The OBR Blog

July 30, 2013 - 09:07 am Posted in ASCO Conference Coverage comments0 Comments

Biomarkers played a prominent role in the research presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting. The Biomarkers France study (Barlesi F. J Clin Oncol. 2013;31 [suppl]; abstr 8000), the largest biomolecular study ever conducted, analyzed the mutation status of 10,000 advanced non-small cell lung cancer (NSCLC) patients and provided molecular profiling of EGFR, HER2, KRAS, BRAF and PIK3CA mutations as well as EML4-ALK translocation and demonstrated the feasibility of genetic tumor profiling. Data presented at ASCO 2013 showed novel clinical implications of biomarkers, including estrogen receptor (ER), progesterone receptor (PR) and HER2 in breast cancer, and EGFR and EML4-ALK in lung cancer. In our post-ASCO discussion, we illustrate the genetic changes throughout the course of disease, acquired resistance, and the influence of biomarkers on testing and treatment.

Genetic Changes throughout Disease Course

Biomarker status agreement was investigated in multiple breast cancer studies. A study of 117 consecutive cases investigated changes in biomarkers ER, PR, HER2 and Ki-67 between the primary tumor and a recurrence after breast-conserving surgery (Okumura Y et al. J Clin Oncol. 2013; 31 [suppl]; abstr 1116). The PR+ rate decreased significantly (p=0.01) and the mean Ki-67 index increased significantly (p=0.047) from the primary tumor to the recurrence. Discordance in the Ki-67 index between the primary tumor and IBTR was associated with a lower distant disease-free survival (DDFS).

A study of 193 patients (Shin HC et al. J Clin Oncol. 2013; 31 [suppl]; abstr 1039) compared the primary breast tumor and a metastatic recurrence. Investigators looked at the triple receptor status (ER, PR and HER2) and divided the patients into three groups: concordant non-triple-negative (TN), concordant TN and a discordant group. The highest overall survival (OS) rate from the primary tumor was among the concordant non-TN group and the concordant TN group had the lowest OS rate. The relative risk of 2.5 (95% CL: 1.2 to 5.3) among the discordant group showed it to be an independent prognostic factor for death after metastasis.

Another breast cancer study (Ho J et al. J Clin Oncol. 2013; 31 [suppl]; abstr 586) examined the prevalence of genetic heterogeneity of HER2, concordance or discordance, within the primary tumor in 158 breast tumor specimens and its impact on survival. Thirty-six percent of the 158 cases exhibited genetic heterogeneity for HER2. HER2 genetic heterogeneity was associated with significantly higher stage (p=0.028), significantly poorer overall survival (p=0.034) and higher grade. These studies raise important questions. When re-biopsying a patient’s tumor, should multiple disease sites be biopsied to best understand discordance and heterogeneity? Are we using the appropriate testing cut points for HER2, for instance?

Acquired Resistance

Acquired resistance in NSCLC provides an analogous example of the utility of predictive biomarkers and targeted therapies in oncology.  An ASCO 2013 presentation, “Beyond Progression: Treating EGFR or ALK-Positive Non-Small Cell Lung Cancer (NSCLC) after First-Line Therapy,” on acquired resistance in EGFR- and ALK+ NSCLC points out that for cancers with a known driver mutation, continued inhibition of a sensitive target may be beneficial even after progression, even when a heterogeneity of tumor markers exists in one patient.

Plasma DNA Testing

A study of breast cancer patients (Beaver J. J Clin Oncol. 2013; 31 [suppl]; abstr 11019) evaluated PIK3CA mutation rates in both tumor specimens and pre-surgery plasma samples using polymerase chain reaction (PCR). The results showed both a high sensitivity (92.3%) and specificity (100%) between the FFPE samples and the pre-surgery plasma.

Similarly, Mok et al., reporting on the detection of EGFR mutations from plasma DNA of NSCLC patients, showed that when using tissue as a comparator, the sensitivity of plasma test was 76% (68 of 89 patients) and the specificity of plasma test was 96% (130 of 135 patients) (J Clin Oncol. 2013:31 [suppl]; abstr 8021). This study concluded that an EGFR blood test can be used to reliably detect EGFR mutations in plasma and is a potent predictor of survival outcomes.

Conclusion

Established biomarkers including ER, PR, HER2, EGFR and ALK hold great potential for the continued development of new targeted therapies and have repercussions for future treatment decisions. Genetic changes over time, acquired resistance, and genetic heterogeneity all have the potential to change a tumor’s behavior and sensitivity throughout the course of the disease. The plasma DNA studies could indicate improvements in diagnostics and advancements in therapeutic decision-making. They also raise the question of the effectiveness of the plasma DNA test if there is discordance between the primary tumor and a recurrence.  What is the acceptable and clinically meaningful level of agreement between plasma DNA testing and tumor DNA testing in order to establish plasma DNA as a surrogate tissue for biomarker testing in the case of PIK3CA, for instance? These studies also raise important questions about companion diagnostics – when and how often should the testing occur? It is clear that the impact of biomarkers on treatment will continue to grow and improve the capacity to provide targeted therapy to cancer patients safely and effectively.

By Julie Katz, MPH, MPhil, Associate Consultant, Clinical & Scientific Assessment, Kantar Health

July 08, 2013 - 09:07 am Posted in Featured comments0 Comments

Introduction

In an effort to provide you with timely market feedback from ASCO 2013, OBR and MDoutlook are pleased to share results from MDoutlook’s fourth OncoPoll™ from the meeting exploring immunotherapy.

