All indications suggest biomarkers could aid cancer immunotherapy development and help doctors predict therapeutic impact. But industry still has to agree harmonised assays and standards, say experts.
Predictive biomarkers are not a new concept. They have been used to diagnose disease and forecast patient response to therapies that are directed against these diseases for many decades.
For example, skin cancer patients who carry a BRAF V600 mutation are more likely to respond to BRAF inhibitors like Roche’s Zelboraf (Vemurafenib) than people without such mutations.
Similarly, in other cancers, EGFR mutations, NTRK fusions and ALK fusions are all used as biomarkers because they indicate patients are likely to respond well to targeted therapies.
Immunotherapies
The challenge now is to use predictive biomarkers for non-targeted therapies, particularly in areas like immuno-oncology where determining likely response to treatment is crucial.
Finding and using such biomarkers is complicated, according to John Haanen, Professor of Translational Immunotherapy of Cancer at Leiden University Medical Centre in the Netherlands and European Society for Medical Oncology (ESMO) expert.
“The presence of PD-L1 expression is often associated with a better response to anti-PD-(L)1 therapy. Similarly, high TMB is correlated with better response to immune checkpoint inhibitors, so is the presence of TIL or a T cell GEP.
“But unlike biomarkers for targeted therapy like BRAF inhibitors which are categorical, the biomarkers for immunotherapy are continuous, without very good cut-offs that will help us decide whom to treat or whom not to treat,” he said.
Tumour mutational burden
TMB – or tumour mutational burden – is a measurement of mutations carried by tumour cells. It is a good example of the difficulties involved in using a biomarker to predict the impact of a therapy that does not target it directly.
In June 2018, Bristol Myers-Squibb sought approval for Opdivo and low-dose Yervoy in lung cancer in patients with a TMB of greater than ten mutations per megabase.
Initially B-MS reported promising data for the combination therapy from a phase 3 trial called Checkpoint-227. However, last October it released analysis showing survival in patients with high TMB and low TMB was comparable.
In other words, a patient’s TMB level was no help when it came to predicting whether the combined regimen would work. B-MS withdrew its supplemental Biologics License Application (sBLA) in January this year, explaining that ‘further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy on OS in first-line NSCLC patients’.
The timing of the withdrawal was ironic given that, in the same month, FDA Commissioner Scott Gottlieb highlighted ‘TMB as a potential biomarker for enriching clinical trials testing immunotherapies’.
Harmonisation
Gottlieb has since resigned, but his comments have not gone unheeded. ASCO expert, Catherine S Magid Diefenbach said assay developers and the immunotherapy industry have ramped-up their biomarker R&D efforts.
“The response has been a surge of interest in developing novel companion biomarkers, and biomarkers that allow personalisation of therapy. This is a field that is just beginning and the support of the FDA has been a vital force driving this development.”
She added that “many of the immune biomarkers that are under investigation have exciting clinical data in small studies”, citing minimal residual disease (MRD) in haematologic malignancies such as CLL or mantle cell lymphoma minimal as an example.
Sarah Hardison, therapeutic area director from Clarivate Analytics, has also seen an industry response.
“Harmonisation is occurring between reference standard vendors and the producers of assays and/ or the end users, diagnostics labs, to improve the sensitivity and reliability of these measures.
“The confounding issue is that, in the case of PD-1/PD-L1 drugs, each developer uses its own companion diagnostic that is required to prescribe the drug. Harmonisation has been addressed in this case by the development of a ‘complementary’ diagnostic by DAKO, which can be used to indicate PD-1/PD-L1 therapy independent of specific drug,” she said.
Patient safety drive
For John Haanen, demands for safer immunotherapies are also a factor in the FDA’s call for biomarker and assay harmonisation.
“It is clear that in order to [avoid] treating patients with ineffective but highly costly and potentially highly toxic drugs, solid predictive biomarkers are required, especially for immunotherapies.
“FDA is stimulating this approach and one can see the development of, for instance, TMB assays, targeted gene panels, that can be stand- alone tests, or complementary or companion diagnostics.”
He also cited an FDA-approved TMB test developed by Foundation Medicine and Memorial Sloan Kettering Cancer Center as an example.
R&D impact
How greater use of biomarkers in immunotherapy development will impact industry in the longer term is – ironically – hard to predict. Diefenbach said: “The promise of being able to tailor cancer therapy to biology and risk is at the forefront of the drive to discover novel biomarkers.
“If a novel biomarker can predict who will respond to which therapy, or who is cured and who is not, we will be able to personalise cancer therapies in the future far more precisely.”
The potential downside, Magid Diefenbach said, is that immunotherapy firms may focus drug development on diseases that have established biomarkers and assays.
“The risk in developing therapies that are biomarker-driven, is that patients whose disease lacks a biomarker will be left out of novel therapy development, and of risk prediction or personalisation.”
She added: “[It is important] to balance the needs of patients with rare malignancies or subtypes of malignancies, and developing biomarkers with broad generalisability for a broad cross section of patients.”
Clarivate Analytics’ Sarah Hardison also acknowledged that industry may focus on cancers with biomarkers, but sees such an approach as an extension of established drug R&D practices.
“The idea of cancer biomarkers is to find one that exists to the exclusion or near-exclusion of others so that you can identify the ideal therapy.
“The questions being asked are, what does an individual’s mutational profile look like, and do we have a drug to treat it; ie, do they have EGFR mutations, KRAS or IDH-1 mutations,” she added.
Clinical evolution
Greater use of biomarkers is also likely to impact the development of combination immunotherapeutic regimens, according to John Haanen, who suggested the biggest changes will be seen in trials.
“Pharma is combining a lot of its drugs, sometimes with good biological rationales, but often without, and performing trials with many expansion cohorts to find a signal of response.
“In general, good biomarkers mean fewer patients per group. The advantage may be that smaller trials are required to convince regulatory bodies to prove a certain drug is effective, but there is quite a difference between FDA and EMA in policy here, as the latter requires larger RCT.”