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  • Beyond KRAS exon 2: Research at ASCO and Important Treatment Implications for Metastatic Colorectal Cancer

    New biomarker data in metastatic colorectal cancer (mCRC) presented at ASCO 2014 showed clinical implications of RAS mutations. The influence of RAS mutations on testing and treatment patterns of mCRC has profound implications on a tumor’s behavior throughout the course of the disease.

    The EGFR monoclonal antibodies, Erbitux® (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck KGaA) and Vectibix® (panitumumab, Amgen), have been shown to benefit patients with wild-type KRAS, but not patients with mutant KRAS exon 2. In Europe, both drugs’ labels were restricted to KRAS wild-type patients. The FDA recommended in 2009 that both drugs be used only in patients with wild-type KRAS.

    To understand the implications of some KRAS exon 2 wild-type patients not benefiting from anti-EGFR therapy, a retrospective analysis of the PRIME study evaluated the benefit of increasing the definition of a KRAS mutation. PRIME randomized 1,183 previously untreated patients to FOLFOX or FOLFOX plus Vectibix. Vectibix’s benefit was seen only in patients with KRAS exon 2 wild-type. (Douillard, J  Clin Oncol, 2010). PRIME followed patients forward, studying all RAS mutations, other mutations in KRAS, and mutations in NRAS. Expanding the definition of RAS wildtype to include other KRAS mutational sites as well as NRAS improved the HR for progression or death with combination therapy from 0.80 to 0.72. Progression-free survival was not improved by Vectibix in KRAS exon 2 wild-type patients who had other KRAS mutations in other exons (HR 1.28); (Douillard, NEJM, 2013).

    The PEAK Study, presented at ASCO 2013, evaluated Vectibix in mCRC patients with wild-type KRAS exon 2 and in patients wild-type for exons 3 and 4 of KRAS, and in exons 2, 3 or 4 of NRAS. Comparing Vectibix plus mFOLFOX6 or Avastin plus mFOLFOX6, 285 patients were randomized. In the KRAS exon 2 wild-type intent-to-treat group, progression-free survival was not significantly different between the two arms (HR 0.62, p=0.353). In the extended RAS wild-type subgroup,[1] patients on the Vectibix arm had a progression-free survival benefit (HR 0.65, p=0.029) compared to patients treated with the Avastin combination (Schwartzberg, J Clin Oncol, 2014).

    Retrospective RAS mutation status tumor sample analyses were performed from the OPUS and CRYSTAL studies and presented at ASCO 2014.  In the OPUS study, which evaluated FOLFOX4 plus Erbitux versus FOLFOX4 alone, Erbitux improved progression-free survival in KRAS exon 2 wild-type patients (Bokemeyer, Ann Oncol, 2011). Extended RAS mutations, beyond those in exon 2, were detected in 26% of patients. Extending this to consider both KRAS exon 2 and the extra possible mutation sites indicated further Erbitux benefit, as Erbitux had no benefit in KRAS exon 2 wild-type patients who possessed other KRAS mutations (median PFS: 7.5 months vs. 7.4 months, HR 0.77, p=0.60; Bokemeyer, Abstract 3505, ASCO 2014).

    The CRYSTAL study, Erbitux and FOLFIRI was associated with a significantly improved progression-free survival benefit compared to FOLFIRI in patients with the KRAS exon 2 wild-type phenotype (Van Cutsem, NEJM, 2009). Extended RAS mutations beyond that of KRAS exon 2 were detected in 15% of KRAS exon 2 wild-type patients. In these extended RAS wild-type patients, a significant benefit was associated Erbitux and FOLFIRI; mean progression-free survival: 11.4 months versus 8.4 months, HR 0.56, p=0.0002.  In patients with wild-type KRAS exon 2 but with mutations in other locations in KRAS or NRAS, there was no benefit from adding Erbitux to FOLFIRI in progression-free survival (7.2 months versus 6.9 months, HR 0.81, p=0.56; Ciardiello, Abstract 3506, ASCO 2014).

    Kantar Health’s CancerMPact® Biomarker Analysis Report reports approximately 36% of US CRC patients possess KRAS exon 2 mutations. Nearly 18,000 mCRC patients in 2014 are ineligible for first-line treatment with an anti-EGFR monoclonal antibody. These trials’ retrospective analyses suggest that 15-26% of patients who are seemingly wild-type for KRAS exon 2 actually possess other RAS mutations. For a common tumor like CRC, the percentage of patients not benefiting from targeted therapy is considerable.

    Also, discordance among tumor lesions has important testing implications. An ASCO 2014 presentation examined whether KRAS biomarker status was consistent between various lesions in mCRC patients. In 115 pairs of sequenced primary and metastatic tissue, the KRAS mutation concordance rate was 89%. Chemotherapy was associated with 3.5-times higher odds of discordance compared to patients who did not receive therapy between resection of primary and metastatic tumors (P = 0.008; Kopetz, Abstract 3509, ASCO 2014). A cohort of 10 patients showed that KRAS variant allele frequency differed between primary and metastases based on treatment.  (Graham, Abstract 3510, ASCO 2014). RAS mutation testing will likely be subject to mutation status discordance between the primary tumor and metastasis in mCRC, with important treatment and prognostic ramifications.

    Data at ASCO 2014 showed that anti-EGFR monoclonal antibodies are inactive in patients with KRAS exon 2 mutations and in patients with a mutation in any part of KRAS or other RAS genes. Retrospective analyses indicate that it is not sufficient to test mCRC patients for only KRAS exon 2 mutational status, but that all RAS mutations should be considered during pathological evaluation. Only patients who are wild-type for all RAS genes should be treated with EGFR-inhibitors. While the European Medicines Agency has already modified its authorization for Erbitux and Vectibix to exclude patients with any RAS mutations, the FDA still labels these agents for patients without KRAS exon 2 mutations. Discussions to expand the FDA label are presumed to be under way.

    Submitted by Julie Katz, MPH, M.Phil., Associate Consultant, Global Oncology Epidemiology, Kantar Health and Arnold DuBell, Ph.D., Consultant, Kantar Health


    [1] KRAS having no mutations in exons 2, 3 and 4 as well as being NRAS wild-type

    Melanoma: Immediate Impact of 2014 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from ASCO 2014, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ from the meeting. This third report explored presentations in Melanoma.

    OncoPoll™ Methodology

    • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in melanoma utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
    • Timing: June 2014. Launched three days after close of 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 30-June 3, 2014
    • Fielding via <10 minute long interactive internet survey utilizing proven effective methodology via the MDoutlook survey tool
    • Links to discussed abstracts on the ASCO website were provided within the survey
    • Reponses at data collection: 48 on June 24th
    • No financial incentives provided for participation

    Geographic Distribution of Respondents

    Attendance at 2014 ASCO Annual Meeting

    Key Conclusions

    • 60% of survey respondents attended this year’s ASCO annual meeting
    • Greater proportion of attendees than in previous years (typically has been a 50/50 split)

    Survey Participants’ Melanoma Patient Flow: Averaged 45 Total Cases Each Quarter

    Key Conclusions

    • Survey participants* averaged 45 total cases of melanoma in the last 3 months
    • The highest average proportion of cases were represented by stage IV M1c (11 patients or 24%)
      • Oncologists saw eight or fewer patients on average for all other stages over the span of three months

    * Survey Participants = Medical Oncologists with an identified clinical interest in melanoma

    Impact of New Monoclonal Antibodies Targeting the PD-1/PD-1L Axis for Melanoma Immunotherapy Treatments

    Key Conclusions

    • Considering both clinical efficacy and potential adverse events, oncologists have given nivolumab + ipilimumab, nivolumab alone, and pembrolizumab very high ratings
      • Nivolumab + ipilimumab: 5.71 (out of 7)
      • Nivolumab alone: 5.35
      • Pembrolizumab: 5.22
      • Pidilizumab was rated the lowest by oncologists, with a score of 4.39 out of 7

    Forecasting the Integration of Immune Checkpoint Inhibitor Targeting PD-1/PD-1L Axis for Metastatic Melanoma Patients

    Key Conclusions

    • The highest proportion of metastatic melanoma patients that would receive an immune checkpoint inhibitor targeting the PD-1/PD-1L axis are BRAF wild-type patients in their 1st line of treatment (58%) vs. 31% of BRAF V600E/K patients
    • Equal proportions (45%) of BRAF V600E/K and BRAF wild-type patients would receive an immune checkpoint inhibitor targeting the PD-1/PD-1L axis in the 2nd line of treatment
      • Progressively fewer patients would receive an immune checkpoint inhibitor in subsequent lines of treatment

    Importance of Ipilimumab in the Adjuvant Setting for Metastatic Melanoma

    Key Conclusions

    • 75% of oncologists believe ipilimumab will be somewhat important or important as an adjuvant treatment for stage III disease due to improvements in relapse-free survival (RFS) without corresponding benefits in overall survival (OS)
    • 93% of oncologists believe ipilimumab will be somewhat important to very important as an adjuvant treatment for stage III disease due to improvements in RFS and OS

    Impact of the OPTIM Trial – T-VEC’s Effect on Unresectable Melanoma

    Key Conclusions

    • The majority of oncologists (68%) believe that, if gaining regulatory approval, T-VEC will only impact a minority of patients with unresectable melanoma
    • Only 18% of oncologists believe that T-VEC will impact a majority of patients with unresectable melanoma

    Conclusions: Impact of ASCO 2014 on Clinical Practices for Melanoma

    • Survey participants averaged 45 cases of melanoma in the last 3 months
      • The highest proportion of cases were represented by stage IV M1c (24%)
    • Considering both clinical efficacy and potential adverse events, oncologists have given nivolumab + ipilimumab, nivolumab alone, and pembrolizumab very high ratings (>5 out of 7)
    • The highest proportion of metastatic melanoma patients that would receive an immune checkpoint inhibitor targeting the PD-1/PD-1L axis are BRAF wild-type patients in their 1st line of treatment (58%) vs. 31% of BRAF V600E/K patients
    • 75% of oncologists believe Ipilimumab will be somewhat important or important as an adjuvant treatment for stage III disease with only improvements in relapse-free survival (RFS)
    • 93% of oncologists believe Ipilimumab will be somewhat important to very important as an adjuvant treatment for stage III disease with improvements in RFS and OS
    • The majority of oncologists (68%) believe that, if gaining regulatory approval, T-VEC will only impact a minority of patients with unresectable melanoma

    For a more detailed analysis report, please click here to download the full report.

    Submitted by Robert Stephan, Sr. Director Medical Services and Strategy; Jessica Harnisch, Assoc. Global Medical Analyst; and Jan Heybroek, President MDoutlook.

    CLL & Mantle Cell Lymphoma: Immediate Impact of 2014 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from ASCO 2014, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ from the meeting. This second report explored presentations in Chronic lymphocytic leukemia (CLL) and other B cell lymphomas.

