Predictive Markers for Anti-PD-1/PD-L1 Therapy in Non-Small Cell Lung Cancer

Where Are We?

Matthew Evans; Brendan O'Sullivan; Matthew Smith; Philippe Taniere


Transl Lung Cancer Res. 2018;7(6):682-690. 

In This Article

The Future: Combinations of Markers, Combinations of Therapies

In the immunotherapeutic workup of NSCLC, much remains to be proven conclusively. However, what can be stated with confidence is that no single marker is likely to be sufficient to provide all the necessary predictive information for immunotherapy response. PD-L1 expression assessment is firmly established in routine practice, and its predictive power is likely to be refined in future by TMB and—possibly—by CD8 T-cell assessment.

Immunotherapy far from the whole picture, however. Targeted therapies against molecular drivers offer the greatest prospect of long survival in NSCLC, and so future testing algorithms will need to incorporate EGFR mutation, ALK translocation and ROS1 translocation testing. Furthermore, the fact that histological tumour type, stage and patient fitness—above all else—are the most important determinants of the most appropriate treatment cannot be overlooked.

This combination of patient fitness, tumour histology, tumour stage, molecular drivers and immunotherapeutic markers makes for an astonishingly complex management algorithm, which must be informed by clinically-validated trial data. It is clear that—under such circumstances—the question, "how should I treat this patient?", may well be unanswerable by simple recourse to guidance or common-sense. Indeed, it is probable that such complexity will require computerised algorithmic decision-making, using probabilistic calculations based on trial data (Figure 2).

Figure 2.

An algorithmic approach to determining the most appropriate management for a patient with NSCLC—based on the results of clinical trials incorporating data relating to tumour stage, tumour histology, targetable molecular alterations and immunotherapy predictors. NSCLC, non-small cell lung cancer; TMB, tumour mutation burden; PD-L1, programmed death-ligand 1; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, ROS proto-oncogene 1.

As if that were not complex enough, it is clear that the sharp divisions between classical chemoradiotherapy, targeted molecular therapy and immunotherapy are beginning to become blurred. Recent data, for example, suggest that combination pembrolizumab-chemotherapy is superior to pembrolizumab monotherapy,[35] and ongoing studies are exploring the efficacy of combination anti-EGFR tyrosine kinase inhibitor-checkpoint inhibitor therapy in NSCLC.[36]

Clearly, the need for morphological, immunohistochemical, targeted molecular and immunotherapeutic tests places considerable demands on tissue. This would not be an issue if it were the case that all NSCLC specimens underwent resection prior to testing, but this is not at all the case: indeed, many such cancers will never be resected, and the only tissue ever acquired may be a small biopsy. Given that patients with NSCLC often have significant comorbidity and may not be able to undertake numerous invasive procedures, it is incumbent on the pathologist to ensure that maximal use is made of whatever tissue is available. In part, this is a technical issue which can partially be overcome by the development and use of technologies which use tissue as efficiently as possible. In part, though, it also requires that practitioners be judicious in their use of tissue, keeping wastage to an absolute minimum.

Not only this, but time also poses a great challenge. Patients with NSCLC have a poor prognosis and, if treatment is to be at its most effective, it must be instituted as rapidly as possible. Furthermore, because the various markers of interest are interrelated from management points of view, all results have to be available rapidly; there is at present, for example, little point in providing a very timely PD-L1 expression result if an EGFR mutation result takes weeks, because according to licencing anti-PD-1/PD-L1 therapy requires the absence of a sensitising EGFR mutation. Again, of course, improvements in technologies can help, but above all else a robust logistical setup is essential.

Of great interest in the last few years has been the prospect of testing circulating tumour DNA in plasma for molecular alterations. This is established in the case of EGFR mutations in NSCLC as a surrogate or complement to tissue testing at the time of diagnosis, or clinical progression under tyrosine kinase inhibitor therapy to detect a secondary T790M mutation. It remains to be demonstrated that such a test can be used to monitor patients under treatment. With regards wider mutation screening which could be used to assess TMB, no data currently exist to demonstrate its clinical utility; the major challenge in this case is the small amount of circulating tumour DNA, the lack of technique to distinguish tumour-derived from non-tumour-derived DNA, and the level of sensitivity required to be clinically relevant. Prospective trials, perhaps, hold the key in clinically validating gene mutation testing on plasma.