Dr. Jack West

Should We Add Avastin (Bevacizumab) to Tarceva (Erlotinib) for EGFR Mutation-Positive NSCLC?

July 28th, 2014 - by Dr. Jack West

I recently had the honor of providing the expert commentary at the ASCO 2014 conference on three high impact lung cancer presentations, all on the subject of treatment options for molecularly defined populations (EGFR and ALK). I’ll review the findings from these three abstracts and my perspective on each of these, starting with a very provocative presentation by Dr. Kato from Japan that attempted to ask the question of whether we should add Avastin (bevacizumab) to Tarceva (erlotinib) as first line therapy for EGFR mutation-positive advanced NSCLC.

There have been a few large trials that directly tested the combination of Tarceva/Avastin vs. Tarceva alone — one as second line treatment (called BeTa), and one as maintenance therapy (called ATLAS).  These have failed to demonstrate a significant benefit for the combination, but they were in molecularly unselected patients, meaning that they were a broad population and not just patients with a specific molecular feature like an activating EGFR mutation.  However, both of these trials provided hints that the combination appeared to be especially effective for specific patients, most likely those with an EGFR mutation. For instance, the BeTa trial showed that two particular clinically defined subsets demonstrated an overwhelming benefit for the combination over Tarceva alone — Asian or Pacific Islander, and never-smokers.  Of course, these are also two subgroups known to be highly enriched for having an activating an EGFR mutation.  The subgroup analysis also showed that the small subgroup with an EGFR mutation also did far better with the combination, corroborating our presumption about why the Asian/Pacific Islander and never-smoker groups did so well.

BeTa Trial Subsets


Moreover, the same clinically defined subgroups — Asian or Pacific Islander, as well as never-smokers — were also the two standout subgroups that appeared to benefit most in the ATLAS trial. The subgroup analysis from that trial did not include an analysis by EGFR mutation, but I suspect it would have shown the same effect as seen in the BeTa trial.

ATLAS trial subsets



Dr. Kato and colleagues looked specifically at the potential benefit of adding Avastin at 15 mg/kg IV once every three weeks to daily Tarceva at 150 mg daily as first line systemic therapy for advanced NSCLC patients with a prospectively identified EGFR mutation. They randomized 154 patients, of whom 152 received treatment, and demonstrated a rather remarkably improvement in median progression-free survival (PFS) of more than 6 months, increasing from a median of 9.7 months for Tarceva alone to 16.0 months with the Tarceva/Avastin combination. Though the response rate was not significantly different, about 2/3 of patients showing significant tumor shrinkage (called an objective response) in both groups, the disease control rate, which is the combination of patients who demonstrate tumor shrinkage with those who demonstrate at least stable disease, was different, favoring the combination, at 99% of patients on the combination showing tumor shrinkage or stable disease, vs. 88% for those receiving Tarceva alone.

Also quite interesting was the difference between the two common types of activating mutation.  Specifically, both subtypes of activating EGFR mutation — exon 19 deletion and L858R on exon 21 — demonstrated a major improvement in PFS with the combination compared with Tarceva alone. But the patients with an exon 19 deletion had a longer PFS compared with the exon 21 patients, whichever treatment they received.   The improvement in PFS was especially remarkable in exon 19 deletion patients, who actually demonstrated an improvement of nearly 8 months in median PFS, which was a full 18 months with the combination!

PFS by mutation subtype

While moderately severe or greater side effects were more common with the combination, this was primarily high blood pressure and proteinuria (spilling protein into the urine), rather than more fearsome problems, and there were no treatment-related deaths. And while the discontinuation rate for Avastin was 41% over the course of treatment, higher than the 10-15% seen in earlier trials, this was again often due to more chronic side effects that I suspect were a product of the long time that people were on Avastin, because they were doing so well — being on a treatment for a long time leads to a higher risk of side effects, especially cumulative ones.

The other issue that could be a real barrier is cost. The patients on the Avastin arm received a median of 16 cycles of treatment, which costs “the system” at least $120,000 on top of the already significant cost of Tarceva from month to month.

