vinorelbine.

Doctor Knows Best

Physicians typically refer to clinical trials, compendia listings, NCCN guidelines, and their own clinical experience to determine the best course of care for their patients.

Obviously, the FDA’s ruling in July ‘10 had an adverse effect on the use of Avastin in breast cancer, causing large decreases in sales, but it by no means stopped all use of the product in this setting. While the FDA decision does influence, it does not completely dictate drug usage. In fact, we start to see a flattening in the decline at the end of 2010, which could be due, in part, to the NCCN affirming its recommendation for use of Avastin in the treatment of metastatic breast cancer.

Accompanying the NCCN affirmation, a revision in the related guideline footnote now reads:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

This modification highlights that, while increased overall survival is not obtained, there is benefit seen in time to progression and response rates. This is likely one of the reasons we see more Avastin use in subsequent lines of therapy, rather than as a first-line of defense.

Physicians have become familiar with Avastin, and the IntrinsiQ data underscore the decision being made by physicians to use Avastin in latter lines of metastatic disease rather than first line. We see in our data that, on average, patients who receive Avastin have a longer time to progression, compared with those patients not receiving the drug when it is given as a second or later treatment option. Data also suggest that the same is not true, on average, in the metastatic first-line setting.

This use of Avastin in the latter lines of metastatic therapy, where it has the most impact, is further supported by NCCN guidelines which cite the benefit beyond initial therapy and confirmed by IntrinsiQ analysis of actual clinical usage.

Looking to the future, while the volume of patients prescribed Avastin for breast cancer will not grow to reach prior levels, physicians will continue to incorporate the drug into treatment, particularly in second-line or latter settings where options become more meager and the use of Avastin shows clinical advantage in terms of time to progression.

The next question then becomes, when used:  where does Avastin fit best in the sequencing of therapies, particularly with new therapies like Eisai’s Halavan, available for latter line treatments?

Julie Moloney is director of pharmaceutical product development for IntrinsiQ, LLC the market research company that works with oncology clinicians and pharmaceutical teams to advance the understanding of cancer care. She can be reached at Julie.Moloney@IntrinsiQ.com.

February 16, 2011 - 06:02 am Posted in Featured comments0 Comments

February 15, 2011: The study of detection, treatment, and management of prostate cancer is moving forward, according to three presentations slated for the upcoming ASCO Genitourinary Cancers Symposium February 17-19, 2011, in Orlando, Florida. The presentations were highlighted at a pre-meeting press cast.

The first study suggests that a baseline prostate specific antigen (PSA) of 3 is an appropriate cut-off for the need for biopsy, and men with PSA <3 can be screened at much longer intervals than is the current standard. The second presentation found that dutasteride, a drug commonly used to treat an enlarged prostate gland, can delay the progression of prostate cancer in men with early, low-risk prostate cancer currently managed by active surveillance (i.e., “watchful waiting”). The final presentation found that although robotically-assisted laparascopic radical prostatectomy (RALP) is widely used in the U.S. to remove a cancerous prostate gland, the learning curve to achieve the necessary expertise is much longer than has been assumed.

Prostate Specific Antigen <3

The first study focused on a cohort of Dutch men enrolled in the larger European Randomized Study of Screening for Prostate Cancer. The cohort comprised 42,376 men aged 55 to 74 years living in the greater Rotterdam area. Participants were randomized to either screening or control. About 20,0000 men were initially screened for prostate cancer, and biopsies were recommended for those with PSA scores of 3 or higher with 4-year screening intervals. Of 19,950 men, 15,758 (79%) had an initial PSA <3. After 11 years of follow-up, 915 men developed prostate cancer and 23 died.

Among men with baseline PSA <3, incidence of prostate cancer, aggressive prostate cancer, and death from prostate cancer increased with increasing PSA levels. Men with baseline PSA between 1 and 1.9 had a 4-fold increase in prostate cancer compared with men whose baseline PSA was <1; men with a baseline PSA of 2 to 2.9 had a 10-fold increase in prostate cancer compared to those with a baseline PSA <1.  Similar trends were observed for the risk of developing aggressive prostate cancer and for prostate cancer-related death, although the incidence of deaths was quite low among all men with baseline PSA <3, said lead author Monique Roobol, PhD, an epidemiologist in the Department of Urology at Erasmus University Medical Center in The Netherlands.

