Gee (G719X) Whiz: Novel Mutations and Response to Targeted Therapies

In a recent online forum a patient described her experience using Tarceva as a therapy for an EGFR mutation negative lung cancer. For those of you familiar with the literature you will know that Lynch and Paez both described the sensitizing mutations that allow patients with certain adenocarcinoma to respond beautifully to the small molecule inhibitors.  The majority of these mutations are found in Exon 19 and Exon 21, within the EGFR domain. Response rates for the EGFR-TKI (gefitinib and erlotinib) clearly favor mutation positive patients. Depending upon the study, mutation positive patients have response rates from 53 – 100 percent, generally around 70 percent, while mutation negative response patients have a response rate of 0 – 25 percent, generally about 10 percent.

So why don’t all the mutation positive patients respond and conversely why do some mutation negative patients respond?

The story outlined in this online forum gives some insight. The individual in question carried a rare, and only recently recognized, Exon 18 mutation known as a G719X. This uncommon form of mutation had previously been unknown and few laboratories knew to test for it. Nonetheless, G719X positive patients respond to erlotinib and related agents. Indeed, there may be reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-272, may be even more selective for this point mutation.

The excellent and durable response described by this individual, would not have been possible had the patient’s first physician followed the rules. That is, had her physician refused to give erlotinib to an (putatively) EGFR mutation negative patient she might well not be here to tell her story. More to the point, her good response (a clinical observation) led to the next level of investigation, namely the identification of this specific EGFR variant

The lessons from this experience are numerous. The first is that cancer biology is complex and, to paraphrase E.O. Wilson, was not put on earth for us to necessarily figure it out. The second, is that molecular biologists can only seek and identify that which they know about apriori.  To wit, if you don’t know about it (G719X) and you don’t have a test for it, and you don’t know to look for it, then it’s a virtual certainty that you aren’t going to find it.

The premise of our work at Rational Therapeutics is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Crizotinib was originally developed as a clinical therapy for patients who carried the CMET mutation. Serendipity led to the recognition that the responding subpopulation was actually carrying a heretofore-unrecognized ALK gene rearrangement. Sorafenib was originally evaluated for the treatment of BRAF mutation positive diseases. Yet it was the drug’s cross-reactivity with the VGEF tyrosine kinases that lead to its broad clinical applications. Each of these phenomena represents accidental successes. Were it not for the clinical observation of response in patients, the investigators conducting these trials would have been unlikely to make the discoveries that today provide such good clinical responses in others.

To put it quite simply, these patients and their disease entities educated the molecular biologists.

When we first identified lung cancer as a target for gefitinib, and began to administer the closely related erlotinib to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that we observed. It didn’t matter why it worked, but that it worked.  While the EGFR story has now been well-described, might we not use functional analytical platforms (functional profiling) to gain insights into the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc., etc., etc. . . .

Gee (G719X) Whiz: Novel Mutations and Response to Targeted Therapies

In a recent online forum a patient described her experience using Tarceva as a therapy for an EGFR mutation negative lung cancer. For those of you familiar with the literature you will know that Lynch and Paez both described the sensitizing mutations that allow patients with certain adenocarcinoma to respond beautifully to the small molecule inhibitors.  The majority of these mutations are found in Exon 19 and Exon 21, within the EGFR domain. Response rates for the EGFR-TKI (gefitinib and erlotinib) clearly favor mutation positive patients. Depending upon the study, mutation positive patients have response rates from 53 – 100 percent, generally around 70 percent, while mutation negative response patients have a response rate of 0 – 25 percent, generally about 10 percent.So why don’t all the mutation positive patients respond and conversely why do some mutation negative patients respond?

The story outlined in this online forum gives some insight. The individual in question carried a rare, and only recently recognized, Exon 18 mutation known as a G719X. This uncommon form of mutation had previously been unknown and few laboratories knew to test for it. Nonetheless, G719X positive patients respond to erlotinib and related agents. Indeed, there may be reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-272, may be even more selective for this point mutation.

The excellent and durable response described by this individual, would not have been possible had the patient’s first physician followed the rules. That is, had her physician refused to give erlotinib to an (putatively) EGFR mutation negative patient she might well not be here to tell her story. More to the point, her good response (a clinical observation) led to the next level of investigation, namely the identification of this specific EGFR variant

The lessons from this experience are numerous. The first is that cancer biology is complex and, to paraphrase E.O. Wilson, was not put on earth for us to necessarily figure it out. The second, is that molecular biologists can only seek and identify that which they know about apriori.  To wit, if you don’t know about it (G719X) and you don’t have a test for it, and you don’t know to look for it, then it’s a virtual certainty that you aren’t going to find it.

The premise of our work at Rational Therapeutics is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Crizotinib was originally developed as a clinical therapy for patients who carried the CMET mutation. Serendipity led to the recognition that the responding subpopulation was actually carrying a heretofore-unrecognized ALK gene rearrangement. Sorafenib was originally evaluated for the treatment of BRAF mutation positive diseases. Yet it was the drug’s cross-reactivity with the VGEF tyrosine kinases that lead to its broad clinical applications. Each of these phenomena represents accidental successes. Were it not for the clinical observation of response in patients, the investigators conducting these trials would have been unlikely to make the discoveries that today provide such good clinical responses in others.

To put it quite simply, these patients and their disease entities educated the molecular biologists.

When we first identified lung cancer as a target for gefitinib, and began to administer the closely related erlotinib to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that we observed. It didn’t matter why it worked, but that it worked.  While the EGFR story has now been well-described, might we not use functional analytical platforms (functional profiling) to gain insights into the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc., etc., etc. . . .

The False Economy of Genomic Analyses

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications.

So, let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order ALK gene rearrangement     $1,500
•    And EGFR mutation analysis     $1,900
•    The costs associated $1,500 + $1,900 x 100 people =    $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient =     $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order an EVA-PCD analysis    $4,000
•    The costs associated: $4,000 x 100 people =    $400,000
•    With 65 percent of patients responding, this
constitutes a cost per correctly identified patient =     $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques.

No wonder we call our group Rational Therapeutics.