New discoveries and ongoing research continue to confirm the powerful therapeutic implications of precision medicine for cancer patients. The recent FDA approval of pembrolizumab for patients whose cancers have a specific biomarker is no exception.
This is the first time the FDA has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. With this approval, pembrolizumab is now indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have microsatellite instability-high (MSI-High) or mismatch repair (MMR) deficiency.
“This is an important first for the cancer community,” said Richard Pazdur, MD, Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and Director of the FDA's Oncology Center of Excellence, in a recent statement. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor's biomarker without regard to the tumor's original location.”
This approval, as well as recent research, supports the oncology community's growing ability to treat cancers based on their molecular profiles and tailor treatments to the individual not simply the disease. One such study offers additional evidence that microsatellite instability can drive therapeutic strategies for patients with solid tumors (Science 2017; doi:10.1126/science.aan6733).
The phase II study recruited patients with treatment-refractory progressive, metastatic, mismatch repair-deficient cancers from six cancer centers.
The clinical trial, which sought to evaluate the efficacy of pembrolizumab in advanced MSI-High or MMR-deficient patients, enrolled 86 patients, with 12 different tumor types, including colorectal, endometrial, and gastroesophageal. Participating patients received at least one prior therapy and had evidence of progressive disease prior to enrollment.
Each participating institution determined mismatch repair deficiency by immunohistochemistry for mismatch repair proteins or by PCR-based tests for microsatellite instability. MMR was confirmed in each enrolled patient at a central location, researchers noted.
Initially, the trial was conducted utilizing a Green-Dahlberg two-stage design, according to study authors, which included three parallel cohorts:
- Cohort A: patients with mismatch repair-deficient colorectal adenocarcinomas;
- Cohort B: patients with mismatch repair-proficient colorectal adenocarcinomas; and
- Cohort C: patients with mismatch repair-deficient solid tumor malignancies but not colorectal adenocarcinoma.
Utilizing next-generation sequencing (NGS), comprehensive genomic profiling (CGP) identified patients with MSI-High solid tumors by evaluating more than 7,000 microsatellite regions across approximately 2,200 cases, according to researchers.
Patients were considered MSI-High if they had at least 43 altered microsatellite regions. This was determined by comparing NGS results to traditional PCR analysis. The NGS platform performed at 95.8 percent sensitivity and 99.4 percent specificity, study authors reported.
Investigators administered pembrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 14 days. Overall response rate, based on RECIST 1.1, was the primary endpoint for Cohorts A and C.
Researchers conducted safety assessments prior to each treatment. Additionally, radiographic assessments were performed at week 12, then every 8 weeks for the first year and every 12 weeks after year one. Post-treatment biopsies were obtained from measurable lesions after 4 or 20 weeks, according to study authors.
Data from the study demonstrated durable responses with pembrolizumab, regardless of tumor origin, with an objective radiographic response rate of 53 percent and a complete response rate of 21 percent. At this time, median progression-free and overall survival have not yet been reached.
Based on trial findings, researchers concluded, “these data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.”
When it comes to measuring MSI, there isn't a simple solution, noted John Marshall, MD, Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer at Georgetown Lombardi Comprehensive Cancer Center, Chief of the Division of Hematology-Oncology at MedStar Georgetown University Hospital in Washington, D.C., and Chairman of Caris Life Sciences' Precision Oncology Alliance (POA) Executive Committee.
“There is a fair bit of confusion among all of us about how best to test for this, so there are a variety of techniques that have emerged to do the testing,” he explained. “The majority of these options come out of the colon cancer literature, where MSI is needed to manage those patients.”
Traditionally, this is accomplished by conducting immunohistochemistry on tissue to determine the presence or absence of four key proteins. Another method to measure MSI is fragment analysis, which utilizes DNA sequencing. “This technique requires normal tissue that is then compared to the tumor,” noted Marshall.
In this study, utilizing CGP allowed researchers to use a pure NGS process that does not require normal tissue and can be done on the tumor, according to Marshall. “This is important because increasingly, for all tumor types, we are doing NGS to look for not only MSI, but other abnormal genes that may help guide therapies.”
Since this tumor profiling platform does not require normal tissue like the PCR assay, it enables more patients to receive MSI results and provides the tools for clinicians to accurately identify MSI-High patients so they receive the best possible therapy, Marshall noted.
“[Comprehensive genomic profiling] has dramatically simplified the process for oncologists to be able to order such tests that can identify MSI and other key genes,” he emphasized. “The findings from this study provide a foundation for this testing process and shed light on the ongoing evolution of molecular testing for MSI.”
While CGP has profound implications for oncology practices, Marshall cautioned, “As we expand genetic testing and this specific MSI testing to other cancers, we need to make sure this [process] continues to hold up, that CGP accurately predicts and identifies these patients.
“In addition, this is not going to be the only way that we are going to identify patients who benefit from immune therapy,” he continued. “Overtime, I believe more biomarkers will emerge that will further expand and identify patients who will benefit from these treatments.”
The groundwork is being set for a shift in the utilization of precision medicine in oncology.
“The results of this study, along with the FDA approval of pembrolizumab for MSI-High or mismatch repair-deficient solid tumors, mark a turning point where precision medicine is now becoming standard of care for all solid tumor patients,” Marshall said in a statement.
“This is a practice-changing moment,” he reiterated to Oncology Times. “I would recommend, and I realize this is a charged comment, that MSI testing should be done for all solid tumor patients with metastatic cancer, even though the probability of finding an MSI abnormality is relatively low for any individual patient. However, if you are one of those patients, you would want to know and have access to the appropriate treatments.
“Given the low odds, the cost-effectiveness of testing is not optimal, nonetheless, if you look at not only MSI, but also the many other molecular tests that may help determine the benefit of other therapies, I believe CGP is justified,” Marshall concluded. “This research confirms the value of molecular profiling for metastatic cancer patients, as well as the importance of comprehensive genomic profiling in the development of innovative, personalized cancer treatments.”
Catlin Nalley is associate editor.