    OncoPoll™ Methodology

    • Primary research phase involved a global survey to verified and validated oncologists and multi-disciplinary physicians with an identified clinical interest in CLL and other B cell lymphomas utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
    • Timing: June 2014. Launched three days after close of 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 30-June 3, 2014
    • Fielding via <10 minute long interactive internet survey utilizing proven effective methodology via the MDoutlook survey tool
    • Links to discussed abstracts on the ASCO website were provided within the survey
    • Reponses at data collection: 49 on June 24th
    • No financial incentives provided for participation

    Geographic Distribution of Respondents

    Attendance at 2014 ASCO Annual Meeting

    Key Conclusions

    • Less than 50% of survey respondents attended this year’s ASCO annual meeting
    • Fewer proportion of attendees than in previous years (typically has been a 50/50 split); also lower than for two other ASCO2014 OncoPolls. This reflects higher percentage of hematologic oncologists as survey respondents who more typically attend ASH and EHA instead of ASCO

      P

      Survey Participants’ CLL and Other B Cell Lymphoma Patient Flow:  Averaged at Least 16 CLL Cases Each Quarter

      Key Conclusions

      • Survey participants* averaged 30 cases of CLL (treatment naïve) in last 3 months
        • Nearly double CLL (relapsed/refractory) or DLBCL patients
      • Survey participants* also averaged 19 mantle cell patients in the last 3 months

      * Survey Participants = Oncologists with an identified clinical interest in CLL and other B cell lymphomas

      P

      Usage of Ibrutinib for CLL Patients: Impact of the RESONATE Trial

      Key Conclusions

      • In the next three months, 43% of Del 17p patients and 32% of Del 11q patients are expected to be treated with ibrutinib
      • In comparison to ibrutinib usage for CLL patients in the last three months, the usage of ibrutinib in the next three months for treatment naïve patients is expected to increase by 189%
      • Usage of ibrutinib for relapsed/refractory, Del 17p, and Del 11q patients is expected to increase by ~100% (relative percent increase between 106%-116%)

      P

        Oral Syk Inhibitor for Relapsed/Refractory CLL: Impact of GS-9973

        Key Conclusions

        • Oncologists recognize that there will be a clinical impact due to GS-9973
        • Nearly 40% of oncologists believe that GS-9973 will have a large impact on a minority of relapsed/refractory CLL patients
          • 30% believe that GS-9973 will only have a small impact on a minority of relapsed/refractory CLL patient
        • Only a small percentage (11-15%) of oncologists believe that GS-9973 will have an impact of any size on a majority of these patients

        P

          Impact of VR-CAP in the Front-Line Setting for Mantel Cell Lymphoma

          Key Conclusions

          • A slightly higher proportion of Oncologists would chose to use VR-CAP (42%) for their transplant-ineligible Mantle cell lymphoma patients, in comparison to using R-CHOP (36%)
          • 21% of oncologists would prefer to use other regimens as a front line treatment

          P

            Conclusions: Impact of ASCO 2014 on Clinical Practices for CLL and Mantle Cell Lymphoma

            • CLL-treatment naïve is the largest proportion of lymphoma patients seen in clinical practices
              • Mantle cell lymphoma patients are the second most seen per quarter
            • In comparison to ibrutinib usage for CLL patients in the last three months, the usage of ibrutinib in the next three months for treatment naïve patients is expected to increase by ~200%
              • Usage of ibrutinib for relapsed/refractory, Del 17p, and Del 11q patients is expected to increase by ~100%
            • The highest proportion of oncologists (39%) believe that GS-9973 will have a large impact to a minority of their relapsed/refractory CLL patients
              • A small percentage (11-15%) of oncologists believe that GS-9973 will have an impact of any size on a majority of their of relapsed/refractory CLL patients
            • Oncologists would expect to use VR-CAP in a higher proportion (42%) of their transplant-ineligible Mantle cell lymphoma patients in comparison to R-CHOP (36%)

            P

              For a more detailed analysis report, please click here to download the full report.

              Submitted by Robert Stephan, Sr. Director Medical Services and Strategy; Jessica Harnisch, Assoc. Global Medical Analyst; and Jan Heybroek, President MDoutlook.

              Colorectal Cancer: Immediate Impact of 2014 ASCO Presentations on Clinical Practice

              Introduction

              In an effort to provide you with timely market feedback from ASCO 2014, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ from the meeting. This first report explored presentations in colorectal cancers (CRC).

              OncoPoll™ Methodology

              • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in gastrointestinal cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
              • Timing: June 2014. Launched two days after close of 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 30-June 3, 2014
              • Fielding via <10 minute long interactive internet survey utilizing proven effective methodology via the MDoutlook survey tool
              • Links to discussed abstracts on the ASCO website were provided within the survey
              • Reponses at data collection: 50 on June 24th
              • No financial incentives provided for participation

              Geographic Distribution of Respondents

              Attendance at 2014 ASCO Annual Meeting

              Key Conclusions

              • Nearly three quarters of survey respondents attended this year’s ASCO annual meeting
              • Higher proportion of attendees than in previous years (typically has been a 50/50 split)

              Survey Participants’ GI Cancer Patient Flow:  Average Over 13 Cases Each Month

              Key Conclusions

              • Survey participants* averaged 35 cases of colorectal cancer last 3 months
                • More than all other gastrointestinal cancers combined
              • Cases of pancreatic cancer were much more common than HCC

              * Survey Participants = Medical Oncologists with an identified clinical interest in gastrointestinal cancers

              Inclusion of Bevacizumab or Cetuximab with 1st Line Chemotherapy for KRASWT mCRC: Impact of the CALGB/SWOG 80405 Trial

              Key Conclusions

              • Results of the CALGB/SWOG 80405 Trial are not going to change treatment usage in the 1st line setting
                • Small increases in cetuximab usage are expected, but not at the expense of bevacizumab
              • Inclusion of biologics with chemotherapy for 1st line setting is going to remain the standard of care
                • FOLFOX is and will remain the standard chemotherapy backbone for mCRC