“According to these Dutch data, men aged 55 to 74  with a baseline PSA <1 could be screened at 8-year intervals. This study suggests we can reduce the intensity and frequency of screening for prostate cancer,” stated Nicholas Vogelzang, MD, moderator of the press cast. Dr. Vogelzang is Chair and Medical Director of the Developmental and Therapeutics Committee of US Oncology.

Treatment with Dutasteride

A multicenter, placebo-controlled, phase 3 study suggested that 3 years of treatment with dutasteride [Avodart; GlaxoSmithKline]—a drug commonly used to treat benign prostatic hyperplasia—may also be useful as part of a “watchful waiting” strategy (i.e., active surveillance) to delay the progression of prostate cancer in men with early prostate cancer. Among 302 men with low-risk, early stage prostate cancer enrolled in the REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer) study, dutasteride delayed the time to prostate cancer progression, increased the percentage of men with no detectable prostate cancer on repeat biopsy, and improved anxiety related to prostate cancer. The study was sponsored by GlaxoSmithKline.

Many men with low-risk prostate cancer assigned to active surveillance, experience anxiety because they are not getting any treatment for their cancer. Dutasteride lowers this anxiety, partly because the men are getting some treatment and partly because the drug typically lowers the PSA level, providing reassurance to patients. In addition to relieving anxiety, dutasteride delayed the progression of prostate cancer, said lead author Neil Fleshner, MD, who is Head of Urology at the University Health Network in Toronto, Ontario, Canada, and Love Chair in Prostate Cancer Prevention at the Princess Margaret Hospital in Toronto. Dr. Fleshner emphasized that this is an off-label use of dutasteride, but said in his opinion, men with low-risk prostate cancer should consider use of this drug.

Men with low-risk prostate cancer were randomized to dutasteride or placebo for 3 years and had repeat 12-core biopsies performed at 18 and 36 months or at any time during the study for indications of disease progression. Dutasteride reduced time to cancer progression by 38.9% relative to placebo (P=.007). Prostate cancer progression was found in 54 patients (38%) in the dutasteride group vs 71 (49%) in the placebo group.  Men in the dutasteride group also had less chance of prostate cancer detected at the final biopsy. At the final biopsy, 50 (36%) in the dutasteride group vs 31 (23%) in the placebo group had no cancer detected.

No new drug-related adverse events related to dutasteride were found in the trial.

Robotically-assisted Laparascopic Radical Prostatectomy

A separate retrospective review of 3794 patients who underwent RALP between 2003 and 2009 found that it took 3 surgeons a total of 1600 RALP procedures to achieve competence at an acceptable level, which is having positive surgical margins in less than 10% of tumors resected. The 3 surgeons worked at high-volume centers. The investigators of this study did not report the number of cases it took per surgeon to gain expertise; rather, they presented the total number of procedures for all 3 surgeons.

RALP has enjoyed exponential growth in the U.S., although not in Europe and the U.K. Currently about 80% of the 90,000 radical prostatectomies performed in the U.S. are done robotically, said lead author Prasanna Sooriakumaran, MD, PhD, a visiting fellow at the Weill Cornell Medical College in New York City.

The findings of this study are contrary to common assumptions about RALP, he continued. It takes much more experience to achieve technical competence than has been commonly assumed. The reported learning curve for RALP is 25 to 40 cases for safety, but these figures do not address surgical outcomes in terms of positive or negative margins of the tumor specimen.

“Even for surgeons who perform hundreds of these surgeries a year [as in the study], it takes a long time to get to the stage where they are getting the best possible cancer control results. This study suggests that RALP should only be used by high-volume surgeons at centers of excellence and not at community hospitals. Surgeons who want to learn how to do this procedure should train at high-volume hospitals,” stated Dr. Sooriakumaran.

