New Hope for EGFR Mutant NSCLC with Acquired Resistance to Tarceva (including T790M!)

Dr Pennell

I am sorry to say that there were few surprises or earth-shatteringly positive results at this year's ASCO meeting in Chicago (unless you count my button-shattering belly expansion from too many pizza lunches and dinners). However, in my mind there was one presentation that stood out above the others in terms of real hope for a particularly frustrating subset of lung cancer patients, namely those with EGFR activating mutations that develop resistance to Iressa (gefitinib) or Tarceva (erlotinib). The presentation was the initial results of a phase II trial combining afatinib (Tomtovok; BIBW 2992) with the anti-EGFR antibody cetuximab in TKI-resistant NSCLC patients.

This is a very frustrating group to treat. They tend to be younger, and most have never smoked or for only a short while, and they tend to respond wonderfully to TKIs like Tarceva. However, most patients will eventually go on to progress despite the TKI, and the reasons behind this progression have been a very active area of research. We know that about 50% of them, for example, will develop a second EGFR mutation in exon 20 called the T790M mutation.

There have been a number of strategies tested to overcome this resistance. The two major strategies have been to use a better TKI, such as the irreversible inhibitors BIBW 2992 and HKI 272, or to add a second drug to the TKI that inhibits a parallel pathway. One example of this strategy is the trial testing the addition of a MET inhibitor (ARQ 197) to Tarceva, which is now open all over the globe.

However, to date none of these strategies have proven to be particularly effective. One disappointing example was the LUX LUNG 1 study, which randomized patients who had failed chemotherapy and then progressed after benefit from a first-generation TKI (enriching the group for EGFR mutant cancers) to either afatinib or placebo. The goal of this study was to test if the irreversible TKI (afatinib) could overcome resistance by itself. Unfortunately, this trial failed to show a survival benefit from afatinib over placebo as a single agent. There were also only 7.4% of TKI-resistant patients who responded to afatinib.

So why not jump one step and try the strategy of combining afatinib with another agent in TKI resistant patients? Knowing the LUX LUNG 1 results, I would not have been very excited by this strategy. And now knowing the results of the phase I/II trial by Dr. Janjigian testing the combination of cetuximab and Tarceva in TKI-resistant patients, I would be even less enthusiastic. This trial, recently published in online form showed no hint of efficacy (zero of 13 patients responded to the combination).

So it is not surprising that this presentation was stuck in the poster discussion session at ASCO rather than in the more prestigious oral presentations. I spoke to one of the scientific program organizers who told me that this abstract had no results available yet at the time of submission, so it was lucky to make it in at all!

Enough build-up: how about the results, you ask? OK fine, you win. In another study by Dr. Janjigian, 26 patients with NSCLC with acquired resistance to TKIs were originally enrolled and treated with afatinib and escalating doses of cetuximab. At the maximum tolerated dose they began to enroll an additional 80 patients, and this poster described the first 45 pts on the trial. All of the patients but two had mutation status tested, and almost all of them had EGFR mutations. Over half had T790M mutations, as would be expected. The schema is pasted below.

schema_bibw (click on image to enlarge)

The confirmed overall response rate in the first 45 evaluable NSCLC patients was 40%, with the response rate in the T790M patients being 50% unconfirmed (unconfirmed means they had not yet done a second set of scans to see if the tumor was still responding over 2 time points). The waterfall plot for all the 45 patients is below, with the red bars representing the T790M patients.

waterfall_bibw

This is the first time anyone has described activity for any targeted drug in the T790M EGFR population, and this provides the first glimmer of hope for the many patients out there who face the reality of knowing that their tumors are still dependent on EGFR mutations but for whom Tarceva simply doesn't work anymore

Why does the combination work? Cetuximab binds to the outside of the EGFR protein while afatinib binds the inside, so perhaps it takes 2 to make a thing go right. Cetuximab binding tends to make the EGFR protein move from the outside of the cancer cell to the inside, which might interrupt signaling somehow. The truth is we don't know why just yet, but this has to be considered one of the most promising trials in recent years. One person I talked to in the know suggested this might make next year's ASCO plenary session, reserved for the most prestigious and practice changing studies. I can only hope this emerges as a new avenue for these increasingly common patients.

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