Because this wasn’t a large, definitive study, it is debatable whether the strength of the evidence is great enough to warrant a change in how we approach EGFR mutation-positive NSCLC. My view was that while the study wasn’t so large that it offered incontrovertible proof that Avastin is very helpful, and it doesn’t show a survival benefit (the patients are almost all still alive, so we can’t know if it improves survival for a while), I consider the magnitude of the improvement in PFS to be very impressive and convincing.  I argued that with targeted therapies given to targeted population, we often see a staggering impact, with response rates and progression-free survival results that are so overwhelmingly better than what we could otherwise expect that you don’t NEED a 1000-patient phase III trial and additional years of follow-up to prove a survival benefit.  We know that XALKORI (crizotinib) was amazingly helpful when it gives a 60% response rate and responses that last for >6 months, and the FDA was wise to not deny its benefits to thousands of people while waiting for years of additional studies after the first overwhelmingly convincing early evidence came in. I would consider the benefits here with the Tarceva/Avastin combination to be quite convincing, even if it’s only a little more than 150 patients.

Some may want to see a confirmatory study done, perhaps outside of Japan (since Japanese patients may sometimes have genetic differences in how they respond vs. other genetic populations). Some may want to see a survival difference, which may occur, because few patients will cross over to get Avastin later, but these patients will often live for one to several years after initial progression and benefit from later treatments that could diminish the survival effect from a first treatment given.  My concern is that the compulsion for a higher level of evidence isn’t really because people remain unconvinced that there is a major benefit from adding Avastin, but that it’s a bias introduced by the cost of the treatment.

I noted that I think it’s perfectly fair to openly discuss the cost of a drug and ask whether the benefit is enough of a value. However, I don’t think it’s appropriate to have cost remain just an undercurrent that taints the judgment of people by making them reluctant to accept the credibility of the benefit but not acknowledge that it’s the cost that leads to their concern.

Unfortunately, as the cost of new cancer drugs creeps beyond $10,000 month, we’re likely to see a higher threshold to have the cancer community become convinced that an observed benefit is  fair value relative to its cost.  In this case, I remain impressed that Avastin provides a meaningful, striking benefit along with Tarceva, but I may find it hard to convince and insurer that the evidence is strong enough.  And if it’s not covered by an insurer, adding a $120,000 price tag to treatment is going to mean that people can’t benefit from it.

What do you think?

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Dr. Jack West

Not all EGFR Activating Mutations are Created Equal: Time to Stop Pooling Them Together

July 3rd, 2014 - by Dr. Jack West

It’s been a decade since EGFR gene mutations were first identified as highly correlated with a high probability of response to EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib), and more recently Gilotrif (afatinib).   We’ve learned that there are an array of EGFR mutations, and that the two most common ones, an exon 19 deletion or an L858R substitution on exon 21 (an exon is a specific expressed portion of a gene), each somewhere around 40-45% of  the EGFR mutations seen, are actually the ones consistently associated with a dramatic and often long-lasting response to EGFR TKIs. In contrast, the other 10-12% of EGFR mutations, most commonly on exon 18 or exon 20, are a heterogeneous group with a less clear benefit from EGFR TKIs.

For about the last 5 years, the lung cancer community has reached a pretty clear consensus that the exon 19 deletions and exon 21, L858R substitutions represent so-called “activating mutations”, and patients with these specific mutations in their tumors are the ones that have, in trial after trial, been shown to have a markedly higher response rate (RR) and longer progression-free survival (PFS) with EGFR TKIs than with standard chemotherapy.  Over that time, they have been pooled together and largely presumed to be very comparable. More recent research presented at ASCO 2014, however, rekindles questions that go back many years and cast doubt on whether we should really pool these two mutations together.

Back in 2006, two different publications came out — one from Boston’s Dana Farber Cancer Institute (on the top of the figure below), and another from New York’s Memorial Sloan-Kettering Cancer Center (bottom of figure below) — each independently reported that while both mutations were associated with very good responses to Iressa or Tarceva, the exon 19 patients seemed to do better, potentially in terms of both PFS and overall survival (OS).

