2011 ASCO: Matching Targeted Therapies To Specific Tumor Gene Mutations Key to Personalized Cancer Treatment
Posted by Paul Cacciatore on June 3, 2011
Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all” approach by tumor type, may be more effective for some types of cancer, according to research presented today at the American Society of Clinical Oncology annual meeting by the M.D. Anderson Cancer Center. In patients with end-stage disease, matched patients achieved a 27% response rate, versus 5% in those unmatched.
Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all approach” by tumor type, may be more effective for some types of cancer, according to research conducted by The University of Texas M.D. Anderson Cancer Center.
M.D. Anderson’s phase I clinical study findings were presented today on the opening press program of the 47th Annual Meeting of the American Society of Clinical Oncology. Apostolia-Maria Tsimberidou, M.D., Ph.D., associate professor in the M.D. Anderson Department of Investigational Cancer Therapeutics, and the principal investigator of the study, presented the data.
Marking the largest scale on which this approach has been examined to date, the study analyzed the results of matching targeted therapies with specific gene mutations in patients. The data indicated that this strategy was associated with higher rates of response, survival and failure-free survival than observed in non-matched patients.
Pairing Patient and Treatment
“This preliminary study strongly suggests that molecular analysis is needed to use the right drug for the right patient. Up to this point, we have treated tumor types, but this study shows we cannot treat all patients with a tumor type the same way. We need to take into consideration a number of factors, and this study suggests that a personalized approach is needed to improve clinical outcomes for patients with cancer,” said Tsimberidou.
The identification of pathways involved in carcinogenesis, metastasis and drug resistance; new technologies enabling tumor molecular analysis; and the discovery of targeted therapies have stimulated research focusing on the use of targeted agents as part of a personalized medicine approach, she said.
“Over the past decades, a personalized medicine approach using Gleevec has changed the way we treat chronic myeloid leukemia, as well as survival rates,” said Razelle Kurzrock, M.D., professor and chair of the M.D. Anderson Department of Investigational Cancer Therapeutics. “We wanted to apply a similar approach to solid tumors.”
“Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis. …
This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients. The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients. …”
–Razelle Kurzrock, M.D., Professor & Chair, Department of Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center
Research Methods and Results
In the initial analysis, Tsimberidou analyzed 1,144 patients with metastatic or inoperable cancer who underwent testing for molecular aberrations at M.D. Anderson. Their median age was 58, and the median number of prior treatments was four. Of these patients, 460 had one or more gene aberrations, including:
- 10 percent with a PIK3CA mutation;
- 18 percent with a KRAS mutation;
- 8 percent with a NRAS mutation;
- 17 percent with a BRAF mutation;
- 3 percent with an EGFR mutation;
- 2 percent with a CKIT mutation;
- 21 percent with a PTEN loss; and
- 37 percent with a p53 mutation
Patients with gene aberrations were treated on clinical trials with matched targeted agents, when available. Regimens included one or more therapies targeting PIK3CA, mTOR, BRAF, MEK, multikinases, KIT or EGFR. Outcomes of patients with gene aberrations treated with matched therapy were compared with those patients with gene aberrations who were not treated with matched therapy because of issues such as eligibility, study availability; insurance coverage and/or logistical problems with the study calendar.
For the 175 patients with one aberration, the response rate was 27 percent with matched targeted therapy. The response rate was 5 percent in 116 patients when treated with non-matched therapy.
Patients who received matched targeted therapy had median survival of 13.4 months, while median survival for patients treated with unmatched targeted therapy was nine months. Median failure-free survival in patients who received matched targeted therapy was 5.2 months, compared to 2.2 months for patients who received unmatched targeted therapy.
Further Research Needed
These preliminary results merit further investigation and confirmatory, prospective studies are needed, especially because the study was not a randomized study and therefore biases could influence the results.
“M.D. Anderson’s goal is to better understand the biology involved in each patient’s carcinogenesis by testing each tumor for genetic abnormalities driving tumor growth to guide treatment selection. This strategy will lead to the optimization of personalized therapy,” Tsimberidou said.
Another goal is to match targeted therapies to patients earlier in treatment.
“When Gleevec was first introduced, it was tested in patients in blast crisis and the response rate was about 15 percent. In contrast, when tested in the front line setting, and with the introduction of similar but increasingly potent second- and third-generation drugs, patients’ response rate was close to 100 percent, and now their expected survival is 25 years and counting,” said Kurzrock. “Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis.”
About the Phase I Program – The Time is Now
The M.D. Anderson’s Phase I program is the largest of its kind and accounts for the majority – but not all – of the institution’s earliest clinical studies. In 2010, of the 11,000 patients who participated in M.D. Anderson clinical trials, more than 1,150 were enrolled in one of the 120 Phase I trials in the program.
Currently, tumors are tested for up to 12 molecular aberrations, but at the rate technology is rapidly advancing, Kurzrock expects that number to climb to more than 100 in the near future.