He said that there are no good studies that compare the learning curves of open radical prostatectomy with typical laparoscopic prostatectomy or RALP. “There are only case studies,” he noted.

By Alice Goodman

February 11, 2011 - 09:02 am Posted in Featured comments0 Comments

As a continuation of the collaboration between OBR and MDoutlook, we will be presenting you with a series of detailed post-ASH and post-SABCS trends research into the immediate clinical impact and integration of research presented at both meetings. The trends research is based on a series of Quick Polls across the MDoutlook platform of 47,000 cancer treaters globally. Feedback was collected within one week of each meeting and from more than 500 cancer treaters (approx 40% of respondents were attendees). No financial incentives were provided to participants.

This report covers the immediate impact on breast cancer management.

Attendance at 2010 SABCS

Key Conclusions

  • Just over 1/3 of survey respondents attended SABCS in 2010
    • Slightly higher proportion of EX-US respondents attended meeting (47% vs 34%)
  • Indicates the importance of this meeting as source of information is much wider than only those in attendance

SABCS and ASCO are Top Live Meetings for New Developments in Breast Cancer

Key Conclusions

  • SABCS and ASCO were ranked as the most important sources of information for breast cancer
    • Similar results as post-ASCO Quick Polls
  • Although low number of respondents selected “Other,” it was very important to those who did

Abstract Title

  • Ranking was done from 1 = Least important to 7 = Most Important
  • Average ranking for each meeting was calculated from all respondents
  • “Most important” defined as a ranking of 7  by those who ranked that meeting
  • EBCC = “European Breast Cancer Conference”

Oncologists Appreciate the Importance of Having a Choice Between Steroidal and Non-Steroidal Aromatase Inhibitors

Key Conclusion

  • Half of oncologists rated the equivalence of steroidal and non-steroidal AIs as adjuvant therapy as having a high impact on their clinical practice

Oral Presentation Title

  • Oral Presentation S1-1: “Final Analysis of NCIC CTG MA.27: A Randomized Phase III Trial of Exemestane Versus Anastrozole in Postmenopausal Women with Hormone Receptor Positive Primary Breast Cancer.”

CYP2D6 Genotyping Will Not Play an Important Role in Determining Tamoxifen Usage as Adjuvant Therapy for
Breast Cancer in 2011

Key Conclusions

  • Use of CYP2D6 genotyping will be reduced by half in 2011 compared to today’s levels
  • Most oncologists will NOT use CYP2D6 at all
  • Calculated use drops from 10.5% of patients to 5.7%
  • Few strong proponents of this diagnostic methodology

Oral Presentation Titles

  • Oral Presentation S1-7: “Lack of Correlation between Gene Variants in Tamoxifen Metabolizing Enymes with Primary Endpoints in the ATAC Trial.”
  • Oral Presentation S1-8: “Outcome According to CYP2D6 Genotype among Postmenopausal Women with Endocrine-Responsive Early Invasive Breast Cancer Randomized in the BIG 1-98 Trial.”

The Results of the AZURE Trial Will Have a High Impact on Clinical Practice for Breast Cancer

Key Conclusions

  • Vast majority of respondents see the results of the AZURE trial as being highly important to their clinical practices
  • Suggests that knowing what not to do may be as important as new therapeutics
  • Additional studies are needed to see if these results impact use of zoledronic acid in other types of metastatic cancers and/or for the prevention of osteoporosis in women who had / have breast cancer

Oral Presentation Title

  • Oral Presentation S4-5: “Adjuvant Treatment with Zoledronic Acid in Stage II/II Breast Cancer: The AZURE Trial (BIG 01/04)”

Targeting HER2 with Multiple Agents Will Have Significant Clinical Implications for the Management of HER2+ Breast Cancer

Key Conclusions

  • Strategies that combine multiple ways of targeting HER2 is seen as a very important clinical approach for HER2+ breast cancer
  • Adding lapatinib to trastuzumab is currently seen as a slightly better approach than adding another antibody (pertuzumab)
    • May reflect the current availability and clinical familiarity of lapatinib