Exon 19 vs. Exon 21 2006

(click on image to enlarge)

However, in the years that followed, a smattering of trials suggested better results in exon 19 patients, while others showed no real differences. In fact, I summarized the general thinking about this question of exon 19 deletions vs. exon 21, L858R substitutions back in 2011 in a post here.  Essentially, while there might be some differences, the results have been inconsistent, so we have to divide EGFR mutations as “activating mutations” on either exon 19 or 21 for which EGFR TKI therapy is the leading first line treatment of choice, or “rare mutations” for which the value of EGFR TKIs is much less clear.  These paients were included on the LUX-Lung 3 and 6 trials, comprising 10-12% of the study population, but they were removed from the survival analysis, almost certainly because they skewed the results in an unfavorable direction — we don’t extrapolate that the consistently favorable results of EGFR TKIs for exon 19 and exon 21 patients applies to those with rare EGFR mutations.

But then, at ASCO 2014, a couple of highlighted presentations clearly indicated that there are two distinct populations within that group with an activating EGFR mutation. One was the Japanese trial by Kato and colleagues of Tarceva alone or with Avastin (bevacizumab) in EGFR mutation-positive patients that I described a couple of weeks ago.  This showed that, while those with either common mutation demonstrated a significant benefit from addition of Avastin, those with an exon 19 deletion had a superior PFS compared to those with an exon 21 L858R mutation whether you’re looking at Tarceva alone or the Tarceva/Avastin combination.    That study is still too immature to provide any OS results.

The difference between outcomes in exon 19 vs. exon 21 patients was more highlighted in the pooled analysis of the LUX-Lung trials with afatinib that I just reviewed.  The survival benefit with first line afatinib was entirely a product of a very significant benefit in those patients with an exon 19 deletion, while those patients with an L858R substitution trended toward a better survival with chemo.

Combined OS analysis:


This trend toward an unfavorable survival is a very surprising result after these same patients likely experienced a very striking improvement in RR and PFS for afatinib — though we haven’t yet seen the RR and PFS data presented broken down by mutation subtype, except in this slide provided to me by Dr. Yang, which is remarkably helpful, showing PFS and OS  benefit for EGFR TKI or chemo in a wide range of trials as a function of specific mutation:

Mutation breakdown across multiple studies

The figure above, called a forest plot, shows greater benefit for one treatment or another by how much each yellow dot shifts from the vertical line. With the white vertical line representing the two treatments leading to equal results, a dot off to the left represents a benefit for EGFR TKI, and a yellow dot to the right represents a benefit for chemotherapy — and the further from the vertical line, the greater the benefit for one strategy vs. another.  The horizontal bars on either side of each yellow dot are called error bars, and they capture the variability in the results within the group, so longer horizontal bars represent a lot of variability in the results and therefore less confidence that the yellow dot really belongs where you see it. The full length of the horizontal bars on either side of the dot represent the place where the dot could really belong 95% of the time, and if the horizontal bars cross the vertical white line, the difference is not statistically significant.  Finally, the numbers listed under HR, for hazard ratio, is a reflection of the improvement or detrimental effect of EGFR TKI. A HR of 0.35 corresponds to 65% improvement with EGFR TKI vs. chemo, while a HR of 1.35 represents a 35% better result with chemotherapy.

That’s a lot of explanation, so I’ll just summarize what I see as the key points. The various EGFR TKI studies show that all of the EGFR TKIs tested against chemo in EGFR mutation-positive patients showed a clear improvement in PFS, usually with comparable results in exon 19 deletion and L858R mutation patients, but occasionally a less impressive effect in L858R-positive patients. In contrast, the OS effect always becomes diluted and moves toward less benefit with EGFR TKI, sometimes with overall survival crossing equivalence and having the exon 21 patients on the side more favorable for chemotherapy. This effect was most pronounced for the LUX-Lung 3 and 6 trials with afatinib, for whatever reason.