              Adjuvant Chemotherapy for Localized Rectal Cancer: Impact of the ADORE Trial Results

              Key Conclusions

              • Oncologists recognize the clinical importance of the ADORE trial
                • Over half rate the presentation as important or higher
              • Due to these results, usage of adjuvant therapy for stage II rectal cancer is expected to increase by over 1/3 from current levels
                • Usage will be nearly 60% of the amount for stage III disease
              • Widespread usage of adjuvant therapy for stage III disease will continue
                • Slight increase to 80% of cases

              Conclusions: Impact of ASCO 2014 on Clinical Practices for Colorectal Cancers

              • Colorectal cancer is the main type of gastrointestinal cancers seen in clinical practices
                • Oncologists’ patient flow in colorectal cancer is ~85% of their GI cancer patient flow
              • FOLFOX + bevacizumab is and will remain the most common 1st line treatment approach for KRASWT metastatic colorectal cancer
                • Minor increases in usage of cetuximab are expected, but not at the expense of bevacizumab
                • Chemotherapy with a biologic is the standard of care in the 1st line setting
                • FOLFOX will continue to be preferred over FOLFIRI
              • Adjuvant chemotherapy is seen as an important therapeutic approach for stage II and III rectal cancers
                • A 35% increase in its usage for stage II disease is expected, so that nearly half of patients will receive it
                • Widespread usage for stage III disease will expand even more, to 80% of patients
              • Oncologists use a wide variety of sources to learn about the results presented at ASCO

              For a more detailed analysis report, please click here to download the full report.

              Submitted by Robert Stephan, Sr. Director Medical Services and Strategy; Jessica Harnisch, Assoc. Global Medical Analyst; Justin Boag, Consultant; and Jan Heybroek, President MDoutlook.

              New Treatments for Prostate Cancer, CLL, and Melanoma Draw Attention at ASCO 2014

              By Dave Johnson, Vice President, Encuity Research

              The sentiments of oncologists following their experiences at ASCO translate into prescribing behaviors throughout the year. At Encuity Research, we know that the perceptions oncologists take away from ASCO are of high interest to pharmaceutical and biotech companies developing and commercializing products in this space.

              To get a sense of the impact that the 2014 annual meeting of ASCO had on physicians, we surveyed 100 oncologists who attended the event. Oncologists reported that themes centered on new treatments for prostate cancer were the most important new clinical information presented at this year’s ASCO conference. Treatments for breast cancer, melanoma, lung cancer, and chronic lymphocytic leukemia (CLL) followed. Specifically, new treatments for prostate cancer, with an emphasis on docetaxel, were cited by 35% of respondents, while advances in the treatment of breast cancer were cited by 18% of respondents (Figure 1).

              Physicians rated information on Janssen/Pharmacyclic’s Imbruvica in chronic/small lymphocytic leukemia and mantle cell lymphoma the highest for overall value of information at the conference. Top-rated product themes also included Bristol-Myers Squibb’s nivolumab and Yervoy. Information related to Imbruvica in chronic/small lymphocytic leukemia and mantle cell lymphoma was highly rated by 73% of physicians, while information related to nivolumab and Yervoy in melanoma were highly rated by 59% of physicians.

              Unaided, ASCO attendees highlighted news about Imbruvica and Sanofi’s Taxotere as the most valuable product information presented at the 2014 ASCO conference. Both products were cited by 20% of respondents. Nivolumab (18%) was close behind, while Yervoy (10%), Eli Lilly’s ramucirumab (9%), and Astellas/Medivation’s Xtandi (9%) rounded out the top products.

              As in 2012 and 2013, oncologists overwhelmingly named Genentech/Roche as the company providing the most valuable information at ASCO in 2014. Unaided, 66% of physicians named Genentech/Roche as providing the most valuable information, with Bristol-Myers Squibb in second with 35% of mentions, followed by Novartis (26%), Pfizer (22%), and Merck (20%).

              ASCO attendees recognized Pharmacyclics (11%), Gilead (10%), and Teva (9%) as the top three up-and-coming companies in the treatment of cancer. Seattle Genetics ranked fourth (7%).

              Oncologists who attended the 2014 ASCO meeting gave the conference high overall ratings for its value. Over half of physicians rated it as very or extremely valuable, with 94% reporting that it was equal to or more valuable than the 2013 conference. (Figure 2).

              Not only did oncologists find the conference valuable, it was also influential. The percentage of physicians who reported that they are more likely to change patient treatment based on 2014 ASCO findings increased compared with the 2013 conference. Nearly one-quarter (24%) of attendees indicated that they were very or extremely likely to change behavior following the 2014 conference, versus just 16% following the 2013 conference.

              Using research such as this to measure and refine the impact of presenting at critical venues like ASCO is vital for a cost-conscious industry. Through the use of turnkey research, companies can quickly illuminate the influence of their clinical information and promotional efforts on physicians’ perceptions, understanding, and intent to prescribe.

              Download the ASCO Impact Report
              Encuity Research—the market research and analytics subsidiary of Campbell Alliance—conducted this survey to evaluate the relevancy and effectiveness of company-sponsored clinical data and promotions. The full results of the survey are summarized in the ASCO Impact Report, which provides an encompassing view of ASCO attendees’ intent to change treatment plans, their perceptions of clinical information presented, and their ratings of information offered by pharmaceutical and biotech companies. For a full version the ASCO Impact Report, please visit http://www.encuity.com/asco.