Oral Presentation Titles

  • Oral Presentation S3-1: “Lapatinib vs Trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: Primaryefficacy endpoint analysis of the GEPARQUINTO STUDY (GBG 44).”
  • Oral Presentation S3-2: “Neoadjuvant pertuzumab (P) and trastuzumab (H): Antitumor and safety analysis of a randomized phase II study (‘NeoSphere’).”
  • Oral Presentation S3-3: “First results of the NeoALTTO trial (BIG 01-06/EGF 106903): A phase III , randomized, open label, neoadjuvant study of Lapatinib, Trastuzumab, and their combination plus Paclitaxel in women with HER 2-positive primary breast cancer.”

Usage of Lapatinib + Trastuzumab Dual HER2 Inhibition Approach Will Double in 2011

Key Conclusions

  • Just over half of oncologists reported using the dual HER2-targeted approach (lapatinib + trastuzumab) in at least some of their breast cancer patients in 2010
  • Vast majority (~85%) expect to use this approach in 2011
  • Almost twice as many HER2+ breast cancer patients are expected to receive this dual approach in 2011 as compared to 2010
    • 25.0% vs 12.9%

Awareness and Rating of New Therapeutics Being Developed for Breast Cancer

Key Conclusions

  • Parp inhibitors (olaparib, iniparib, ABT-888) and novel HER2-targeted agents (TDM-1 and neratinib) are highly regarded new therapeutics in development for breast cancer
    • Little difference in ratings among the 3 Parp inhibitors
  • Overall awareness has very good correlation with ratings
    • Consistent with stage of clinical development

Additional Information

  • Each drug was rated  independently on a scale from 1 = Little to No Impact to 10 = Very large Impact
  • Respondents were asked to consider only the relevant population of breast cancer patients (ie. HER2+ disease for HER2-targeted agents, etc.)
  • Average rating was calculated ONLY from those respondents who were aware of the drug
  • % unaware calculated from the total number of respondents

Conclusions from the 33rd Annual San Antonio Breast Cancer Symposium Quick Poll

  • SABCS is a very important source of information about new developments in breast cancer for the global community of oncologists
  • Oncologists recognize that CYP2D6 genotype does not impact tamoxifen responsiveness and will reduce their testing of it accordingly
  • Results from the AZURE trial showing that adjuvant zoledronic acid has no effect on disease free survival in breast cancer is very important
  • The results of the MA.27 trial showing relatively equal efficacy of steroidal and non-steroidal AIs is impactful but not quite as much as those of the AZURE trial
  • Using two or more agents targeting HER2 is going to become a widely used therapeutic approach
  • New Parp inhibitors have wide levels of awareness and are expected to be very important therapeutics for breast cancer (presumably triple negative subtypes)
  • New HER2 targeted agents TDM1 (antibody-drug conjugate) and neratinib (oral HER2 and EGFR TKI) are also widely expected to be effective new agents

Final Thoughts

Quick polls are a fast way of measuring expected acceptance of clinical data post major medical meetings, and perhaps can be used to make some assumptions about adoption amongst providers. In today’s information hungry environment, the speed at which these polls can be conducted and analyzed can be advantageous for market planning and “pressure testing” acceptance of data amongst key stakeholders.

Submitted by Jan Heybroek, President, The Arcas Group

Email Jan Heybroek

February 03, 2011 - 10:02 am Posted in Featured comments0 Comments

As a continuation of the collaboration between OBR and MDoutlook, we will be presenting you with a series of detailed post-ASH and post-SABCS trends research into the immediate clinical impact and integration of research presented at both meetings. The trends research is based on a series of Quick Polls across the MDoutlook platform of 47,000 cancer treaters globally. Feedback was collected within one week of each meeting and from more than 500 cancer treaters (approx 40% of respondents were attendees). No financial incentives were provided to participants.

This report covers Acute Myeloid Leukemia (AML).

