GRACE :: Lung Cancer


Dr West

FLEX Trial Redux

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I covered the highlights of the FLEX trial, reported at the Plenary Session of ASCO 2008, a full year ago, but in that time, we never showed the survival curves or covered all of the details. It’s time to rectify that, now that it’s actually been published, and we’re left to reflect on whether certain subgroups benefit more or less, and how the subject of the FLEX trial, the EGFR monoclonal antibody Erbitux (cetuximab) should be used in treating advanced NSCLC.

The European sudy compared standard chemotherapy alone to the same chemotherapy with weekly Erbitux in previously untreated advanced NSCLC. It included over 1100 patients, who were screened as needing to have the EGFR protein on their tumor by a test called immunohistochemistry (IHC), because this is the target that the EGFR monoclonal antibody is supposed to bind to. The definition of a positive test for EGFR by IHC was extremely liberal, since only a single cell with the protein was required for patients to be enrolled. Even with such liberal criteria, 15% of the screened patients had no EGFR protein on a single cell and were excluded from the trial.

As with most recent trials with targeted agents, it was degined to give up to six cycles of chemo with or without the novel agent,in patients who didn’t show progresison after six cycles, patients assigned to the experimental arm (with the new agent) would continue on weekly Erbitux as a maintenance therapy. The specific chemo used was cisplatin/navelbine (vinorelbine), a combination rarely used for metastatic NSCLC in the US but a common standard in Europe.

Putting this all together, the trial design is shown here.

FLEX Trial Design

FLEX Trial Design

(click on figure to enlarge)

The study showed that the likelihood of significant tumor shrinkage was higher in the recipients of Ebritux with chemo (36% vs. 29%, p = 0.010), and that despite the fact that the median progression-free survival was the same in both arms, there was a significant survival benefit with Erbitux added to chemo.

FLEX Overall Survival Curves

FLEX Overall Survival Curves

The curves do separate, and the one-year survival rate is higher in the recipients of Erbitux (47% vs. 42%), but it’s a puzzling pattern. Notice in the curves above that the separation occurs after more than 6 months, when the majority of patients had already come off of chemo, and the majority were off of Erbitux as well. Why and how did survival increase on the Erbitux arm after the time when the majority were off of first line treatment? We can’t really explain that. And how did survival improve when there wasn’t an improvement in progression-free survival. Another point that is hard to refute.

If you combine that with the fact that the improvement in median overall survival was only 1.2 months (from 10.1 to 11.3 months), you end up with a trial that left as many questions as answers. Most oncologists have struggled with the real clinical significance of this trial, regardless of its statistical significance.

As we sift through the data, we hope to find groups of patients who did particularly well or poorly, so that we might select patients who are especially likely to benefit, or those particularly unlikely to benefit. Those groups may be defined by race, NSCLC subtype, other clinical factors, or possibly molecular variables. We’ll cover the differences among these various groups in a couple of upcoming posts.

2 Responses to FLEX Trial Redux

  • Dr. Pinder says:

    The results with Erbitux to me are reminiscent of the way in which immunotherapies might alter cancer course and may require us to rethink how we evaluate some cancer therapies. The findings are remarkably similar to the findings with Provenge, the prostate cancer vaccine, which found a substantial overall survival benefit without any benefit in progression-free survival. Because Erbitux can stimulate the immune-system through antibody-dependent cell-mediated cytotoxicity (ADCC), I think this long latency time to effect may tell us that it is working through the body’s immune system rather than a direct anticancer effect.

    That is not to say that these results are particularly impressive in themselves. BUT if Erbitux does work through ADCC, maybe an agent that is more effective at stimulating the immune system in this way might show more impressive results. This trial (and perhaps the prostate cancer trials) tell us that progression-free survival would probably not be the endpoint to look at for these drugs.

    I find that bringing patients in WEEKLY for therapy, particularly for maintenance treatment after their initial chemotherapy is a big negative in terms of quality of life. I’m looking forward to your upcoming posts on the factors that determine benefit!

  • Dr West
    Dr West says:

    Yes, I particularly agree that weekly maintenance therapy after 4-6 cycles of chemotherapy is a particular challenging concept. Many docs AND patients feel that a break from treatment is well-deserved after 3-5 months of ongoing chemo, particularly if that patient has had a response or at least apparent arrest/non-progression of the cancer. I’m reasonably convinced of the benefit of maintenance therapy in people who don’t have a very indolent cancer and/or a very good response to first line treatment, but I think the concept is far more compatible with an infrequently administered well tolerated IV therapy like Alimta (pemetrexed) or a generally well tolerated oral therapy like Tarceva (erlotinib). I think my patients like me just fine, but I still think it’s a tough sell to ask them to come in every week for an intervention that probably has a relatively modest, marginal benefit over a less intensive follow-up/treatment plan.

    More on clinical factors and markers later.

    -Dr. West

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