The programmed death-1 receptor and its programmed death ligand-1 are key components of an immune checkpoint that has now been successfully targeted in several malignancies. Antibodies directed against PD-1 (pembrolizumab and nivolumab) as well as PD-L1 (atezolizumab and durvalumab) are now approved in a number of malignancies, including non-small cell lung cancer. Of these, only pembrolizumab treatment is contingent upon verification of PD-L1 expression.
PD-L1 expression is routinely measured using immunohistochemistry, an assay which stains tissue specimens according to the presence or absence of a biomarker, and how much of that biomarker is expressed (for example, darker staining indicates higher expression). PD-L1 expression ranges from 0% to 100% on tumor cells, and when assessing if a patient is a candidate for pembrolizumab (Keytruda, Merck), it is reported as a tumor proportion score (TPS). The TPS is defined as the percentage of tumor cells showing partial or complete PD-L1 membrane staining, versus all the tumor cells (both positive and negative for PD-L1) present in the specimen field. Infiltrating immune cells, normal (nontumor) cells, dying cells and other cellular debris are excluded from scoring. In pathology reporting, PD-L1 expression is generally reported as:
All four immunotherapies carry different indications in NSCLC. Durvalumab (Imfinzi, AstraZeneca) is the only of these that is indicated in unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiotherapy.1 Both the indication statement of durvalumab as well as the National Comprehensive Cancer Network guidelines do not require PD-L1 expression testing.
Similarly, nivolumab (Opdivo, Bristol-Myers Squibb) and atezolizumab (Tecentriq, Genentech) treatment does not require prior testing for the PD-L1 biomarker.2,3 Their use is restricted to patients who have progressed on or after platinum-based chemotherapy or, if positive for an EGFR or ALK genomic tumor aberration, who have progressed on one of the targeted therapies approved for those mutations.
In contrast, treatment with single-agent pembrolizumab requires verification of PD-L1 expression, either as a TPS of 50% or more in the first-line setting, or a TPS of 1% or more in the second-line or later setting.4 Pembrolizumab also carries a separate first-line indication in combination with pemetrexed (Alimta, Eli Lilly) and carboplatin chemotherapy for the treatment of nonsquamous NSCLC; use under this indication is not contingent upon PD-L1 expression.
Based on this, current guidelines from the NCCN recommend PD-L1 testing for all newly diagnosed patients with NSCLC who do not carry either EGFR or ALK genomic tumor aberrations.5 This applies to both patients with squamous and nonsquamous histologies. The NCCN guidelines also state that the PD-L1 threshold cutoff of a TPS of 50% or more is seemingly arbitrary, as patients with PD-L1 expression levels just below and just above this cutoff will likely have similar responses. The guidelines further note that regardless of PD-L1 expression levels, PD-1/PD-L1-targeted immunotherapy seems to be less effective in tumors with an actionable genomic tumor aberration (ie, an EGFR mutation, ALK translocation or MET mutation). In other words, all patients with newly diagnosed metastatic NSCLC who are negative for EGFR or ALK genomic tumor aberrations should undergo PD-L1 expression testing, as this will inform whether that patient should receive first-line pembrolizumab. PD-L1 testing in the second-line or later setting is only necessary for treatment with pembrolizumab; treatment with either nivolumab or atezolizumab may proceed without PD-L1 testing.
Although it is broadly considered to not be an optimal biomarker, measuring PD-L1 expression levels is currently the best available biomarker to assess patients for treatment with pembrolizumab. However, measuring PD-L1 expression as a biomarker also carries a number of challenges, including the use of different testing platforms and antibodies, the subjective nature of assessing PD-L1 expression and varying definitions of PD-L1 positivity. In addition, tumor expression of PD-L1 is notably heterogeneous and dynamic, and discrepancies have been observed between expression levels of primary vs. metastatic sites. Finally, both anecdotal observations as well as data from clinical studies of these agents demonstrate that many patients with tumors that have no or low PD-L1 expression still respond to these agents. Thus, earnest effort is ongoing in the identification of novel biomarkers to best determine those patients who are most likely to response to PD-1/PD-L1 targeted immunotherapy.
One of these, tumor mutation burden, is a reflection of the number and extent of mutations that have occurred in the tumor cells. In tumor cells, multiple mutations can arise as a result of exposure to carcinogens, dysfunctional DNA repair mechanisms and other alterations to the DNA. Among solid tumors, NSCLC is noted to have one of the highest tumor mutation burdens. One hypothesis for why a high tumor mutation burden may be associated with greater immunotherapy checkpoint inhibitor benefit is that these tumors tend to have higher expression of neoantigens, the fragments of altered proteins produced from mutated DNA. These neoantigens can be recognized as ‘foreign’ by the immune system to help drive the anticancer immune response.
Studies of tumor mutation burden in other tumor types, such as melanoma, have shown that patients with high tumor mutation burden had longer overall survival after treatment with another immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb).6 This has also been shown with the response to PD-1/PD-L1 immunotherapy treatment, which shows improved overall survival, progression-free survival and response rates among those patients with the highest tumor mutation burden. For example, this study demonstrated that among 33 patients who responded to anti–PD-1/PD-L1 therapies had a higher median tumor mutation burden compared with those patients who did not respond (median tumor mutation burden: 37.1 vs. 12.8 mutations per megabase; P = .002).7 Tumor mutation burden may be particularly of use for metastatic NSCLC in patients with a heavy smoking history, as exposure to the carcinogens in tobacco may result in a high tumor mutation burden among these patients.
Another potential biomarker for PD-1/PD-L1 response is mismatch repair (MMR) deficiency, an extension of tumor mutation burden. Tumor cells with MMR tend to have many accumulating DNA mutations that can in turn lead to cancer. MMR deficiency describes cells that have mutations within certain genes that are involved in DNA repair mechanisms. Thus, cells with MMR deficiency are less able to correct mistakes that commonly occur when the DNA is copied in a cell during routine DNA replication. MMR-deficient cells usually have many DNA mutations, which may ultimately lead to cancer. The use of MMR status as a biomarker for PD-1/PD-L1 response is bolstered by the recent approval of pembrolizumab for the treatment of microsatellite instability–high or MMR-deficient solid tumors. This approval, the first of its kind, was based on studies that demonstrated patients with these genetic abnormalities show significantly higher response rates and prolonged survival compared with patients who have fewer genetic abnormalities.
Other blood-based biomarkers have also been explored as potential indicators for response to PD-1/PD-L1 checkpoint immunotherapy, particularly in NSCLC. One of these is the neutrophil-to-lymphocyte ratio (NLR); in one study a pretreatment NLR of 5 or more was associated with worse overall survival and PFS among nivolumab-treated NSCLC patients.8
Continuing efforts have identified several tissue and plasma based-biomarkers predictive of checkpoint inhibitors in solid tumors including NSCLC. Although initial studies of these biomarkers have been performed in small and retrospective settings, their findings hold promise that future insights can be gleaned for optimization of PD-1/PD-L1 immune checkpoint inhibitors.
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