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 immunotherapy utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
  • Timing: June 2013. Launched two days after close of 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 31-June 4, 2013
  • 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: 103 on June 27th
  • No financial incentives provided for participation

Geographic Distribution of Respondents

Attendance at 2013 ASCO Annual Meeting

Key Conclusions

  • About half of all survey respondents attended this year’s ASCO annual meeting
  • Proportionally, Ex-US respondents had slightly more attendees than US respondents
  • In-line with results from previous years

Importance of Immunotherapy: US and Ex-US View Immunotherapy as an Important Treatment Approach

Key Conclusions

  • US and Ex-US oncologists perceive immunotherapy as playing an important role in the treatment approach for their patients
    • A majority of US and Ex-US oncologists rated the importance of  selecting immunotherapies as a treatment approach at 8 out of 10
    • Mostly consistent between US and Ex-US physicians, and between their own view and their patients’ perspectives

PD-1/PD-1L Antibody Treatments: Majority of Patients are Expected to Benefit from New Treatments

Key Conclusions

  • US oncologists anticipate PD-1 targeted immunotherapies to impact a majority of their patients with RCC, melanoma, and NSCLC
    • 50% of US oncologists expect PD-1 targeted immunotherapies to have a large impact on a majority of their melanoma patients compared to 33% for RCC and NSCLC patients
    • <10% of US oncologists expect PD-1 directed therapies to have little to no impact on their RCC, melanoma, and NSCLC patients

PD-1/PD-1L Antibody Treatments: Majority of Patients are Expected to Benefit from New Treatments

Key Conclusions

  • Ex-US oncologists anticipate PD-1 targeted immunotherapies to impact a majority of their patients with RCC, melanoma, and NSCLC
    • 55% of Ex-US oncologists expect PD-1 targeted immunotherapies to have a large impact on a majority of their melanoma patients compared to ~33% for RCC and NSCLC patients
    • ~10% of Ex-US oncologists expect PD-1 directed therapies to have little to no impact on their RCC, melanoma, and NSCLC patients

Clinical Importance of PD-1L Expression: US and Ex-US Oncologists Have Differing Views on the Importance of PD-1L Expression

Key Conclusions

  • Ex-US oncologists have greater concerns than US oncologists regarding the importance of PD-1L expression
    • 62% of Ex-US oncologists have a great concern that PD-1L expression does not  appear to be required for clinical response
    • US oncologists are divided over the importance of PD-1L expression; 42% with little concern and 42% with great concern

Using Multiple Immune Checkpoint Blockade Strategies: Combinatorial is Anticipated to be the Preferred Methodology

Key Conclusions

  • 70% of Ex-US oncologists believe that a combinatorial treatment is the best approach when anti-PD1 targeted treatments become commercially available
  • Largest proportion of US physicians require more data before making a decision on the best treatment strategy
    • Of the US physicians that have decided on an approach, ~60% prefer combinatorial treatment
    • 20% of US treaters will use known entity (anti-CTLA-4 mAb) first

Impact of T-VEC Vaccine for Melanoma: Most Believe Its Use Will Be Limited to Minority of Patients with Unresectable Melanoma

Key Conclusions

  • Most melanoma treaters believe T-VEC will be used in fewer than half of melanoma patients with unresectable disease
    • The expected magnitude of its impact is split in the marketplace, with US treaters expecting a little greater usage than the Ex-US treaters
  • About 1 in 5 melanoma treaters expect T-VEC to be used in majority of cases with unresectable melanoma
  • Few melanoma treaters see no role what-so-ever for this therapeutic approach

Conclusions: Impact of ASCO 2013 on Clinical Practices for Immunotherapy

  • Overall, US and Ex-US oncologists view the selection of immunotherapies to be of great importance for the treatment of their patients
    • A majority of oncologists rated importance 8 out of 10; limited variability between regions
  • Oncologists have a favorable view of PD-1 targeted immunotherapies for the treatment of patients with RCC, melanoma, and NSCLC
    • 50% of US oncologists expect PD-1 targeted immunotherapies to have a large impact on a majority of their melanoma patients compared to 33% for RCC and NSCLC patients
    • 55% of Ex-US oncologists expect PD-1 targeted immunotherapies to have a large impact on a majority of their melanoma patients compared to ~33% for RCC and NSCLC patients
  • Ex-US oncologists have greater concerns than US oncologists regarding the importance of PD-1L expression
  • Most treaters expect the T-VEC vaccine to be used as a treatment of unresectable melanoma, but in a minority of cases
    • Roughly even split in the expected size of impact T-VEC will have for these patients, with US treaters a little more enthusiastic
  • When using PD-1 targeted immunotherapy 70% of Ex-US oncologists believe a combinatorial approach with anti-CTLA-4 treatment is the best strategy
  • Largest proportion of US melanoma treaters (43%) are unsure whether sequential or combinatorial approach is the best strategy
    • This suggest US oncologists need more clinical data before drawing a conclusion
    • Of the US oncologists that have decided on a treatment approach, 60% prefer the combinatorial approach

Submitted by Jan Heybroek, President and Robert Stephan, Sr. Director Medical Services and Luan Dao, Global Medical Analyst, MDoutlook

article register

Recent Posts

Recent Comments

Archives

Categories