The Role of Biomarkers and Tumor Histology in the Diagnosis and Treatment of NSCLC

Course Director

Corey J. Langer, MD

Corey J. Langer, MD
Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania


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Dr. Corey Langer provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

With the evolving understanding of the role of tissue histology in determining optimal therapeutic strategies in advanced non-small-cell lung cancer (NSCLC), and the recent identification of relevant predictive markers that can further predict and refine selection of targeted and systemic therapy for NSCLC, we are moving rapidly towards an era of individualized therapy. It is increasingly evident from clinical data that accurate tumor histology and the presence or absence of certain gene abnormalities are critical in selecting therapy for patients with NSCLC. However, current formal indications may lag behind newly established guidelines and best practice recommendations for NSCLC. In this activity, Dr. Corey Langer addresses 3 key questions about the use of biomarkers in NSCLC from a survey of US-based oncologists.


In day-to-day clinical practice, please provide clear guidance on which marker study we need to order to manage our patients with NSCLC.

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.

Table 1


Table 2



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Should biomarker testing be done on all NSCLC patients regardless of histology?

Answer: I would argue strongly that all patients with adenocarcinoma histology be tested, as well as any patient with not otherwise specified histology, what we typically call NOS. The utility in patients with squamous cell histology is debatable. I would certainly consider testing in any patient with a mixed adenosquamous carcinoma.

The one group I tend not to test routinely is current or former smokers with pure squamous histology. The likelihood of having a marker for a targeted agent is extraordinarily low in that group, probably less than 1 in 500, or 1 in 1000. The exceptions are never smokers with squamous histology, where the mutations have been identified.

Now, these recommendations are based on what we’ve seen in the past 3-4 years. The answer to this question would have been very different in 2007, and it’s likely to change again in the next few years. In the meantime we still have confusion: some clinicians don't test for any specific marker, while there are many others who test for everything, but honestly don’t know what to do with the results. We all know about the EGFR mutation, and we’re learning about EML4-ALK rearrangement. We’re still not sure how to grapple with the cytotoxic markers, ERCC1, RRM1, and TS.

So which mutations should we test for? Some experts have argued that all we need is the KRAS mutation test. If that's positive, we don't need to do an EGFR or EML4-ALK test, since a patient with KRAS mutation is extraordinarily unlikely to have either EGFR mutation or EML4-ALK translocation. We recommend testing for “actionable” targets, EGFR mutation and EML4-ALK rearrangement.

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When a patient with NSCLC has tested positive for EGFR mutation, should I start him or her on an EGFR inhibitor first line or should I still wait until second line?

Answer: My bias is to introduce the EGFR-TKI as early as possible. The IPASS trial yielded a major improvement in progression-free survival in the EGFR-positive population compared to frontline chemotherapy. Conversely, in the wild-type population, those receiving chemotherapy did better than those getting the EGFR-TKI.22 About 70% of patients with the EGFR mutation will respond to a TKI, compared with maybe a 35%-40% response rate for chemotherapy.

We frequently encounter the scenario where tissue testing results come in after the patient has started chemotherapy. What’s the best course of action? I would be hard-pressed to discontinue chemotherapy in a patient who has stabilized or improved on chemotherapy, and I will generally introduce the EGFR-TKI after 4-6 cycles of the chemotherapy, as maintenance treatment. But obviously, if the patient is not tolerating the chemotherapy, or the chemotherapy is not working, I would quickly switch over to an EGFR-TKI.

We are sensitized to giving an EGFR-TKI early, either first line or as maintenance, but I also want to make the point that we should not abandon this agent in the absence of the mutation, especially in the second-line setting and beyond (Figure). Remember, the original indication for erlotinib in the second- and third-line setting was in an unselected patient population, which included both wild-type and EGFR mutants. So we should not assume that because a patient is negative for the EGFR mutation, erlotinib does not have any role. Results of the BR21 trial established the role for erlotinib versus placebo in the second- and third-line setting in a largely wild-type population.9

Figure



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References

  1. Johnson DH et al. J Clin Oncol. 2004;22:2184-2191.
  2. Sandler A et al. N Engl J Med. 2006;355:2542-2550.
  3. Scagliotti GV et al. J Clin Oncol. 2008;26:3543-3551.
  4. Lynch TJ et al. N Engl J Med. 2004;350:2129-2139.
  5. Pao W et al. Proc Natl Acad Sci U S A. 2004;101:13306-13311.
  6. Giaccone G et al. J Clin Oncol. 2004;22:777-784.
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  8. Herbst RS et al. J Clin Oncol. 2005;23:5892-5899.
  9. Shepherd FA et al. N Engl J Med. 2005;353:123-132.
  10. Thatcher N et al. Lancet. 2005;366:1527-1537.
  11. Cappuzzo F et al. J Thorac Oncol. 2009;4(suppl 1):S289; abstract A282.281.
  12. Miller VA et al. J Clin Oncol (ASCO Annual Meeting Abstracts). 2009;27:Abstract LBA8002.
  13. Kwak EL et al. N Engl J Med. 2010;363:1693-1703.
  14. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Accessed November 3, 2011.
  15. Kris MG et al. 2011 American Society of Clinical Oncology Annual Meeting (ASCO 2011). Abstract CRA7506.
  16. Olaussen KA et al. N Engl J Med. 2006;355:983-991.
  17. Lee JJ et al. Lung Cancer. 2010;70:205-210.
  18. Takezawa K et al. Br J Cancer. 2011;104:1594-1601.
  19. Simon GR et al. J Clin Oncol. 2007;25:2741-2746.
  20. http://clinicaltrials.gov/ct2/show/NCT00373425?term=RADIANT&rank=4. Accessed November 11, 2011.
  21. http://www.clinicaltrials.gov/ct2/show/NCT00775385?term=Taste&rank=2. Accessed November 12, 2011.
  22. Mok TS et al. N Engl J Med. 2009;361:947-957.

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