Just before the ASCO annual meeting last June, I interviewed Tom Lynch in an oceanfront hotel on Miami Beach, where Mark Socinski and Rogerio Lilenbaum were throwing their annual lung cancer CME program.

Tom and I reflected back on the first time we met for an interview, in 2004 at the very same venue, and how we’d joked about the kids screaming at the pool below while their disinterested parents baked in the South Florida sun. Tom’s now-classic New England Journal lead article on EGFR mutations in non-small cell was about to be published, and as a result, the lung and oncology paradigm would change permanently.

Four years later, as we sat down again, another critical piece in the non-small cell puzzle had just been added in the form of a press release regarding the “positive” findings of the FLEX trial, evaluating chemotherapy with or without cetuximab as first-line therapy for advanced disease.

Of course, the true essence of FLEX would not be available until the full findings were presented at ASCO, where Tom would be the discussant of the paper, but even at this early point, it was apparent that the treatment algorithm had shifted, and both of us could see that a subset approach to lung cancer was emerging that was conceptually similar to what has been integral to breast cancer management for many years.

Over the next few months, listeners to our Lung Cancer Update audio series heard the details of this important story from a number of investigators, including Robert Pirker (the principal investigator of FLEX), Alan Sandler (the principal investigator of the ECOG-E4599 study, demonstrating an advantage to the addition of bevacizumab to carbo/paclitaxel) and others.

It turns out that the results of FLEX were both modest (five weeks advantage in survival) and puzzling (no advantage in progression-free survival), but in spite of the these shortcomings, most investigators believe that cetuximab — if it were made available — would be a reasonable consideration for patients not eligible to receive bevacizumab, particularly those with squamous cell cancer.

In breast cancer, ER and HER2 measurements are routinely considered in any systemic treatment decision, and for many patients an Oncotype DX^® Recurrence Score^® is now also integrated into treatment planning. Since the FLEX data came on board, along with other recent findings in lung cancer, a similar approach to clinical segmentation is now evident in lung cancer, and when we examine some of the major clinical dilemmas currently facing medical oncologists (see Figures 2 and 3) this emerging tissue-based strategy is very evident.

This issue of Patterns of Care (our second in lung cancer) illustrates some of the key characteristics that distinguish one lung cancer patient from another and how the following factors are considered in treatment decision-making for metastatic disease:

1. EGFR mutation status/IHC and FISH assays for EGFR

As Tom predicted in our 2004 interview, EGFR mutation status is becoming one of the most fascinating areas of translational oncology, and both IHC and FISH assays for EGFR have now been used to identify patients likely to benefit from EGFR TKIs and antibodies. The breathtaking biology here is not yet routinely part of clinical practice, and even nonsmokers undergoing surgical resection — with which there is usually plenty of tissue — rarely have this type of tissue assay panel performed. You can bet the house (what’s left of its equity, anyhow) that if I had a primary nonsmall cell tumor removed, these assays would be done and would be integral to my treatment decision.

2. Bevacizumab “eligibility” (Figure 1: Entry and exclusion criteria for E4599)

Patients who could have entered trials like ECOG-E4599 are another important segment of the non-small cell population. The criteria here are evolving, and it’s interesting that both investigators and docs in practice estimate that about a third of patients are “bev eligible” (Figure 19). This subset is an evolving target, with, for example, new data suggesting that bev might be an option for patients treated for brain metastases. For patients who don’t meet the bev criteria, the FLEX trial raised the option of cetuximab, which required that an IHC assay for EGFR be done and at least one positive cell be identified.

Histology is also salient, and for patients with squamous tumors cetuximab, based on the FLEX data, is a definite consideration. Some, like Dr Pirker, even argue that it could be offered to bev candidates. Our current Patterns of Care survey suggests that practicing docs and investigators believe that chemo/bevacizumab might be more effective than chemo/cetuximab, although bev-associated hemoptysis does give some of them pause.

3. K-ras status

The correlation between K-ras status and benefit from cetuximab is being assessed in FLEX and other studies, although currently a number of investigators believe that EGFR TKIs should not be administered to patients with K-ras mutant tumors.

Will this “individualized medicine” strategy fundamentally improve the outcomes of new agents and treatments? Unfortunately, the skeptic in me remembers a time when chemotherapy was the answer, as long as we figured out the correct dose and schedule.

We now know that the testicular cancer/chemo model never came to fruition in most common cancers and thus we must temper our expectations and cross our fingers as we hope and pray that the current paradigm of tissue-based predictors of response to novel biologics will deliver the “goods” we have sought for so long.

Click on the image to enlarge

— Neil Love, MD
DrNeilLove@ResearchToPractice.com
January 8, 2009

Select Publications