Answer: First of all, histology is the initial decision point in any advanced patient with NSCLC. The differentiation between squamous and adenocarcinoma is paramount. Up until about 2005, we had a one-size-fits-all approach to treating NSCLC; chemotherapy combinations with respect to therapeutic outcome appeared essentially equivalent. There did not seem to be any distinction in response or survival based on histology, and certainly there was no marker testing at that point. Our therapeutic decisions hinged on convenience, toxicity, baseline patient function, and patient comorbidities, but the actual histology or marker status of the tumor had no bearing on treatment selection.
The agent that changed our focus was bevacizumab, which was the first targeted agent to be approved for the treatment of advanced NSCLC. The initial randomized phase 2 trial showed untoward toxicity in patients with squamous cell histology, with an unacceptable rate of life-threatening and fatal pulmonary hemorrhage.1 Further testing was restricted to a non-squamous population. The approval of bevacizumab was based on the results of the phase 3 ECOG 4599 trial in a non-squamous population, which showed a clear-cut survival advantage for the addition of bevacizumab to paclitaxel and carboplatin in combination compared to chemotherapy alone.2
We also saw that histology was important with another drug, pemetrexed. Pemetrexed was originally approved in all NSCLC histologies in the second-line setting. However, a phase 3 randomized study in the first-line setting3 showed that pemetrexed had a specific advantage over gemcitabine in combination with platinum in the non-squamous histology group. For the first time, a cytotoxic therapy yielded different outcomes in advanced NSCLC based on tumor histology.
After histology, molecular marker tests have started to gain currency since the identification of the epidermal growth factor receptor (EGFR) mutation. Lynch and Pao were the first to identify the presence of the EGFR mutation.4,5 These studies showed a marked association between EGFR mutations and sensitivity to the EGFR tyrosine kinase inhibitors (TKI): in this country, erlotinib, in much of the rest of the world, gefitinib. They also showed that patients with adenocarcinoma, women, never smokers and East Asians were far more likely to harbor EGFR mutations. There have now been at least six separate phase 3 trials in the first-line setting, either in phenotypically favored patients or strictly in mutant-positive patients that have shown a clear advantage for EGFR-TKI over chemotherapy with respect to response rate and progression-free survival.6-12 These are not subtle advantages: we are seeing a doubling or tripling in response rate, and incremental improvement in progression-free survival (PFS) of 4 to 10 months. These have not yet translated into an overall survival advantage because of crossover at the time of disease progression from the control arms (chemotherapy upfront).
I think it's safe to say that any patient with an EGFR mutation should receive an EGFR-TKI up front (Table 1). Certainly, in day-to-day clinical practice, testing a patient for EGFR mutation should be standard in those with adenocarcinoma histology.
The second important molecular abnormality in NSCLC is the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement. This was only just discovered in the past 2-3 years; 4%-8% of advanced NSCLC patients harbor an EML4-ALK rearrangement in contrast to the 10%-15% that have EGFR mutations. Again, phenotypically these patients look very similar to those with an EGFR mutation. They tend to be never smokers, or remote former smokers. They almost exclusively have adenocarcinoma histology, probably a more even gender distribution, and are not of East Asian ethnicity.13
What's particularly interesting is that these molecular abnormalities tend to be mutually exclusive, though there have been cases where two or more abnormalities have been seen. If a patient harbors an EML4-ALK translocation, they appear to be exquisitely sensitive to c-MET and ALK inhibitors. The prototypical agent here is crizotinib, which received conditional approval in August 2011 based on favorable response and PFS data.14 So, it would make sense to test for EML4-ALK in patients with adenocarcinoma.
The third molecular marker is a bit more controversial (Table 2). Approximately 20% to 25% of advanced NSCLC patients harbor KRAS mutations.15 These mutations are much more common in current or former smokers, and histology is usually adenocarcinoma, very rarely squamous. Like EGFR and EML4-ALK, KRAS tends to be mutually exclusive of other molecular abnormalities. For example, a patient with a KRAS mutation is unlikely to have the EGFR mutation or EML4-ALK translocation.
Unfortunately, KRAS is not yet an “actionable” target. A number of ongoing trials are looking at MAPK/ERK kinase (MEK) inhibitors and various other agents, and we're hopeful these agents may actually yield activity in patients with KRAS mutations. But by and large, it seems to be a marker of poor prognosis. People with KRAS mutations seem to do worse no matter what treatment they receive.
Finally, there are a number of other markers specific for response to cytotoxic agents. High levels of excision repair cross-complementation group 1 protein (ERCC1) are associated with platinum resistance, and high levels of ribonucleotide reductase M subunit 1 (RRM1) are associated with gemcitabine resistance.16,17 High levels of thymidylate synthetase (TS) are associated with pemetrexed resistance.18 We have no prospective phase 3 data in advanced NSCLC that have validated these markers. There are ongoing trials, including the phase 3 MADeIT study led by Drs. George Simon and Gerald Bepler that will ultimately determine whether these markers are worth obtaining, but for now, I do not advise routinely obtaining these markers.19
In the adjuvant setting, the role of molecular testing is still experimental. The RADIANT trial, which just finished accrual, will offer some insight in this setting.20 Eligibility was based on EGFR positivity by either immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH), but EGFR mutation was not required. Patients were then randomized to either erlotinib or placebo.
Ongoing trials are looking at adjuvant erlotinib in EGFR-positive patients with NSCLC. Probably the most important is an ongoing trial in Europe called TASTE.21 This trial is the only prospective phase 3 assessment of the EGFR mutation in the adjuvant setting. The premise of the study is that patients receiving customized therapy, based on their baseline tumor ERCC1 levels and EGFR mutation status, will achieve better disease-free survival rates than patients in the control arm receiving noncustomized therapy. The study will randomize patients with stage II and IIIA, non-squamous NSCLC to receive either standard therapy or molecularly determined therapy. The control arm will consist of cisplatin plus pemetrexed. In the genotypic arm, patients with low ERCC1 levels will also receive cisplatin and pemetrexed. Those with EGFR mutations will receive erlotinib. If they are EGFR-wild type with high levels of ERCC1, they will be observed. I strongly believe this is an exceedingly important trial, but we won't know the value of this approach in the adjuvant setting until the trial is done.