How can these treatments lead to clear improvement in the early result of PFS, which measures the beneficial effect of the first treatment, and then switch to a trend of harmful effect for OS? The short answer is that we don’t know if this is a real effect. It hasn’t been seen consistently and didn’t reach statistical significance, but it raises the question to me of whether the sequence of therapy may be important.   Though we’ve largely presumed that it shouldn’t matter if you give an EGFR TKI or most therapies now or 6 months from now, as long as a patient is still fit enough to tolerate it, we’ve seen hints that this may not be true.  For instance, the TORCH trial looked at molecularly unselected patients  in Europe (very few of them likely to have an EGFR mutation) and randomized patients to cisplatin/gemcitabine initially, followed by Tarceva at progression or Tarceva initially, followed by cisplatin/gemcitabine at progression (see figure below for visual representation). While we might have suspected that both groups would perform comparably if getting the same drugs over time, the trial was actually terminated early, after a significant survival difference was seen that favored initial chemotherapy:

TORCH Trial figure

This result was a key finding that led us to conclude that we don’t want to start someone on an EGFR TKI based on their status as a never-smoker with an adenocarcinoma: if you don’t know someone has an EGFR mutation, they are better served by starting with chemotherapy rather than presuming they have an EGFR mutation.  Sequence must matter in ways we don’t yet understand well.  Here, it may be that patients with an L858R mutation do less well after they receive an EGFR TKI, or at least afatinib.

It’s important to underscore the variability from one trial to another.  The CALGB trial of Tarceva alone vs. combined with carboplatin/paclitaxel chemotherapy included never- or light prior-smoking patients with an  advanced lung adenocarcinoma, and a subset of patients were tested and found to have an EGFR mutation. The breakdown of results in the patients with exon 19 vs. exon 21 mutations is shown below and shows a clear, striking difference in RR and PFS with Tarceva or Tarceva/chemo, but survival was just as good in patients with an exon 21 mutation:

Janne CALGB 30406 results


I don’t think we can tie up the results of these studies neatly with a tight conclusion. Instead, the findings indicate that we should be more careful about looking at the results of EGFR TKI therapy trials as separate for the two common mutations. The EGFR TKIs may possibly have different activities in one group or another, sequence may matter quite a bit, and the optimal treatment sequence may be different for patients with an exon 19 deletion vs. an L858R substitution.  While efficacy of the EGFR TKIs seems to be most favorable in those patients with an exon 19 deletion, the survival differences are less consistent.

It’s time to back up and question some of the dogma we established over the past 5-6 years.  There are actually two distinct populations in that pooled group of  patients with activating EGFR mutations.

Do you feel this should change how we manage patients? Should it dampen enthusiasm for EGFR TKIs in those with an L858R mutation?

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Dr. Jack West

New Approval for Zykadia (LDK378/ceritinib) in ALK-Positive NSCLC: Why It Matters Even if You’re Not ALK-Positive

April 30th, 2014 - by Dr. Jack West

Yesterday, the FDA approved the oral second generation ALK inhibitor LDK378, also known as ceritinib and newly christened Zykadia, for ALK-positive NSCLC who have progressed on or are intolerant of XALKORI (crizotinib). It is a treatment option that represents a major step for the 4-5% of NSCLC patients in the US who test positive for an ALK rearrangement, to be sure, but there are several implications for people outside of this narrow population as well.

The approval is based on the extremely favorable results with Zykadia in a phase I trial published in the New England Journal of Medicine earlier this year by Dr. Alice Shaw and colleagues, in which a total of 130 patients were treated with the agent, which is 20-fold more potent in inhibiting ALK than XALKORI. An initial 59 were part of the dose escalation phase, which ended when the dose of 750 mg was selected as the maximum tolerated dose. Beyond that point, an additional 71 patients were enrolled in an expansion phase and received the dose now approved as a starting dose.  The objective response rate was 58% for the 114 patients who received a dose of at least 400 mg daily: encouragingly, this was nearly identical in the 80 patients who had received and become refractory to XALKORI vs. the 34 patients among the 114 who were XALKORI-naïve (56% vs. 62%, respectively).  Below you can see a “waterfall plot” in which each patient’s response is represented by a downward line  on the right (for tumor shrinkage) or upward line (on the left), with the length of the lines proportional to the degree of change; the “waterfall” transition being so far toward the left illustrates that most patients are experiencing tumor shrinkage, and you can see from the long lines on the right that many are experiencing a lot of shrinkage.  The bottom portion of the figure shows a “before vs. after” PET scan, with most of the disease now no longer visible.


