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How Much Does Treatment Sequence Matter in Lung Cancer?

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One of the general rules in oncologist is that we typically use our most effective treatments first, and often early, though there are certainly exceptions. Women with metastatic breast cancer may have a higher response rate by receiving combination chemotherapy than single agent chemo, but when a gentle single drug chemotherapy or hormone therapy option will do very well and provide fewer side effects, that’s usually the approach we recommend until bigger guns are needed. Similarly, patients with slow-growing cancers like chronic lymphocytic leukemia (CLL) often do well for many years and sometimes forever without needing treatment, so we often hold on initiating any treatment unless there’s a good reason to (and I think the same argument can be made for some lung cancers, most commonly indolent bronchoioloalveolar carcinoma, or BAC). So we don’t want to treat patients with less therapy than they need, but we’d also prefer not to treat them with more.

When you have multiple potential treatments to pursue, one question that becomes relevant is whether the sequnce matters. If you have choices A, B, and C, does it matter if you give AB followed by C, or C followed by AB or even A followed by B and then C? First, we need to take a step back and recognize that this is a good dilemma to have, because 10 years ago we didn’t have multiple effective treatments to try to position. For advanced NSCLC, the value of giving chemo for metastatic disease was debated until about 10-12 years ago, when the survival benefit of platinum-based doublet chemo regimens became a clear standard. In 2000 or so, second line taxotere emerged as a second line treatment option that improved survival and was approved by the FDA in that setting. A few years later, additional treatment options for previously treated patients with advanced NSCLC were approved, ushering in agents like alimta and EGFR inhibitors (initially iressa and then tarceva, with iressa removed from the US marketplace. These all became viable options, and over the last few years all of these agents have also been studied as first line treatments. Taxotere and alimta are now both FDA approved as first line combination therapy with platinum, and the EGFR inhibitors have also been studied as first line treatment and have appeared particularly attractive in certain subsets of patients, such as those with an EGFR mutation or patients with advanced BAC.

So just getting to the point, does the order of treatment matter? Most of the time we ask this specifically with regard to the question of giving an EGFR inhibitor before or after chemotherapy. Chemotherapy is a more time tested and standard approach, but don’t see 70% response rates or durations of treatment responses lasting a year or more with standard chemo: we only see these results by giving a targeted therapy like an oral EGFR inhibitor (tarceva, iressa), to patients whose cancers are heavily driven by that target. You might make the argument that the patients who are destined to be the great responders to an EGFR inhibitor should get that immediately, since it’s possible that they could benefit less if they decline significantly before getting that treatment. On the other hard, the patients not destined to do well with an EGFR inhibitor, who would be better served by chemo, could decline significantly before starting chemo if we were to give an EGFR inhibitor first. In fact, a trial of patients with marginal performance status, who were not selected for having EGFR mutations or other features predictive of a good result with EGFR inhibitor therapy, did significantly better if they started with chemotherapy than if they started an EGFR inhibitor, presumably because many of these patients “missed their chance” by declining too much to benefit from subsequent chemotherapy.

Last year, I was involved in a debate at a national lung cancer meeting in which I was arguing against routine testing for EGFR mutation testing. Among the arguments against it was my review of some limited data that it didn’t seem to matter whether patients received an EGFR inhibitor first line or second line or later, so if you were planning to give tarceva as a second or third line therapy, there wasn’t a clear incentive to rush it into your first line strategy. I noted that in the early work in iressa, the evidence showed that the response rate was every bit as good for patients who had received many lines of prior therapy as for the patients who had received fewer lines of prior therapy:

Kris Gefi IDEAL by prior Rx

(Click to enlarge)

I also reviewed the data from a couple of trials in advanced BAC, a trial of iressa for BAC that I led (SWOG 0126), and another led by investigators at Memorial Sloan Kettering that administered tarceva. Both studies showed no real suggestion of meaningful differences in outcome whether a patient received a tyrosine kinase inhibitor as first line therapy or as a later intervention:

EGFR TKIs in BAC does sequence matter

Finally, I noted that even in some work with patients who were identified as having an EGFR mutation, the survival benefit of treatment with tarceva vs. chemo in a Spanish population of patients was every bit as good whether these mutation positive patients received tarceva first line or later.

Even recently, I discussed the results of the very provocative IPASS trial that compared iressa to carbo/taxol as first line treatment among Asian never-smokers or light former smokers. The results of this trial demonstrated that the subset patients with a tumor harboring an EGFR mutation had a remarkably better progression-free survival with first line iressa, while the opposite was true for the patients who did not have an EGFR mutation.

IPASS PFS by mutation status

One additional thing that is striking is the very rapid drop on the PFS curve for recipients of iressa who don’t have an EGFR mutation (highlighted by the red oval in the figure on the right, above). If this leads to a clinical decline that precludes some of these patients from getting chemo that would have been beneficial for them, the order of treatment definitely matters.

The IPASS trial also reported preliminary overall survival results, which weren’t different for the trial population as a whole, but when looked at broken down by EGFR mutation status are worthy of further discussion:

IPASS OS by mutation status

Though the differences don’t reach statistical significance, the same trend is present as was seen with progression-free survival: patients with the mutation show a strong trend toward living longer if they received an EGFR inhibitor to begin with, while the patients without an EGFR mutation show a strong trend toward a superior survival with initial chemotherapy. And these results represent just the third of patients who had tissue available, so we might have seen statistically significant differences if more patients had been included in the mutation analysis.

