Biomarker Based Chemotherapy Approach Improved Outcomes Interview with:

Maria Schwaederle PharmD Clinical Research Scientist Center for Personalized Cancer Therapy UCSD Moores Cancer Center La Jolla, CA 92093

Dr. Maria Schwaederle

Maria Schwaederle PharmD
Clinical Research Scientist
Center for Personalized Cancer Therapy
UCSD Moores Cancer Center
La Jolla, CA 92093 What is the background for this study? What are the main findings?

Dr. Schwaederle: We performed this analysis with experts in the field, including but not limited to Drs Schilsky, Lee, Mendelsohn and Kurzrock, all known for their experience in the area of precision/personalized medicine.
Historically, phase I trials (which are often first in human or highly experimental in other ways) were believed to be examining only toxicity. Our meta-analysis of 13,203 patients shows that in the era of precision medicine, this historical belief needs to be discarded. Second, it is the use of precision medicine that makes this belief outdated.
Indeed, Phase I trials that utilized a biomarker-driven approach that is the essence of precision medicine had a median response rate of about 31%, which is higher than many FDA approved drugs, and this is in spite of the fact that phase I patients are a highly refractory group having failed multiple lines of conventional therapy.

Importantly, however, it was not the use of targeted agents alone that was important. It was the biomarker-based approach where patients are matched to drugs. Without matching, response rates were dismal—about 5%. What should readers take away from your report?

Dr. Schwaederle: To our knowledge this is the largest meta-analysis of phase I studies and perhaps the only one that looks at the impact of a precision medicine (biomarker-based) approach.

We found the following:
1. Using a biomarker-based approach was an independent predictor of improved outcome variables (response rate and progression-free survival—overall survival could not be analyzed because there was inadequate published data as Phase I studies usually do not examine this variable). This was not about simply having better drugs. Targeted drugs that were developed the traditional way—without a biomarker—performed poorly with only a median response rate of 5% (close to cytotoxic therapy).

2. Genomic biomarkers were better than protein biomarkers (Median response rate = 42% (which is really remarkable in a phase I population) versus 22%).
Key findings for lay readers: First, phase I clinical trials with our current approaches that include targeted therapies, both genomically targeted and immunotherapy, can result in encouraging response rates. Therefore enrollment in a clinical trial for patients with advanced cancer is a reasonable and even attractive treatment option.

Second, these trials were not dangerous. The median death rate that was even possibly related to the drug in the trial was about 2%. To put this in perspective, previous published data shows that 50% of patients with advanced cancer who are of the type that enroll on phase I trials are dead at 9 months. Therefore, the fears about the safety of new drugs are really unfounded. We know how to do these trials safely.

Finally, even in the most challenging patient situations, that is patients who have failed multiple lines of conventional therapy, a precision medicine approach (biomarker-selection, especially with the use of genomics) can substantially increase response rates. What recommendations do you have for future research and patient’s care as a result of this study?

Dr. Schwaederle:

Research: Next steps include large scale prospective trials and registries to determine the impact of precision medicine. There are many efforts along these lines, including trials like WINther, NCI-MATCH, ASCO’s TAPUR and others.

Patient’s care:
1. It should encourage patients to enroll on clinical trials, including phase I trials, and it should encourage physicians to refer patients to these trials. We know that only about 3% of adult cancer patients enroll on a clinical trial. This is way too low.
2. It should encourage payors to keep on covering these trials. The old claim that phase I trials in oncology were not therapeutic is simply not true today.
3. It should encourage the use of genomically matched treatments. If we can get response rates of 42% in the most heavily pretreated advanced patients, it is plausible that response rates would be so much higher in a group of patients with less advanced disease. How does this study relate to prior research in the field?

Dr. Schwaederle: This research is really consistent with multiple prior studies.

1. There have been numerous studies, especially in the melanoma and lung cancer field, two diseases previously considered untreatable, that show that use of the right drugs (genomically matched or immunotherapy) in the right patients can have quite a remarkable impact on outcomes, including survival.

2. We have published two other meta-analyses, one in the phase III setting of drugs that went on to FDA approval and one in the phase II setting. The combined total number of patients in those analyses were about 70,000. And the results were exactly what we show here—patients on biomarker-matched therapy did far better than patients without a biomarker-based approach, especially if genomic biomarkers were used. The data supporting the use of genomics in cancer diagnosis and treatment is therefore now very robust. Thank you for your contribution to the community.

Citation: 2016ASCO abstract:

Impact of Precision Medicine in Refractory Malignancies

Poster Board Number:
Poster Discussion Session (Board #217)

J Clin Oncol 34, 2016 (suppl; abstr 11520)

Author(s): Maria Clemence Schwaederle, Melissa M. Zhao, J. Jack Lee, Vladimir Lazar, Brian Leyland-Jones, Richard L. Schilsky, John Mendelsohn, Razelle Kurzrock; Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA; Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, La Jolla, La Jolla, CA; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; Worldwide Innovative Network for Personalized Cancer Therapy (WIN Consortium), Paris, France; Avera Cancer Institute, Sioux Falls, SD; American Society of Clinical Oncology, Alexandria, VA; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; University of California, San Diego, La Jolla, CA

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
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