Notably, most of the patients who didn’t achieve a response that qualified as a significant one still had some tumor shrinkage or disease stability, so the “disease control rate” was approximately 80%.  The median duration of response was approximately 7 months, though there are several patients who remain without progression for a few years and ongoing.

An additional important benefit of this agent, as well as several other second generation ALK inhibitors such as alectinib and AP26113, is that patients with brain metastases demonstrated responses.  While XALKORI does not penetrate into the central nervous system (CNS), which is a “sanctuary site” in which we often see new disease appear in patients on XALKORI, Zykadia may be far better at preventing new disease from appearing in the CNS and can potentially treat pre-existing disease there.

Toxicity is a potential challenge, more so than with XALKORI, especially gastrointestinal issues. Nausea was noted in 82%, diarrhea in 75%, vomiting in 65%, fatigue in 47%, and liver function tests were noted to be abnormally elevated in 35%.  These issues were dose-related, and many of the researchers with the greatest experience with this agent have conveyed that the dose of 750 mg daily may be too high for many people, but that they have often had a more successful balance of efficacy and tolerability after reducing the dose to 600 mg or sometimes 450 mg per day (4 or 3 tablets, respectively).

Obviously, this is a significant treatment opportunity for the 4-5% of patients with an ALK rearrangement, whether they have progressed on XALKORI or not. For those who have progressed and don’t have good access to a trial with Zykadia or another promising agent, this approval now enables them to avail themselves of a treatment with responses seen in nearly 2/3 of patients and disease control in about 4 out of 5, and with responses that typically last for many months or sometimes a year or years.  It can also be an attractive option for others, such as my patient with a brain metastasis in his midbrain, a location where there is greater risk in doing a stereotactic radiosurgery approach (Gamma Knife) — perhaps Zykadia will provide a response within the brain after he has demonstrated progression of the lesion on XALKORI.

The approval is significant in other ways as well. It’s the first approval and proven effective therapy for “acquired resistance” to a targeted therapy in lung cancer, the progression we see after an initial great response to an ALK or EGFR inhibitor in patients with the right driver mutation.  While it’s wonderful for patients with one of these mutations to respond well, the question of what to do when progression sets in remains a vexing issue. For the first time, we have a way to get the genie back into the bottle.  As new agents are being tested in acquired resistance for EGFR and ALK, we’ve broken the impasse and have shown that it’s possible to do good trials on narrow populations with an uncommon target and who have developed acquired resistance.  Patients will find their way to these studies, in droves.

It’s also important that the drug was approved relatively quickly by the FDA, just a few years after the first patient received the drug. Given the high response rate, the FDA didn’t require a randomized trial with hundreds of patients — it is now getting the drug into the hands of oncologists and patients in a very timely way, pretty much as soon as the safety and efficacy could be clearly established.  This bodes well for future targets that may be found in only 1-5% of the broader lung cancer population.  I suspect that pharmaceutical companies are reassured that it is worth developing agents for these patients.

Finally, it’s encouraging for the 1% of NSCLC patients with a ROS1 rearrangement, who have a very high probability of responding well to XALKORI but who don’t have many other target-specific options available, including in clinical trials.  We will likely see ROS1-positive patients trying Zykadia soon, if they can get it.

More to come. These are exciting times.