My prior arguments against the importance of treatment sequence are still there, but I consider the IPASS mutation breakdown to represent the best test of whether sequence of treatment matters. I think that these findings are at least suggestive if not conclusive that it may be important to choose the best treatment as possible as an early treatment for a patient. What we want to avoid is a swing and a miss that allows a patient to decline before they get the opportunity with the best drug or regimen for them. It’s also an argument for more molecular variable- and histology-based treatment, because there’s likely to be a real cost to flying blind, which is essentially what we’ve done up until now.

Postscript

For those of you who have followed my writings on these subjects, I’ll acknowledge that this is a revision of my prior view. Though I don’t like to be inconsistent, I do think it’s important to change your perspective when new information becomes available. For me, having the chance to see and study the survival curves of the IPASS trial has led me to at least step back and strongly consider that for patients with a significant possibility of carrying an EGFR mutation (patients with an adenocarcinoma or BAC, never or remote prior smokers), the optimal approach could be to try to clarify as well as possible whether EGFR inhibitor therapy is likely to be a good early option. The limited availability of tissue and the delay of several weeks before obtaining mutation results are real barriers, which leads me to consider the appeal of a blood-based test for favorable outcomes with an EGFR inhibitor, but I would say that I’m becoming a convert on the value of molecular testing for at least a subset of patients. I think the sequence of treatment may truly matter now.


4 Responses to How Much Does Treatment Sequence Matter in Lung Cancer?

  • Country Onc says:

    Do you think all adenoca’s regardless of smoking history should have EGFR mutation analysis performed? Not sure what the incidence is for EGFR mutations in current and former smokers (I have seen 6% and 9% referenced) but the EGFR mutation is only $1,500 (the Genzyme cost – not much in comparison to the cost of bevacixumab/erlotonib/pemetrexed, ect) and it could alter treatment by moving erlotinib up in treatement sequence in these patients.

  • Leslie Rowe says:

    My husband first diagnosed june 2006 with adenocarcinoma with BAC features had an EPP with Sugarbaker in May 2007. February 2009 Reoccurrence with mets to the 10th rib, T7 in spine, sternum, multiple lymph nodes and adrenal glands. Began treatment with Cisplatin, navelbine and erbitux with Dr. Tom Lynch. My husband does not have the EGFR mutation do they still see a benefit with the erbitux without the mutation? Also, what are the statistics of survival with this regiment, since it is new to the US I am having difficulty finding any info! Thank you!

  • Dr. West says:

    Country Onc,

    At Memorial Sloan Kettering, they do EGFR mutation testing for every patient with an adenocarcinoma, but it’s fair to say that they’re on one of a continuum of focus on EGFR mutations. Plenty, and I would say really most community oncologists and experts, really don’t send it routinely. I’ve seen the results of the IPASS trial shift people like me to being a believer for never-smoking patients, but I don’t think I’d generalize this to all patients with an adenocarcinoma regardless of smoking history.

    It’s still an issue of pre-test probability, and also the consequences of being “wrong” — if you’re still likely to give an EGFR inhibitor second line, it’s not especially likely you’ll miss that opportunity if you wait until second line. The rate of EGFR mutations is about 9-10% overall, and it’s about 30-50% in never-smokers, probably about 6% in former smokers, and even lower in current smokers. It’s also related to how much someone previously smoked and when they quit, so a former smoker who has a 10 pack-year history and quit 30 years ago has a much higher probability of a mutation than a longtime 2 pack per day smoker who quit last year.

    Another factor is that it takes several weeks to get the results back on EGFR mutation testing, so testing everyone with a lung adenocarcinoma would entail a 3-4 week delay for a very large proportion of patients who wouldn’t benefit from the result of that test. It’s important to bear in mind that the IPASS study didn’t put treatment on hold while the mutation testing was done: the analysis was done later, and treatment was assigned prospectively. Perhaps waiting to start treatment for an extra 3-4 weeks would lead to overall detrimental effects for the entire treatment population compared to just getting started.

    I definitely don’t think it’s a mistake to do EGFR mutation testing on everyone with a lung adenocarcinoma, but I suspect that the folks at Memorial Sloan Kettering or Mass General who build in EGFR testing very commonly also can afford to do this because their lab can do the work far more rapidly (and perhaps less expensively) for their patients than for everyone else who sends tumor tissue to a commercial lab like Genzyme. But I think I’d be far more interested in doing this in never-smokers or people with a rather minimal and remote smoking history.

    -Dr. West

  • Dr. West says:

    Leslie,

    The EGFR mutation appears to be highly correlated with favorable results with oral EGFR inhibitors like tarceva (erlotinib), but the available evidence shows that these mutations really don’t have any correlation with how patients do with an IV monoclonal antibody against EGFR like erbitux (cetuximab). In fact, our knowledge about the biology about the EGFR mutation is consistent with that: it’s a structural change in the part of the molecule where the oral drugs bind the receptor, but it’s not near where the monoclonal antibodies bind to the receptor.

    The statistics for survival are described in this post from the presentation of it at ASCO, our biggest oncology meeting of the year:

    http://cancergrace.org/lung/2008/06/03/flex-asco-presentationi/

    I’ll try to update it with some images now that I have them. I’ll try to get that up in the next few days. In the meantime, though, the stats are included in the link above, but you should remember that those are results from a broad population that some patients do far better and some do worse than the numbers for the median survival.

    -Dr. West

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