              The Three “A’s” of Treatment Options: Approved, Accessible and Affordable. Market Access Implications of Big News from ASCO 2014

              Over the course of five days during ASCO 2014, data from hundreds of clinical trials were shared, answering the question of whether there’s a new treatment option for cancer patients. Increasingly, despite approval the FDA doesn’t have the final say on whether the drug in question represents a viable treatment option for potential patients. Payers too are exerting influence over treatment options through prior authorization requirements, as well as patient cost sharing, which can threaten affordability. In an era when the cost of a course of therapy with branded cancer drugs is typically measured in the tens of thousands of dollars and, not infrequently, over $100,000, FDA approval is no longer sufficient for treatment selection. Accessibility and affordability have become essential considerations as well.

              CALGB 80405: Fodder for prior authorization and pathways?

              The results of this large, Phase III trial were widely anticipated to elucidate conflicting data presented at ASCO in 2013, which demonstrated a survival benefit of Erbitux over Avastin in the first-line treatment of KRAS wild-type colorectal cancer (CRC)1 in the absence of a progression-free survival (PFS) benefit.

              Treatment pathways are becoming a more prevalent means of managing cancer treatment, and CRC is one of the three most common cancers to be the subject of pathways. Whether initiated by payers or practices, treatment pathways are designed to drive selection of “preferred” treatment modalities and products. These products generally represent the most cost-efficient, evidence-based means of treating patients at each line of therapy. While demonstrated efficacy is usually paramount, tolerability and cost are also given critical consideration. When clinical outcomes are comparable, cost is usually the most important driver.

              The secondary but important factors of cost and administrative burden already favor Avastin over Erbitux, and prescribing patterns clearly show a preference for Avastin over Erbitux in first-line, even in patients with the KRAS mutation. The lack of difference in efficacy between Avastin and Erbitux revealed in CALGB 80405 presumably removes the clinical efficacy rational for selecting Erbitux in the first-line setting. Payers may further leverage prior authorization to not only require biomarker testing for KRAS but also the use of Avastin before the more costly Erbitux will be covered. Such action may prompt practices to avoid the administrative burdens associated with Erbitux use. Pathways will likely be leveraged by both payers and oncology practices to further solidify the dominance of Avastin in first-line CRC.

              EORTC 18071: How much of a good thing is too much?

              Malignant melanoma is infamous its poor prognosis. When Yervoy launched in 2011, it represented not only improvement in median overall survival but also the chance at long-term survival for some patients. However, this clinical benefit came with an unprecedented (at the time) price among cancer treatments of $100,000 to $120,000 for a four-cycle course of treatment.

              The strong positive recurrence-free survival data reported in EORTC 18071 for Stage III melanoma patients receiving adjuvant treatment with Yervoy represents a significant advance. However, the cost per cycle in the adjuvant setting is more than three times greater than for the current indication of metastatic disease, due to higher dosing. Further, treatment continues after the initial four rounds with maintenance infusions every three months for up to three years. At the current WAC price of Yervoy, a first year of adjuvant treatment will likely exceed $300,000, a cost likely to spark renewed scrutiny among payers. Until Yervoy receives an FDA indication or National Comprehensive Cancer Network (NCCN) guideline recommendations (level IIb or higher), oncology practices are likely to experience claims rejections due to a dose in excess of the indication.

              Closing Thoughts

              We are in an exciting era of clinical development of cancer treatment. Oncologists and hematologists have an unprecedented array of tools at their disposal to extend the lives of cancer patients. Biopharmaceutical companies have invested countless years and billions of dollars to bring these drugs to market. This investment and the unmet needs that these drugs address are reflected in high prices that are driving explosive growth in spending on cancer care. Not only do physicians have more “tools in their toolbox,” but payers have a growing armamentarium of tools that at their disposal to help rein in the cost trend. Be it through pathways, prior authorization, formulary tiers or cost sharing, payers will continue to leverage these tools to exercise influence over drug selection and utilization. Clinical evidence is and will remain the single most important determinant of access in the U.S., but the evidence can no longer be viewed in scientific isolation. Not only payers but also patients and physicians will weigh the evidence within a broader value context that takes price, therapeutic alternatives and outcomes into account.

              1Heinemann, Abstract LBA3506, ASCO 2013.

              By Debbie Warner, Vice President, Commercial Planning, Kantar Health

              RESONATE Presents a Picture of Improved Options for Relapsed or Refractory CLL Patients

              Both Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) and idelalisib (Gilead) are generating a lot of excitement as potential treatment options in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL).  Arzerra® (ofatumumab, Genmab/GSK) is currently approved for use in refractory CLL patients in both the United States and Europe. Although Arzerra is the second most utilized agent in the United States in CLL patients after their second relapse, it is still only used in 14% of U.S. CLL patients.1 This utilization rate highlights the unmet need for more therapies and helps partly explain the level of excitement for new therapies such as Imbruvica and idelalisib.

              Imbruvica, an inhibitor of the Bruton’s tyrosine kinase (BTK), has already garnered accelerated approvals as a monotherapy for both mantle cell lymphoma and CLL based on Phase II data. While evaluation of these two applications were ongoing with the FDA, Pharmacyclics initiated a Phase III trial (RESONATE™) that compared Imbruvica versus Arzerra in 391 patients with multiple relapsed/refractory CLL or small lymphocytic lymphoma, with a median of two or three prior therapies, depending upon the treatment arm. In January 2014, the companies announced that the trial met its primary endpoint of progression-free survival (PFS) as well as the secondary OS endpoint.  Interim results of the trial were presented in one of the last oral presentations of the American Society of Clinical Oncology (ASCO) 2014 conference.2

              The presenter, Dr. Byrd, stated upon presentation of the primary endpoint data (independent review committee-assessed PFS) that “a picture is worth a thousand words,” and the data in this case supported his statement. Imbruvica was far superior to Arzerra, as it was associated with a 78.5% reduction in the risk of disease progression. The median PFS was not reached in the Imbruvica arm and was 8.1 months in the Arzerra arm (HR 0.215, p<0.0001). It also was associated with a 56.6% reduction in the risk of death, with the median overall survival (mOS) not reached in either arm (HR 0.434, p=0.0049). This hazard ratio could have been even more in Imbruvica’s favor, but 29.1% of the patients treated with Arzerra were treated with Imbruvica at crossover after progressive disease. The overall response rate (ORR) was also significantly improved in the Imbruvica arm (42.6% versus 4.1%, p<0.0001). Importantly, Imbruvica’s PFS benefit was also seen in the subsets of patients with del17p (HR 0.25) or purine analog refractory disease (HR 0.18).

