The Immuno-Oncology Revolution
Immuno-oncology (I-O) has become a catch-all phrase for a latest family of antibody therapies targeting immune checkpoints such as PD-1 and PD-L1, and promising to revolutionize the way cancer is treated. This novel class of agents works by “awakening” a cancer patient’s immune system: stimulating the patient’s own T-cells in recognizing, attacking and killing tumor cells. Predictably this strategy is proving most successful in immunogenic tumor types, such as melanoma, non-small-cell lung cancer (NSCLC), urothelial and renal cell carcinoma, where these agents are already FDA approved and routinely used in the clinic. When first entering the US market, I-O agents were reserved for later line metastatic patients who had exhausted all treatment options. However, success has propelled I-O to earlier and earlier lines of treatment. In October 2015, the FDA approved Yervoy (ipilimumab) in the adjuvant setting for melanoma patients, while several pharmaceutical companies currently in phase III trials are racing for first-to-market positioning in first line metastatic NSCLC.
Moving into Earlier Treatment Lines will Require a PD-L1 Predictive Biomarker
As earlier lines of therapy involve larger numbers of cancer patients, there is suddenly greater payer scrutiny and pressure to limit access to I-O agents to biomarker-selected patients who demonstrate some level of PD-L1 enrichment. Clinical trials geared towards earlier treatment lines certainly attest to this trend, the most notable example being Merck’s KEYNOTE 024 that limited its enrollment to patients demonstrating 50% or higher PD-L1 expression. From the clinician’s perspective, the necessity of preselecting patients based on PD-L1 expression levels is controversial. On the one hand, clinical trial data suggests a greater and more sustained benefit in patients that are PD-L1 enriched. On the other hand, studies have shown that immune checkpoint protein expression at the tumor site is dynamic. Unlike the expression of tyrosine kinases such as EGFR, which are intrinsic to the tumor cell, PD-L1 is an indicator of lymphocyte recruitment in the tumor and as such can fluctuate during the course of the disease. In fact studies have shown that events stimulating an immune response, such as the patient receiving chemotherapy or radiation can trigger lymphocyte recruitment and result in transiently higher PD-L1 expression levels. Some physicians are advocating for induction of PD-L1 expression by pre-treating patients with short chemotherapy or radiation cycles. With that in mind, the medical community is left to wonder when is the best time to test a patient for PD-L1 expression? And how often should a previously low PD-L1 expresser be re-tested?
Pd-L1 Biomarker Plethora will Create Logistical Challenges for Physicians and Patients
The situation is further complicated by the fact that pharmaceutical and diagnostics companies are partnering to co-develop proprietary PD-L1 immunohistochemistry assays. While Roche/Genentech partnered with Ventana to develop its companion diagnostic to Tecentriq (atezolizumab) for bladder cancer, Merck and Bristol Myers Squibb turned to Dako that developed two independent PD-L1 assays complementing Keytruda (pembrolizumab) and Opdivo (nivolumab) respectively as they prepare to enter first line NSCLC. In order to harmonize this diagnostic polyphony the FDA is spearheading an initiative, project Blueprint, to compare the sensitivity and specificity of the various PD-L1 companion diagnostics in an effort to standardize clinical guidelines once multiple PD-1/ PD-L1 targeting agents and companion diagnostics enter the same indications.
Beyond Histology Assays
While these efforts are unfolding in the clinical forefront, alternate diagnostic strategies are brewing in the research sidelines. Some doubt the validity of PD-L1 as a predictor of response to immuno-therapy. They argue instead that high mutational load determined via whole-exome sequencing may be a more adequate approach. Others point out that the invasive biopsy that is a prerequisite for a histological PD-L1 assay is at odds with the dynamic nature of the PD-L1 marker which may require the same patient to be tested multiple times during the lifetime of their disease for PD-L1 status. To that end Biodesix is developing a blood-based assay based on the principles of serum mass spectrometry, which they have shown to have predictive power in selecting for melanoma patients that will reap a survival benefit from nivolumab therapy.
The following video published by OncLive in April 2015 features top US oncologists discussing the issue of PD-L1 testing: