Biomarker Testing in Non–Small Cell Lung Cancer: A Clinician's Perspective

In the 50 years since Stanley Cohen discovered the epidermal growth factor receptor (EGFR), the importance of mutations in driving malignant transformation and the ability to target them with small molecule tyrosine kinase inhibitors (TKIs) has helped expand the field of cancer therapeutics from indiscriminant cytotoxics to targeted therapies. In lung cancer, specifically, the development of targeted therapies and more recently the finding that immune checkpoint inhibition has significant clinical activity has tempered the nihilism that attended many years of limited results from clinical trials. By the turn of the century, it was apparent that chemotherapy doublets had plateaued in achieving clinical benefit.1 A few short years after that, the ability of TKIs, such as gefitinib and erlotinib, to achieve significant clinical responses in a subset of patients with adenocarcinoma signaled the emergence of a new therapeutic paradigm.2 It is important to understand the role that targeted therapies have in the management of patients with advanced lung cancer and how correct pathologic information is essential for patients to receive the best possible care.The difficult and sobering statistics of advanced lung cancer are well known: it is the leading cancer killer.3 Most patients are diagnosed with locally advanced or metastatic disease, although the recent demonstration that screening computed tomography scan offers a survival benefit in high risk patients holds out the promise that we will move the diagnosis of the disease to earlier stages.4 Once a biopsy is obtained, it is important for the pathologist to not only confirm the diagnosis of cancer but also to classify the malignancy as either adenocarcinoma or squamous carcinoma. This distinction is important not only because of the difference in potential driver mutations but also because it has other therapeutic implications as well, because bevacizumab is not used in squamous tumors owing to concerns for fatal pulmonary hemorrhage.5In the United States, approximately 15% of patients have adenocarcinomas that harbor EGFR-activating mutations and another 5% to 7% have anaplastic lymphoma kinase (ALK) translocations. Often these patients are younger and light or never smokers, although even “enriching” the tested population based on clinical characteristics does not capture all of the patients with such abnormalities. These patients often have significant response to targeted therapies that can last for close to a year. In the case of EGFR and ALK, often progression, when it occurs (and it inevitably does) is slow, and the benefit has been demonstrated for continuing the targeted therapy because patients often continue to have an ongoing clinical benefit, often in sharp contradistinction to what we see when patients progress on cytotoxics.6By now, it is no longer an active clinical question: multiple clinical trials have conclusively proven that, in the presence of an activating EGFR mutation, targeted agents are superior to cytotoxic chemotherapy.7–10 For that reason, unless the patient has clinical symptoms necessitating rapid initiation of therapy, most clinicians will await the results of molecular testing before beginning treatment. It is expected that the turnaround time for such results should be 2 weeks at the most, the upper limit of time that a patient and their family can stand to wait for the information. It is certainly true that these mutation-directed therapies retain their ability to cause responses even if used after initial chemotherapy. However, their generally favorable toxicity profile leads most clinicians to prefer to select targeted therapy if the correct driver mutations are present, unless disease burden or severity necessitates a more urgent therapeutic start.Should all adenocarcinomas of the lung be automatically tested for EGFR and ALK? Certainly all patients with advanced disease need those tests, and histology or even the presence or absence of smoking history should not dissuade clinicians from ordering them.11 Although clinical characteristics tend to show that patients with ALK and EGFR mutations tend to be never or light smokers with a younger age, selecting patients on such clinical checklists will still miss a number of patients who could benefit from targeted therapies. Even smokers or patients with poorly differentiated tumors can still harbor the activating mutations, and the determining factor that decides response to TKIs is the presence of the mutation, not the clinical history or tumor grade. Some authors have suggested that the assays be ordered, even for early stage disease. At present, there are few data to confirm that adjuvant TKIs are useful in an adjuvant setting outside of a clinical trial, although that question is being actively pursued.12Even if the knowledge of the presence or absence of drug-treatable mutations would not be used to pick adjuvant therapy, reflex testing of early stage cancers could provide other benefits, much the same way that all breast cancers are tested for HER2/neu and estrogen receptor status. Because 50% to 70% of patients with N1 disease will eventually relapse after lobectomy, the argument can be made that if the EGFR status is already known, the treating oncologist will know which therapeutic bullets to use, which will minimize delays to initiating therapy. The cost-effectiveness of this approach has yet to be studied, and thus, currently, it must be left to the individual institutions to decide on whether to automatically set up reflex testing on surgical resection specimens.Despite the success of TKIs in achieving a meaningful clinical response and prolonging survival in advanced disease in patients with activating mutations, all patients eventually progress. For researchers to better understand the molecular mechanisms that drive acquired resistance, patients will inevitably need to undergo repeat biopsies. Although those procedures are obviously invasive and often will require bronchoscopy, it is essential for best tailoring of subsequent therapies. Sequist et al13 looked at the mutational results in patients who developed acquired resistance after therapy with a TKI. Forty-nine percent (18 of 37) had developed the T790 mutation, but 14% (5 of 37) had developed a small cell transformation, and 5% (2 of 37) had a PI3KCA mutation or MET amplification. Studies are now underway to target the