              Imbruvica was generally well tolerated, but physicians will need to keep note of its associated toxicities.  Imbruvica was associated with increases in diarrhea (all grades, 47.7% versus 17.8%) and nausea (26.2% versus 18.3%). However, these few instances of increased toxicities were not associated with an increased drug discontinuation rate (4.1% versus 3.6%). Several toxicities had been of concern with Imbruvica but may be less so given this data. The rate of Grade 3 or higher infections was similar between the two arms (24% versus 22%), but these values must be considered in the context of a much longer time of treatment for patients on Imbruvica. The incidence of any grade of atrial fibrillation was higher among patients on Imbruvica (5% versus 0.5%); however, this caused discontinuation in only one patient.  Bleeding-related adverse events of any grade were more common with Imbruvica (44% versus 12%), but most were Grade 1.

              However, other data presented at the conference might be of equal interest to clinicians. Dr. O’Brien presented a long-term analysis of the Phase I PCYC-1102 trial of Imbruvica monotherapy in a mixed patient population – both newly diagnosed and relapsed or refractory – with CLL.3,4,5 After three years post-initiation of Imbruvica, 64% of patients remain on the drug (81% of newly diagnosed, 58% of relapsed/refractory). Most of the adverse events were detected in the early stage of treatment and diminish with time. Also, as treatment continued, patients with responses less than a partial response (PR plus lymphocytosis) converted to a true PR, resulting in an updated response rate of 85%.

              As noted above, these data are presented in a disease that has very strong competition. In particular, these data come after release of Phase III data for the PI3Kδ inhibitor idelalisib, in which the efficacy of idelalisib to Rituxan® (MabThera® in Europe, rituximab, Biogen Idec/Roche) was evaluated in 220 relapsed or refractory CLL patients. As presented at the 2013 American Society of Hematology (ASH) conference, idelalisib significantly improved PFS (HR 0.15, p<0.0001) and OS (HR 0.28, p-0.018).6 These data are expected to support FDA approval shortly, which will put Imbruvica and idelalisib in direct competition in the relapsed/refractory CLL setting. In the absence of a head-to-head trial, it might be hard for physicians to choose between these two highly effective and very tolerable agents. In this case, first-to-market may play a role, and this factor favors Imbruvica, which has been approved since February 2014. Other new targeted therapies, such as Gilead’s SYK inhibitor GS-9973 or AbbVie’s Bcl-2 inhibitor ABT-199, are further behind in development.

              Although as the discussant (Dr. Lamanna) noted that there might be instances where cytotoxic chemotherapy will still be preferable in relapsed CLL patients, we have entered a new era of targeted therapy in CLL. Doctors will need to choose between many effective therapies, but in the view of patients this will be a good problem. As all of these agents have already or will soon initiate further Phase III trials in earlier lines of CLL, future competition between these agents is expected to be fierce.  We look forward to seeing more cases where a “picture is worth a thousand words.”

              By Arnold DuBell, Ph.D., Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health

              __________________________________________________________________________________

              [1] Kantar Health, CancerMPact® Treatment Architecture United States, accessed June 3, 2014.

              [2] Byrd, Abstract LBA7008, ASCO 2014

              [3] O’Brien, Lancet Oncology, 2013

              [4] Byrd, NEJM, 2013

              [5] O’Brien, Abstract 7014, ASCO 2014

              [6] Furman, Abstract LBA6, ASH 2013

              Taking a BiTE Out of ALL

              Currently no targeted therapies are approved for the treatment of relapsed/refractory Philadelphia Chromosome-negative (Ph-) acute lymphocytic leukemia (ALL). Moreover, given the toxicities associated with the available chemotherapy options, less than half of patients are treated with second-line therapy.1

              Blinatumomab is an investigational bispecific T-cell-engaging antibody developed using Micromet’s “BiTE” (bispecific T-cell engager) technology. The concept behind the bispecific antibody is that by binding the tumor cell through CD19 ― which is expressed by nearly all tested B-lineage ALL cells (including ALL blasts) ― and T-cells through CD3, the antibody brings the T-cells into closer contact with the tumor cells, thereby promoting T-cell mediated lysis of the tumor cells. In a previous Phase II study conducted in 36 relapsed/refractory B-cell ALL patients, treatment with blinatumomab achieved a complete hematologic remission (CR)/CRh (CR with partial hematologic recovery) rate of 69% (25/36), a median relapse free survival (RFS) of 7.6 months and a median overall survival (OS) of 9.8 months.2 Micromet (now Amgen) sought to confirm the antileukemic activity of single-agent blinatumomab in the difficult-to-treat population with relapsed/refractory ALL with the Phase II trial that was reported Tuesday at ASCO in the leukemia oral session.

