Earlier this week, the FDA approved the oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) for the approximately 10% of advanced NSCLC patients with an activating EGFR mutation in North America and Europe (approximately 30% in Asia). While that’s generally a good thing, and it’s in keeping with the evidence very strongly supporting erlotinib or another EGFR TKI as the optimal systemic therapy for patients with an activating EGFR mutation, the indication was paired with a positive result on a specific mutation test marketed by Roche called cobas and used in the EURTAC trial of Tarceva vs. chemo that was conducted in Europe on patients with an activating EGFR mutation on the Roche test that was approved to be paired with the first line Tarceva indication.
I’m concerned that this development may well be detrimental for patients, even if it’s a shrewd move for Roche. Why? Because there is already a clear consensus that EGFR TKI therapy is the preferred treatment for patients with an activating EGFR mutation, and the evidence supporting it is so overwhelmingly compelling that it’s uncommon to have erlotinib refused by payers as the treatment of choice in EGFR TKI-naive patients, even before the official FDA approval. Moreover, over the past 9 years since activating EGFR mutations were first identified, a wide range of different tests to detect them have been used. We know that the excellent responses with EGFR TKIs are seen primarily in patients with the more common exon 19 and exon 21 mutations, which are the ones specifically detected with the cobas test from Roche, but many other testing platforms can do this quite well and have been used for years and years now to identify patients who are great candidates for early EGFR TKI therapy.
By linking the indication for first line Tarceva in EGFR mutation-positive patients with a positive result on the cobas test, Roche may well have enforced a monopoly on molecular testing, but there is no reason to think that their test is meaningfully better than many other options. To me, this move seems as crass and transparently commercial at the expense of good science and care as seeking an FDA approval that erlotinib needs to be taken daily with a venti Starbucks latte if Starbucks had wrangled their way into a strategic partnership and got written into the EURTAC protocol. My fear is that many people who have had EGFR mutation testing done by other reputable sources will now have their opportunity to receive first line Tarceva jeopardized based on the linked approval of the indication with the test. Some people may require additional biopsies and incur treatment delays, increased risks, and added costs just because Roche finagled an opportunistic rider on the science.
Since we’ve come to appreciate the presence of distinct activating EGFR mutations associated with a very high probability of responding to an oral EGFR inhibitor, the question has emerged about whether there are significant differences in outcomes between the two most common ones, which are a deletion in exon 19 and a “point mutation” in exon 21. Some retrospective work in smaller aggregated series has suggested that patients with an exon 19 deletion tend to do best, but other work has suggested no difference between these two most common mutations. The recently reported trio of prospective trials of patients with an EGFR mutation receiving first line chemo or an EGFR inhibitor provide a good opportunity to evaluate this question.
The studies are actually pretty consistent in conveying that there is a modest trend toward the most favorable progression-free survival (PFS) in people with an exon 19 vs. an exon 21 mutation, but the differences aren’t great. Here are the PFS curves directly comparing the two main types of mutations in the Japanese trials with Iressa (gefitinib):
So while the curve for exon 19 deletion is on top by a small margin, both activating mutations appear to follow a very similar trajectory overall, with no significant difference.
Hi all! I had to take a month off in July as I was forgetting what my family looked like, but am now refreshed and ready to talk (write, really) about more interesting topics in the field of lung cancer. I just returned from the World Conference on Lung Cancer in San Francisco, where Drs. West, Sanborn, and I enjoyed some great foo… I mean, learned a great deal about what is happening in the world of lung cancer.
Of course, much of the truly practice changing research was presented only a couple of months ago at the ASCO meeting in Orlando, but there was certainly enough going on to keep us busy. Today, I thought I would comment on a presentation by Dr. David Jackman from the Dana Farber Cancer Institute in Boston, who is predominantly interested in non-small cell lung cancer containing activating mutations in the EGFR gene. Most who follow posts on this site already know a lot about this topic, but to sum it up: about 10-15% of North American and European NSCLC patients harbor specific EGFR mutations which confer exquisite sensitivity to EGFR inhibitors such as Iressa (gefitinib) and Tarceva (erlotinib).
Dr. Jackman and his group have put together an international database of clinical information from 223 patients with NSCLC who have been treated with EGFR inhibitors as part of five clinical trials over the last decade, along with information about which had EGFR mutations and which did not. These trials, all small single-arm trials, comprise patients from the United States, Europe, and Asia, and some of the patients have been treated with Iressa and some with Tarceva. By grouping these patients in one database, Dr. Jackman is able to draw conclusions about the efficacy of these drugs in different subgroups of patients. For example, he can compare how patients with exon 19 deletion mutations do compared to patients with exon 21 mutations, or how patients in Asia compare to Western patients, or even how patients do with Iressa compared to Tarceva.
Let me be clear that this type of research has clear limitations. This is not a randomized trial in which patients with one of these characteristics is directly compared to others, so most of the time you cannot draw definitive conclusions about outcome differences between groups in this way. But it does provide intriguing and valuable ideas about these comparisons, which can then be verified in a prospective (going forward) study. Continue reading →
It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.
The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.
However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.
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