As the use of complex biomarkers becomes more frequent in oncology, ways of standardizing measurements of those biomarkers becomes more important. Such standardization is especially critical as FDA moves toward tissue-agnostic drug approvals based on genomic data rather than site-specific drug approvals. The Friends of Cancer Research (FOCR) held two online webinars to examine the future use of complex biomarkers; the second of these webinars specifically focused on harmonization of tests for one of those biomarkers—tumor mutational burden (TMB).
Two years ago, FOCR convened stakeholders to work collaboratively on a harmonized measurement of TMB using a reference standard. The organization is leading a large-scale project with TMB Harmonization Working Group members on standardization of TMB calculation and reporting in order to more effectively evaluate whether TMB may be used as a predictive biomarker in oncology.
Defining Tumor Mutational Burden
TMB is a measurement of the number of mutations within the genome of a cancerous tumor. It is a genomic signature now being studied to evaluate its association with patients' responses to immunotherapy. Cancerous cells with a high TMB are correlated with higher levels of neoantigens, leading to an increase in cancer-fighting T cells in the tumor microenvironment and periphery. The hope is that the TMB biomarker will be useful in the clinic in identifying patients most likely to respond to immunotherapy.
A stated goal of the TMB harmonization project is “to align on a minimum or lower-bound cut-off TMB value for a pan-tumor indication that will help harmonize clinical trial design and expedite drug development by aligning on a common strategy for patient recruitment and data collection in pan-tumor drug trials.”
As previously reported by Oncology Times, in June 2020, the FDA granted accelerated approval to pembrolizumab to treat adult and pediatric patients with unresectable or metastatic TMB-high (TMB-H) solid tumors that have progressed following previous treatment and who have no other treatment options. The FDA approved the FoundationOne CDx assay as a companion diagnostic for pembrolizumab.
This approval “represents a paradigm shift toward biomarker-driven cancer treatment,” said Jeff Allen, PhD, President and CEO of FOCR. He noted that TMB is an additional tool to inform treatment of patients with immunotherapies, based on which patients might be most likely to receive benefit from these drugs.
The FDA approval was based on an analysis of 10 cohorts of patients enrolled in the multicenter, non-randomized, open-label KEYNOTE-158 trial. TMB-H solid tumors were defined as those with 10 or greater mutations/megabase. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until unacceptable toxicity or documented disease progression occurred. The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who received at least one dose of pembrolizumab. Among 102 patients, the ORR was 29 percent and the median DoR was not reached, with 57 percent of patients having response durations of 12 months or greater and 50 percent of patients having response durations of 24 months or greater.
Advances in Genomics
TMB as a biomarker “is a relatively new finding,” noted Norman E. “Ned” Sharpless, MD, Director of the National Cancer Institute (NCI). “It's gone from observation to clinical use in record time.”
He stated that the approval of pembrolizumab for TMB-H solid tumors “is a big deal, as it marks another milestone in genomics research and the treatment of cancer,” but noting this biomarker needs to be validated, harmonized, and studied to see how useful it is in different population groups. He said harmonization and standardization of TMB is much harder than it sounds, and also noted that, while TMB is “quite useful,” it is still not enough to be used by itself.
NCI has developed a software tool for TMB calibration, and results to date have established a proof of principle for this calibration tool, said Lisa M. McShane, PhD, Director of the Biometrics Research Program in NCI's Division of Cancer Treatment and Diagnosis. She said that, following publication of trial results, this tool will eventually be made freely available in hopes that it can be implemented in the clinic and assist in clinical decision-making.
TMB testing is a part of a panel of molecular tests, said Matthew D. Hellmann, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center. He said the FDA approval of pembrolizumab for TMB-high solid tumors represents a next step in molecular testing that can help provide treatment options for precision immunotherapy.
“If you look at patients with high TMB, they reliably have some response to immunotherapy,” he said. “This has really brought a new opportunity to patients.”
Hellman's studies of patients with non-small cell lung cancer have shown that some TMB-high patients responded favorably to dual immunotherapy (nivolumab and ipilimumab) as a frontline treatment, and could be spared chemotherapy.
Harmonization of TMB testing will help to provide an equal-access platform that will be good for patients, said Jamie Holloway, PhD, Molecular Sciences Liaison at Caris Life Sciences. She noted that harmonization will help lead to a “democratization of biomarkers,” which will be particularly helpful for cancer patients treated in the community—where the majority of cancer patients receive care—not at academic medical centers. That democratization is needed.
As previously reported by Oncology Times, a new survey from the American Cancer Society Cancer Action Network (ACS CAN) showed that only 39 percent of respondents reported having their tumor tested, and about one in eight respondents said biomarker testing was not covered by their insurer. Holloway said there is going to be a greater need for patient education, because more responsibility is being placed on cancer patients as they participate in decision-making. “Biomarkers in immunotherapy are only going to get more complicated,” she said.
“This is such an important and vital effort,” stated David Fabrizio, PhD, Vice President of Translational Strategy at Foundation Medicine. He noted that adding harmonization provides a framework to establish consistency across TMB measurement platforms that can reduce variations and provide an “apples to apples comparison.”
“It is incredibly important for us to have standardization of this test,” added Nicholas Botwood, MD, Vice President for Oncology Clinical Development at Bristol Myers Squibb. The immune response to cancer is “extraordinarily complex,” he noted, and the TMB harmonization project provides “a foundation from which we can really build.”
For example, he believes it will be important to establish validated TMB measurements in different cancerous tumors to establish cutoff points for treatment. Botwood said it is known that the level of TMB is different in different tumor types, and that TMB is a continuous variable. He said that ideally prospective trials will be a key to establishing the predictive clinical utility of TMB.
Moving forward at FDA, there is a need for best practices for analytical validation of TMB tests, said Reena Philip, PhD, Director of FDA's Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostic Devices and Radiological Health, Center for Devices and Radiological Health. A test developer will have to show clinical validation using clinical data.
From a regulatory point of view, it is difficult to develop a biomarker test used in conjunction with a drug, said Richard Pazdur, MD, Director of FDA's Oncology Center of Excellence. The pharmaceutical industry is not necessarily used to developing companion biomarkers, he noted. But, “the ultimate goal is improved care,” which will push progress toward tissue-agnostic, biomarker-driven cancer treatment forward. “I think this is the future of oncology,” he noted. The number of FDA-approved companion molecular diagnostic assays is growing.
Moving forward in clinical practice, oncologists will need to work closely with pathologists and use targeted biomarker panels earlier, said Naiyer A. Rizvi, MD, the Price Family Professor of Medicine and Director of Thoracic Oncology and Co-Director of Cancer Immunotherapy at Columbia University Irving Medical Center. Rizvi noted that the availability of tumor tissue has been a significant problem in genomic testing, and liquid biopsy represents “a huge opportunity” for biomarker testing.
Asked by Oncology Times what level of validation is needed to use complex biomarkers in the clinic, Hellman said these factors should be considered: 1) Is it feasible to do using routine tools available in the clinic? 2) Is it meaningful?
He emphasized that oncologists are already doing next-generation sequencing (NGS) tests, which represent broad multi-gene panels, so TMB testing is a next step in progress on the immunotherapy frontier. FDA approval of NGS panels demonstrates that the paradigm is shifting from single-gene assays to inform a single therapeutic option in specific cancers to a comprehensive approach, which can detect the patient's entire mutational profile.
Peggy Eastman is a contributing writer.