              This was a large Phase II study (MT103-211; NCT01466179) of blinatumomab in Ph-, relapsed/refractory ALL.3 This confirmatory open-label, single-arm trial was initiated in October 2011. Eligible patients had primary refractory disease; early relapse (duration of first remission was12 months or less); relapse within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT); or any relapsed or refractory disease after first salvage therapy. The primary endpoint was rate of CR / CRh within the first two treatment cycles. Secondary endpoints included rates of CR and CRh, proportion of patients eligible for allogeneic HSCT after CR/CRh rate, relapse-free survival, overall survival, time to hematological relapse, event-free survival, pharmacokinetics, and safety. The trial completed enrollment by November 2013. Before its purchase by Amgen, Micromet initiated the trial with an estimated enrollment of 61 patients. By January 2013, the planned enrollment had been tripled to 180 patients, and Amgen subsequently guided that this will be a pivotal trial to support regulatory approval in this unmet need population.

              The single-arm MT103-211trial enrolled 189 patients who were treated with blinatumomab (28 µg/day, continuous IV, four weeks on, two weeks off; Days 1-7 of Cycle 1 only, 9 µg/day) for a median of two cycles (range = 1–5 cycles). Treatment with blinatumomab resulted in 43% CR/CRh rate during the first two cycles of therapy, and 80% of CR/CRh occurred within the first cycle. Median RFS was 5.9 months and median OS was 6.1 months. Adverse events were consistent with previously reported adverse events. The most frequent Grade 3 or higher adverse events were febrile neutropenia (25%), neutropenia (16%); anemia (14%), nervous system/psychiatric disorders (13%) and pneumonia (9%). Grade 3 or higher nervous system/psychiatric disorders included encephalopathy (3%), ataxia (2%) and confusional state (2%). Fatal adverse events were only seen in patients with uncontrolled leukemia.

              This large Phase II study confirmed the antileukemia activity of single-agent blinatumomab in a difficult-to-treat population with relapse/refractory ALL. The only other approved agent for relapsed/ refractory B-cell ALL is Marqibo® (vincristine sulfate liposome, Talon Therapeutics), which was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of Ph- ALL patients who have relapsed after two or more prior therapies. If we compare the outcomes of these two trials, blinatumomab appears to offer better outcomes than Marqibo (CR/CRh 43% and 15%, respectively) and overall survival (6.0 months and 4.6 months, respectively).4,5 However, the patient demographics are different between these two studies, making comparison difficult; specifically, the blinatumomab trial enrolled a large portion of patients in earlier relapse than the Marqibo trial, which could explain the difference in response rate and survival. Randomized data is not available for either drug, which further limits the ability to assess their clinical merits, but the single-arm Phase II data certainly is encouraging.

              In late 2013, Amgen initiated a Phase III trial (00103311; NCT02013167) that will randomize relapsed/refractory Ph- B-cell ALL patients to either blinatumomab or physician’s choice of chemotherapy. The endpoint of this trial is OS and will most likely serve the need to convert an anticipated accelerated approval (based on the Phase II data reported today) to a full FDA approval; it also will support regulatory filings outside the U.S. An approval will not come fast enough for this setting with high unmet need. The data from this important Phase II trial ushers in the era of targeted immune therapy as a new treatment option for ALL patients.

              By Stephanie Hawthorne, Ph.D., Senior Director, and Greg Wolfe, Ph.D., Senior Consultant, Kantar Health

              ________________________________________________________________________________

              [1] Kantar Health CancerMPact® Treatment Architecture, United States and Western Europe, accessed June 3, 2014

              [2] Topp, et al., Bone Marrow Transplant, 2013

              [3] Topp, et al., Abstract 7005, ASCO 2014

              [4] Marqibo FDA label, accessed June 3, 2014

              [5] O’Brien, et al., J Clin Oncol, 2012

              SQUIRE: Statistically Significant, but is it Clinically Relevant?

              As treatment of lung cancer patients has become more driven by histology and biomarkers, one group of patients had been left out of the clinical advances made in recent years with targeted therapies: non-small cell lung cancer (NSCLC) patients whose tumors have squamous histology. A few different drugs are now being studied in this patient population, and the first of these trials was reported on Monday at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Eli Lilly had stated via press release in August 2013 that necitumumab, their second-generation anti-EGFR monoclonal antibody (mAb), significantly improved overall survival (OS) when combined with gemcitabine and cisplatin as a first-line treatment in 1,093 patients with squamous NSCLC in the Phase III SQUIRE study. That press release did not provide quantitation for the OS benefit found in SQUIRE, but such data was finally made available at the ASCO 2014 session on metastatic NSCLC.

              The data presented at the conference suggest that while the benefit may be statistically significant, it may not be clinically relevant.1Necitumumab was associated with a six-day (0.2-month) improvement in median progression-free survival (mPFS; 5.7 months versus 5.5 months, HR 0.85, p=0.020), and a 1.6-month improvement in median overall survival (mOS; 11.5 months versus 9.9 months, HR 0.84, p=0.012). Interestingly, the only subgroup not to show a survival benefit was the group of patients who were 70 years or older. Finally, the response rate was also slightly but insignificantly improved in the necitumumab-containing arm (31% versus 29%, p=0.400).

              One bright spot for necitumumab was its toxicity profile, which enabled the agent to be generally well-tolerated. Necitumumab was associated with increases in Grade 3 or higher hypomagnesemia (9.3% versus 1.1%), skin rash (7.1% versus 0.4%) and venous thrombolic events (5.0% versus 2.6%).

              During this session a comparison was rightly made to Erbitux® (cetuximab, Bristol-Myers Squibb). As noted above, necitumumab is a second-generation anti-EGFR mAb; past history with the first-generation anti-EGFR mAb Erbitux provides a note of caution. Erbitux had been tested in the first-line setting in two Phase III trials in NSCLC patients of all histologies: FLEX and CA225-099. Erbitux was shown to provide a modest yet significant benefit in the FLEX study when added to cisplatin and vinorelbine (HR 0.871, p=0.044) but failed to show a benefit when added to carboplatin and paclitaxel in the CA225-099 trial (HR 0.89, p=0.17). In an attempt to find a biomarker-defined population that benefited from treatment with Erbitux, investigators developed an EGFR IHC score algorithm, termed the “H-score,” to identify “high EGFR-expressing” patients.4 While an H-score greater than 200 was predictive for patients enrolled in FLEX, it was not predictive for Erbitux benefit in the CA225-099 trial. Unfortunately, in an exploratory analysis presented for the SQUIRE study, the H-score was not predictive for necitumumab activity.