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Dr. Jack West

Reviewing the Personalized Therapies in Lung Cancer Conference: Part 1

March 20th, 2014 - by Dr. Jack West

Over the last couple of years, I’ve attended and spoken at a lung cancer conference that I find to be particularly gratifying. Each fall, the Annual Personalized Therapies in Lung Cancer conference is held at a location in southern California. I wanted to provide a summary of what was covered at the last one, back in November, since it covered a broad range of the topics I think are most interesting here, using an interactive, case-based format integrated into the presentations.

The first session focused on existing targets, specifically the HER/EGFR family and ALK, though the discussions were more forward-looking than reviews of information we already know. Dr. Paul Bunn, former ASCO President and President and then Executive Director of the International Association of the Study of Lung Cancer, started the day with a summary of “game changers” in lung cancer in 2013, a whirlwind tour of the emerging landscape of acquired resistance and discussion of rare variants of mutations. Dr. Phil Mack from the University of California at Davis then described the shifting world of lower costs and wider availability of whole genome sequencing for lung cancer, though he noted that this is still creating a haystack of data in which we’re still looking for needles. Of course, this field will be changing rapidly, and we should expect our practices to follow as the price and turnaround time decrease as the number of clinically useful targets increases.

Dr. Ron Natale from Cedars-Sinai in Los Angeles provided a great summary of the data comparing first and second generation oral EGFR inhibitors.  Specifically, he covered the very consistent evidence that Iressa (gefitinib), Tarceva (erlotinib) and Gilotrif (afatinib) all handily demonstrate overwhelmingly greater activity than standard chemo as first line therapy for patients with an activating EGFR mutation, but we don’t have any direct comparisons of these agents to say that one is clearly superior to another. With regard to less common mutations, those not on exons 19 or 21, work with Gilotrif demonstrated that it isn’t particularly effective outside of those classic, activating mutations.  And looking at the efficacy and side effect profiles of Gilotrif and Tarceva in different trials side by side, it appears that they are very similarly active, with greater diarrhea and probably rash and mouth sores with Gilotrif.

Dr. Fred Hirsch from the University of Colorado then looked at the potential role of IV antibodies to EGFR, such as Erbitux (cetuximab), in advanced NSCLC. He recapped the questions around the FLEX trial, marginally positive for a survival benefit, but with so little absolute difference between the arms that Erbitux hasn’t really entered into routine use. He noted that a related antibody, necitumumab, was actually positive for a survival benefit in the SQUIRE trial, as related in a press release, though we haven’t seen the actual results yet and don’t know if it will become a new, routinely used agent or another near miss like Erbitux.

Dr. Karen Kelly from the University of California at Davis then covered irreversible EGFR inhibitors like afatinib and highlighted the unknowns about whether it is an improvement beyond the reversible EGFR TKIs Iressa and Tarceva.  She reviewed the encouraging phase II research work with dacomitinib (which has just been reported to demonstrate no improvement in efficacy compared with Tarceva in EGFR TKI-naïve patients, and no improvement compared with placebo in EGFR TKI-treated patients with acquired resistance), as well as offering her commentary on Gilotrif – noting that we really won’t know whether it is superior to other options until the outcome of a couple of randomized phase III trials being conducted now are completed – one against Tarceva, and another against Iressa.

Turning to ALK, Dr. Alice Shaw from Massachusetts General Hospital then reviewed established data with XALKORI (crizotinib) and then cataloged exciting new work with second generation ALK inhibitors LDK-378 (now ceritinib, from Novartis), alectinib (from Chugai/Roche), and AP26113 (from Ariad) – all with significant activity in XALKORI-resistant patients, and all with activity against brain metastases, unlike XALKORI. She also noted that several heat shock protein inhibitors (HSP90) have also demonstrated activity in ALK-positive patients and are now beginning to be studied in this setting as well.

I closed the session with a discussion of approaches for acquired resistance for EGFR mutation-positive patients. Starting with the concept that limited progression is appropriate to consider for local treatment like surgery or radiation, and slow, multifocal progression may also not require any change in treatment, I then spoke about options in patients who have more significant progression that warrants a change in systemic therapy. I spoke about the potential value of continuing the same targeted therapy with concurrent chemotherapy, vs. discontinuing it when switching to chemotherapy. I also touched on the early work with CO-1646 from Clovis, AZ9791 from Astrazeneca, the combination of Gilotrif and Erbitux, and the HSP90 inhibitor AUY922.