Patients treated in the Phase I Program are typically very ill and all other approved therapies have failed them. Yet they are “fighters” who are willing to try anything, including studies not specific to their diagnosis to test the effectiveness of a new drug, drug combination or delivery method, said Kurzrock.
“This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients,” said Kurzrock. “The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients.”
In addition to Tsimberidou and Kurzrock, other authors on the all-M.D. Anderson study included N. G. Iskander, David S. Hong, M.D., Jennifer J. Wheler, M.D., Siqing Fu, M.D., Ph.D., Sarina A. Piha-Paul, M.D., Aung Naing, M.D., Gerald Falchook, Filip Janku, M.D., Ph.D., all assistant professors of the Department of Investigational Cancer Therapeutics; Raja Luthra, Ph.D., professor, Department of Hematopathology, Research and Sijin Wen, Ph.D., Division of Quantitative Sciences.
Libby’s H*O*P*E*™ Commentary — Use of Molecular Profiling and Chemosensitivity Testing To Determine Individualized Ovarian Cancer Treatment
It is wonderful that various medical research institutions, including M.D. Anderson, are beginning to match targeted therapies to a patient’s specific molecular tumor characteristics. This approach is generally referred to as “molecular profiling,” and it represents one promising method of matching an individual cancer patient to an effective therapy. As noted in the related Libby’s H*O*P*E*™ postings set forth below, there are several medical and scientific institutions which are pursuing development of molecular profiling for clinical study use. In the most recent related posting listed below, we discuss the molecular profile testing that is commercially available through The Clearity Foundation and Caris Life Sciences.
In the future, it may be helpful to use a form of chemosensitivity testing (e.g., the type of testing provided by Precision Therapeutics, Rational Therapeutics, and the Weisenthal Cancer Group), which is based upon the measurement of actual cancer cell death, as a second method to match a cancer patient to a potential drug or drug combination within the context of a clinical study. In fact, we would like to see a future prospective, randomized ovarian cancer clinical trial in which enrolled women are provided with treatment after assignment to one of three clinical trial arms: (i) treatment based upon the standard of care (e.g., paclitaxel and carboplatin), (ii) treatment based upon molecular profiling, or (iii) treatment based upon chemosensitivity testing. This type of study may uncover additional ovarian cancer treatment insights (both molecular and functional) with respect to the most lethal gynecologic cancer, while ultimately helping women with forms of the disease that may not possess a known molecular characteristic that is potentially “targetable” by an existing clinical trial drug or compound.
This combination of “bottom-up” scientific research (i.e., molecular profiling) performed side-by-side with “top-down” research (i.e., chemosensitivity testing) may represent an effective and efficient approach — albeit provocative — for evaluation of optimal personalized ovarian cancer treatment.
It is important to note that Libby’s H*O*P*E*™ and its founder Paul Cacciatore do not receive financial renumeration or benefit of any kind from the companies referred to in the paragraphs above.
About the University of Texas M.D. Anderson Cancer Center
The University of Texas M.D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, M.D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.
- Tsimberidou, AM, Iskander, NG, Hong DS, et. al. Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative. J Clin Oncol 29: 2011 (suppl; abstr CRA2500).
- Matching targeted therapies to tumor’s specific gene mutations key to personalized cancer treatment, Press Release, University of Texas M. D. Anderson Cancer Center, June 3, 2011.
- Personalized Therapy Benefits Late-Stage Cancer Patients in Clinical Trial, Cancerwise Blog, University of Texas M. D. Anderson Cancer Center, June 3, 2011.
- Stephen B, Wheler JJ, Tsimberidou AM, et. al. Survival of 1,181 patients in a phase I clinic: The University of Texas M. D. Anderson Cancer Center experience. J Clin Oncol 29: 2011 (suppl; abstr 2528).
- El-Osta HE, Falchook GS, Tsimberidou AM, et. al. Clinical characterstics and outcomes of patients with BRAF-mutant advanced cancer in a phase I clinic: The University of Texas M. D. Anderson Cancer Center experience. J Clin Oncol 29: 2011 (suppl; abstr 10535).
- Janku F, Garrido-Laguna I, Wheler JJ, et. al. Screening for PIK3CA mutations, PTEN loss, and RAS/RAF mutations in early-phase protocols with PI3K/mTOR pathway inhibitors. J Clin Oncol 29: 2011 (suppl; abstr 10507).
- Sun M, Falchook GS, Wheler JJ, et. al. Association of VEGF single-nucleotide polymorphisms (SNPs) with response and toxicity in patients treated with bevacizumab. J Clin Oncol 29: 2011 (suppl; abstr e13560).
- Fok J, Kurzrock R, Tsimberidou AM, et. al. An umbrella protocol for histology-independent, phase I modular study based on EGFR mutation status: Using erlotinib alone or in combination with cetuximab, bortezomib, or dasatinib to overcome resistance. J Clin Oncol 29: 2011 (suppl; abstr 2536).
- Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer, November 16, 2010.
- Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, August 3, 2010.
- PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target? November 20, 2009.