The OBR Blog

July 16, 2014 - 10:07 am Posted in ASCO Conference Coverage comments0 Comments

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

July 14, 2014 - 09:07 am Posted in Featured comments0 Comments

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.

July 07, 2014 - 03:07 pm Posted in Featured comments2 Comments

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

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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.

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