The next session covered more general topics, personalizing therapy outside of molecularly targeted therapies.  GRACE’s own Dr. Jared Weiss from the University of North Carolina, Chapel Hill discussed the growing collection of data supporting use of doublet chemotherapy for elderly patients and those with a marginal performance status.  He also summarized the work with Abraxane (nab-paclitaxel) that revealed a very promising efficacy in patients over 70, and which is leading to a subsequent study specifically in the elderly.

The morning ended with a presentation by Dr. Daniel Morgensztern, from Yale, who reviewed the full range of evidence and options in maintenance therapy.  This summary highlighted that there is no single approach of choice, but a choice of approaches.

All of that was just what we did before lunch! I’ll summarize the afternoon’s presentations in part II.

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Dr. Jack West

New Agents for Acquired Resistance in EGFR Mutation-Positive Patients: C01686 and AZD9291

March 10th, 2014 - by Dr. Jack West

Since the introduction of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with lung cancer, we have seen a subset of patients do remarkably well, with dramatic and long lasting responses. Unfortunately, within a few months of those impressive responses, we learned that people invariably develop acquired resistance to these agents.  Over the past period of more than a decade, lab-based scientists, oncologists, and of course patients have been eagerly seeking treatments that can lead to promising responses again in patients who have developed acquired resistance.  A couple of new agents show promise that we haven’t seen before in this setting, and they are now the subject of emerging clinical trials that show the promise of breaking an impasse that has existed for more than a decade.

The first of the two I’d like to highlight is CO1686, from Clovis. This “third generation” oral irreversible EGFR inhibitor effectively blocks not only activating mutations but the most common mechanism of resistance, the T790M mutation that is detected in about 60% of tumors that demonstrate acquired resistance after a response. It also has the potential advantage of not inhibiting “wild-type” (non-mutated) EGFR at the typical doses used, which means that it doesn’t cause the same severity of rash and diarrhea that the EGFR inhibitors we’ve had available thus far produce.

Though CO1686 is still early in testing, Dr. Jean-Charles Soria recently said that 6 of 9 patients with a  T790M mutation-positive cancer demonstrated a significant response at the newly established phase II dose of 900 mg by mouth twice daily, and with no rash.  Though still obviously still in early stages of development, the early promise of two-thirds of the patients in the target group responding is leading to multiple new trials, including

  • A phase II/III study comparing CO1686 head to head against Tarceva (erlotinib) in newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) that is EGFR mutation-positive
  • A phase II trial of Co-1686 in T790M-positive patients after progression on one prior EGFR TKI
  • Another phase II trial of T790M-positive patients after progression on >1 EGFR TKI or chemotherapy
  • A phase II trial of 2nd line or later CO1686 for patients who have a T790M mutation detected by a serum assay; and
  • A phase III randomized trial vs. chemotherapy in second line or later.

Clearly, this reflects a major investment and a lot of optimism in this agent.

A second agent that has shown similar promise is AZD9291, another third generation EGFR inhibitor with essentially the same mechanism of action.  Dr. Malcolm Ranson and colleagues reported on results from an 89 patient trial of patients with an activating EGFR mutation and acquired resistance, though this study allowed patients with either a T790M mutation or not.   The study included testing of the drug at a wide range of doses, from 20-240 mg/day, with no dose reductions required, and almost exclusively mild (grade 1 of 4) rash and diarrhea seen.  What was especially encouraging was that 15 of 35 evaluable patients had a response, including 9 of 18 with a T790M mutation. The follow-up plans for this agent are still being defined, but there is a lot of excitement about this agent as well.

Though we’re talking only about a few dozen patients and still learning about these agents, I’ve never been as optimistic about breaking through the impasse of acquired resistance in EGFR mutation-positive patients.  I hope to share more information about these agents and perhaps others very soon.

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