T790 mutation specifically with second-generation TKIs, whereas other strategies are examining combining cetuximab plus afatinib, a pan-HER inhibitor, or adding heat-shock protein inhibitors.14–16 Although repeat biopsies do subject patients to another invasive test with their attendant risks and discomforts, it is hoped that, in the future, newer technologies will allow physicians to follow EGFR mutations in circulating tumor cells as a real-time measure of response.17,18 Clearly, the rationale for repeating the biopsy in progressing patients is that information may be obtained that has real, tangible, downstream effects on treatment decisions. If a T790 mutation has developed, the patient might benefit from going into a clinical trial of second-generation TKIs targeting that specific mutation, whereas patients lacking the T790 mutation might need to have chemotherapy added to the erlotinib.19 Other mutations that help drive acquired resistance—MET amplification or HER2/neu mutations—might also provide other molecular targets that will eventually need to be tested in clinical trials.The development of targeted therapies for lung cancers that harbor the ALK translocation in many ways mirrors the success achieved by TKIs. Crizotinib was approved by the US Food and Drug Administration in 2011. Studies have shown that crizotinib has a higher response and prolongs survival better than systemic cytotoxic chemotherapy. Shaw et al20 published that the response rate was 65% (112 of 173) with crizotinib compared with 20% (34 of 174) for chemotherapy and progression-free survival was more than doubled. As with other targeted therapies, despite early responses, the tumors eventually develop acquired resistance. Newer, second-generation ALK inhibitors are currently in clinical trials and seem to have significant activity, even in patients with central nervous system involvement. Mirroring the situation in EGFR-mutation–positive tumors, repeat biopsies are needed to assess the mechanisms that propagate ALK resistance and allow the development of rational strategies to combat it.Although there is a consensus on the necessity to test for EGFR and ALK in all cases of advanced adenocarcinoma of the lung, the identification of much rarer mutations that respond well to targeted therapies poses a more difficult question. Cost-effectiveness and intelligent use of resources will mandate prudent use of testing, but the implications for patients who fall into these rare groups are significant.21 An example would be ROS1 mutations, which are found in about 1% of adenocarcinomas and which respond well to crizotinib.22 Should all tumors be tested for ROS1? What other tests should be included in a “panel” of adenocarcinoma mutations? HER2/neu? MET? The ongoing development of targeted therapies that show clinical efficacy will necessitate the ability for broader, faster, and cheaper testing at the time of diagnosis.BRAF mutations and MET amplification are cases in point. Planchard et al23 reported their results of the use of dabrafenib in 17 patients with the V600E BRAF mutation. The patients all had adenocarcinoma and had failed a frontline cytotoxic chemotherapy regimen. The therapy was well tolerated, and the overall response rate was 54%; the longest response was 49 weeks. Although, obviously, the numbers are small and further confirmation is required, the study is another example of a specific mutation allowing a rational small-molecule therapy to be used with clear benefit for responding patients. It bears notice that second-line chemotherapy in unselected patients with non–small cell lung cancer is generally less than 20%.MET has also emerged as a potential target for drugs. MET amplification is noted in about 4% to 7% of patients with non–small cell lung cancer. It is an adverse pathologic feature when detected in patients who have undergone resection with curative intent and predicts for shorter survival than MET− patients. Recently, Spigel et al24 published their results of a trial of onartuzumab and erlotinib versus erlotinib plus placebo in patients with recurrent non–small cell lung cancer. The results revealed that patients with a high MET overexpressing tumor benefitted from the combination therapy with improvements in disease-free survival and overall survival, whereas patients whose tumors did not have MET amplification actually did worse with the combination. Clearly, the further development of biomarkers will allow us to use them as both prognostic, as well as predictive, markers.One cannot discuss advances in our therapeutic arsenal against lung cancer in 2014 and not discuss immunotherapy. Immune checkpoint inhibitors have emerged as one of the most promising classes of lung cancer therapeutics. With overall response rates of around 20%, even in heavily treated patients, responders seem to often have an extended tail of the survival curve, with some patients on the original phase I trial without evidence of disease almost 5 years out.25 Obviously not all patients respond or benefit from those therapies, and a great deal of work is going into trying to understand which biomarkers can provide treating physicians with a better idea of who will benefit.26 Although early, several studies are looking at tumor expression of PDL1 as a biomarker to predict response to immune checkpoint inhibition. Although some patients whose tumors lack PDL1 expression still can respond to PDL1 inhibitors, some early reports have suggested a significantly higher response rate with tumors that highly express PDL1. Thus, PDL1 might eventually serve as a marker to select patients for therapy or to monitor the success of other therapies to induce PDL1 expression that can then subsequently be targeted by PDL1 antibodies. Still, the development of accurate biomarkers to select patients for immune checkpoint therapy is early, and much study needs to be done before definitive answers are known.It has been an amazing decade since Lynch et al2 demonstrated that advanced lung cancer can respond to a small-molecule–targeted agent. Ongoing efforts to describe the genetic and epigenetic landscape of lung cancers will hopefully allow for the continued development of more-specific therapies that improve response while sparing patients either difficult systemic therapies or fruitless endeavors. The advances that we have seen have cemented the study of biomarkers as the lynchpin of clinical decisions regarding therapeutic medical intervention.