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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

EGFR Monoclonal Antibody Therapy in NSCLC: A Focus on Erbitux
Thu, 12/14/2006 - 23:17
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Most of the discussion with about inhibiting the EGFR axis in lung cancer has focused on the orally available tyrosine kinase inhibitors (TKIs) that work inside the cells. However, another way to inhibit the cells is by giving an IV "monoclonal antibody" which is a protein that attaches to the outside of the cell at the EGFR target and can block activity. A figure of the two approaches is shown here, with the antibody circled in red:

EGFR INhibition (Click to enlarge)

Cetuximab, or erbitux, is by far the most studied in cancer. This agent, you may recall, is the one that Martha Stewart was indicted over:

Martha Steward image

It's now approved in colon cancer and also in head and neck cancer, but it's been the subject of much less research in lung cancer than the EGFR TKIs like Iressa and Tarceva.

I mentioned in my last post that I recommend against treating patients with standard chemotherapy and EGFR TKIs at the same time because I am concerned that the activity of these two approaches may interfere with each other. I would not generalize that conclusion to EGFR monoclonal antibodies like Erbitux, which is still not very well studied and just doesn't have enough data either way to say if or how it might be used in lung cancer.

One rather small European study called the LUCAS trial enrolled 86 patients with advanced NSCLC to receive cisplatin and navelbine alone or with weekly erbitux and showed hints of a benefit, which is about the best you could do in such a paltry trial:

LUCAS trial

As is often the case, the preliminary presentation of the trial (abstract here) looked more promising than a later version with more follow-up (abstract here). The results in the figure above reflect the more recent results, which are fairly encouraging, with modest improvements in response rate and survival in the folks who received chemo with erbitux. In terms of side effects, erbitux consistently causes the EGFR rash, which can be quite profound, but not much diarrhea, and otherwise it increases fatigue and the decrease in blood counts compared with chemo alone. Patients can also get a hypersensitivity reaction when it is being infused, an allergic-like reaction that can rarely be severe. It is generally given on a weekly basis, starting with a loading doses that is higher than the ones that follow.

Over the past few years, a few other rather small trials have combined erbitux with other chemo regimens like carbo and paclitaxel (abstract here) and carboplatin and gemcitabine (abstract here), and they have looked modestly promising, but we have yet to see any trial large enough to give a meaningful answer to whether erbitux adds significantly to a chemo doublet alone. The most important trial that can address this is called the FLEX trial, which is a larger version of the LUCAS trial and gives cisplatin and navelbine with or without weekly erbitux, is being conducted outside of the US and has enrolled all of the planned patients, over 1100. There was a safety review (abstract here) that showed no unexpected side effects that would lead to the trial closing. The results of this trial are expected in 2007.

One trial that does have results available is by the Southwest Oncology Group, or SWOG. Karen Kelly, now at the University of Kansas, presented SWOG 0342, a trial in which a total of 225 eligible patients with advanced NSCLC received first-line carbo/paclitaxel, and half of them received weekly erbitux with that. All of the patients received maintenance erbitux weekly until progression or for up to one year after those four initial cycles of chemo with or without erbitux. The trial design is shown here:

SWOG 0342

The trial was fairly encouraging, with the median progression-free survival of about four months, and the arm that received erbitux with chemo showing a little longer overall survival compared to chemo alone followed by maintenance erbitux(10 vs. 9 months). However, the expert who provided commentary after that presentation at our major annual meeting (ASCO) noted that for neither arm were the results particularly impressive compared to what we expect from chemo alone.

The current trial that SWOG is doing will combine carboplatin and paclitaxel along with erbitux AND avastin. Known as SWOG 0536, it will enroll 90 patients who are considered candidates for avastin (no squamous tumors, no brain metastases) and have previously untreated advanced NSCLC. After chemo, patients continue on maintenance avastin every 3 weeks and erbitux weekly. The design is shown here:

SWOG 0536 schema

The participating sites are available by hitting the "Where is this Study Open?" button at the bottom of the page linked here. This trial is designed first to text the safety, specifically assessing the risk of bleeding on this treatment plan, and the second goal is to evaluate survival with this four-drug combination. However, many people have expressed concern that this combination could also have major financial side effects, since both cetuximab and avastin can run in the tens of thousands of dollars per year.

Taking these results together, there really is at this time no clear role that erbitux has in lung cancer, at least not yet. It has shown some hints of promise, but whether this approach adds to what we have with EGFR TKIs is still questionable. Fortunately, the FLEX trial and other studies should provide more information soon.

I'll do another post summarizing the small amount of work that has looked at erbitux as a single agent in lung cancer.

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