              The SQUIRE data, following that of the REVEL study,5 highlighted the difficulty of finding new effective therapies for patients with NSCLC. Both trials showed minimal efficacy benefits, and both trials probably reached statistical significance thanks (in part) to the large patient populations enrolled. However, Julie Brahmer, the discussant for both the SQUIRE and REVEL presentations, noted that according to ASCO’s recently released recommended efficacy targets for new agents in both non-squamous and squamous NSCLC,6 SQUIRE does not come close to meeting the threshold of a 2.5- to 3-month improvement in overall survival and a Hazard Ratio of 0.77 to 0.8. Based on the SQUIRE data, Dr. Brahmer rightfully concluded that it is time to reconsider the notion that wild-type EGFR is a target in NSCLC. Although SQUIRE did present statistically significant survival data in an underserved patient population, questions arise about the clinical relevance of these data. Physicians, along with their patients, will need to have serious  discussions to answer this question.

              By Arnold DuBell, Ph.D., Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health

              _______________________________________________________________________________


              [1] Thatcher, Abstract 8008, ASCO 2014

              [2] Pirker, Lancet, 373: 1525-1531, 2009

              [3] Lynch, J Clin Oncol, 28: 911-917, 2010

              [4] Pirker, Abstract O01.06, WCLC 2011

              [5] Perol, Abstract LBA8006, ASCO 2014

              [6] Ellis, JCO 2012

              Cyramza Yields a Modest Survival Benefit in Second-line NSCLC

              Cyramza™ (ramucirumab, IMC-1121B; Eli Lilly) is a human IgG1 monoclonal antibody directed against the extracellular domain of VEGFR-2. It was recently approved by the Food and Drug Administration (FDA) for advanced gastric cancer or gastroesophageal junction adenocarcinoma. On February 19, 2014, Lilly announced via press release that the REVEL trial was positive for both overall survival (OS) and progression-free survival (PFS) benefit. Results from the randomized, double-blind, placebo-controlled Phase III REVEL trial (NCT01168973) were reported at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). The trial evaluated docetaxel with or without Cyramza in squamous or non-squamous Stage IV non-small cell lung cancer (NSCLC) patients following disease progression after one prior platinum-based therapy.1

              Patients in the REVEL trial, were randomized to receive docetaxel (75 mg/m2 IV Day 1 of a 21-day cycle) plus either Cyramza (10 mg/kg IV Day 1 of a 21-day cycle, n=628) or placebo (n=625) until disease progression or unacceptable toxicity. The primary endpoint was OS, and secondary endpoints included PFS, overall response rate (ORR) and quality of life. REVEL met its primary endpoint with a modest improvement in median OS (10.5 months for Cyramza plus docetaxel versus 9.1 months for docetaxel alone (HR = 0.857; p=0.0235)). The addition of Cyramza to docetaxel improved OS in patients with squamous and non-squamous histologies. The ORR was 22.9% for Cyramza plus docetaxel and 13.6% for the docetaxel arm (p<0.001). Median PFS was 4.5 months for Cyramza plus docetaxel versus 3.0 months for docetaxel (HR=0.762; p<0.0001).

              Treatment-emergent Grade 3 or higher adverse events (AEs) were reported in 78.9% of patients in the Cyramza plus docetaxel arm and 71.8% of patients in the docetaxel arm. The most common Grade 3 or higher treatment emergent AEs in the Cyramza/docetaxel arm compared to docetaxel alone arm included neutropenia (48.8% vs. 39.8%), febrile neutropenia (15.9% vs. 10.0%), fatigue (14.0% vs. 10.5%) and hypertension (5.6% vs. 2.1%). Pulmonary hemorrhage (any grade; all patients) was reported in 2.1% vs. 1.6% of patients but was slightly more in squamous patients (3.8% vs. 2.4%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%).

              Docetaxel is commonly preferred as second-line therapy for patients with NSCLC. These results demonstrate that addition of Cyramza to docetaxel improves median OS by 1.4 months, but at the same time it increases toxicities including neutropenia, febrile neutropenia and hypertension. Recent ASCO recommendations suggest that clinically relevant improvements in OS should be on the order of four months for NSCLC with a hazard ratio of less than 0.8.2 It is obvious that the REVEL results did not clear this bar; however, there are some positives with Cyramza trial.

              REVEL is the first Phase III study to show that the addition of a biologic to standard chemotherapy improves survival compared to chemotherapy alone in second-line NSCLC. In addition, Cyramza was active in squamous NSCLC, where treatment options are more limited. The increased toxicity in REVEL was modest, similar to the toxicity profile observed when Cyramza was combined with paclitaxel in the RAINBOW trial in gastric cancer. Lilly has announced their plans for a regulatory submission for Cyramza for NSCLC in 2014 based upon the REVEL results. Will the REVEL data be sufficient to convince the regulatory authorities to approve Cyramza for NSCLC? If it is approved will physicians utilize Cyramza with such modest clinical benefit? Time will tell.

              By Greg Wolfe, Ph.D., Senior Consultant, and Neesha Suvarna, Ph.D., Consultant, Kantar Health


              [1] Perol, LBA8006, ASCO 2014

              [2] Ellis, JCO 2012