The JAK2 Inhibitor INCB018424 Will Have a Clinically Important Role for Some Patients with Acute Myeloid Leukemia (AML)

Key Conclusions

  • Most oncologists are aware about the new JAK2 inhibitor INCB018424
  • About a half believe INCB018424 will be effective for a subset of patients with AML
    • Dependent on clinical suitability of patient AND regulatory approval / availability
  • Little difference in the expectations for primary vs secondary AML

 Abstract Title

  • Abstract 509: “Phase II Study of the JAK2 Inhibitor, INCB018424, In Patients with Refractory Leukemias Including Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML)”

Administration Schedule Has a Moderate Level of Importance in Both Primary and Secondary AML

Key Conclusions

  • Administration schedule has a moderate level of importance when deciding on of treatment choice for AML
  • No real difference in importance between primary and secondary AML
  • Average 5.4 (primary) vs 5.8 (secondary)

 Additional Information

  • Respondents rated the importance of administration schedule on a scale of 1 = Not at all important to 10 = Extremely important

Arsenic Trioxide Is Expected to Be Very Clinically Important for Acute Promyelocytic Leukemia (APL)

Key Conclusions

  • > 3/4 of oncologists have high expectations for the use of arsenic trioxide (ATO) in relapsed setting for APL
  • Expectations for ATO’s use in the front-line setting are nearly as high
  • Fewer than 10% have low ratings for either abstract
    • Dependent on clinical suitability of patient AND regulatory approval / availability

Abstract Titles

  • Abstract 15: “Treatment of Molecular and Clinical Relapse of Acute Promyelocytic Leukemia (APL) with Arsenic Trioxide: Results of the European Registry of Relapsed APL”
  • Abstract 505: “Arsenic Trioxide (ATO) In the Consolidation Treatment of Newly Diagnosed APL – First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian Swiss APL Group”

CPX-351 Will Have Some Impact on Clinical Practice for Acute Myeloid Leukemia (AML)

Key Conclusions

  • About half of oncologists rated the use of  CPX-351 in AML as Medium
  • 3x more rated it High / Very High than Low / Very Low
  • Suggests most will at least consider using CPX-351 in AML when appropriate
  • Dependent on clinical suitability of patient AND regulatory approval / availability

Abstract Title

  • Abstract 655: “Phase 2B Randomized Study of CPX-351 Vs. Cytarabine (CYT) + Daunorubicin (DNR) (7+3 Regimen) In Newly Diagnosed AML Patients Aged 60-75”

Awareness and Expected Clinical Impact of New Therapeutics for Acute Myeloid Leukemia

Key Conclusions

  • New therapeutics are either well-known or relatively unknown
    • High level of awareness may reflect the limited availability of highly effective treatments for these diseases
    • Lower level of awareness are at early stages of clinical development
  • Most likely that these additional agents will be used in specific patient populations
    • Clofarabine may have significant impact for many with AML)

Abstract Title

  • Respondents indicated the type and extent each drug would impact the treatment landscape (or if unaware of the drug) in AML
    • May have different impacts in other therapeutic areas
  • Values ≤5% not shown

Conclusions from the ASH 2010 Quick Poll on Acute Myeloid Leukemia (AML)

  • The use of arsenic trioxide in APL, both in the front line and relapsed settings, is seen as a clinically important advance
  • Administration schedule plays only a somewhat important role in selecting a treatment regimen for AML
  • Concordantly, CPX-351 is predicted to have a modest impact on the AML clinical landscape
  • For new therapeutics currently under clinical development, there is not much differentiation between primary and secondary AML
    • Unknown if this is due to the lack of awareness on the part of the respondents or to a clinical differentiation
  • Most new drugs being studied in AML are expected to be used in selected subsets of patients, reflecting the growing awareness of molecular subtypes of AML
    • As expected, levels of awareness correspond with stage of clinical development

Final Thoughts

Quick polls are a fast way of measuring expected acceptance of clinical data post major medical meetings, and perhaps can be used to make some assumptions about adoption amongst providers. In today’s information hungry environment, the speed at which these polls can be conducted and analyzed can be advantageous for market planning and “pressure testing” acceptance of data amongst key stakeholders.

Submitted by Jan Heybroek, President, The Arcas Group

Email Jan Heybroek

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