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Lung Cancer Highlights, 2011 by Dr. Weiss, Part 2: ALK and other New Molecular Targets
Here is the second part of the presentation on “Lung Cancer Highlights, 2011″ by Dr. Jared Weiss. This section of his talk focuses on the striking story of the identification of the ALK rearrangement as a relevant target in lung cancer, along with an impressive treatment for this subgroup, and other new targets, such as ROS-1.
Below you’ll find the audio and video versions of the podcast, as well as the transcript and figures.
Dr. Weiss Lung Cancer Highlights 2011, Pt 2 ALK and New Molecular Targets Audio Podcast
Dr. Weiss Lung Cancer Highlights 2011, Pt 2 ALK and New Molecular Targets Transcript
Dr. Weiss Lung Cancer Highlights 2011 Pt 2 ALK and New Molecular Targets Figs
Podcast: Play in new window | Download (Duration: 8:21 — 24.8MB) | Embed
Five Key Insights from the Targeted Therapies in Lung Cancer Meeting
I’m just now returning from the International Association for the Study of Lung Cancer’s “12th Annual Targeted Therapies in Lung Cancer Conference”, which consisted of about 170 very brief talks about several classes of agents, as I described in my last post. Some of these are likely to emerge as viable, truly beneficial therapies for patients; many others will fall by the wayside. Because it’s really not feasible to discuss such a broad range of agents that we only get a snapshot view of, I thought I’d try to convey what emerged as five core takeaway points from the 2012 iteration of this important meeting.
ARQ197: Encouraging Results from ASCO 2010
Continuing with the webinar discussion I had with Dr. Pennell, here is a summary I did of a randomized phase II trial of the novel agent ARQ-197 combined with the EGFR inhibitor Tarceva (erlotinib):
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Dr. West: We’re going to shift gears and move into the metastatic setting, and this is a new agent called ARQ197 that is orally available, which was tested in combination with erlotinib(Tarceva) compared with Tarceva alone. And this was actually in the patients who had received one or more prior lines of chemo and could not have received prior Tarceva or another EGFR inhibitor, directly comparing these two groups that randomized one-to-one. Also, patients who had been assigned to placebo could actually go on the combination at the time of progression, and we did get some interesting information from that.
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ZEPHYR Trial of Zactima (Vandetanib) vs. Placebo Negative
It’s been a while since there was anything to discuss about Zactima (vandetanib), an oral targeted therapy being investigated by AstraZeneca that has the potential to inhibit both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF), key targets of two important pathways in cancer treatment. They launched a total of four large trials looking at the activity of Zactima added to second line chemo, or compared head to head with the FDA-approved EGFR inhibitor Tarceva (erlotinib) in one trial or placebo in another trial. We learned some preliminary results of first three trials more than a year ago, and more complete information was presented at the American Society for Clinical Oncology (ASCO) meeting in early June of 2009. Those results overall indicated that Zactima could provide a modest but real improvement in progression-free survival (PFS) but no real improvement in overall survival (OS) when added to standard second line chemotherapy (statistically significant difference in PFS in a larger trial with Taxotere (docetaxel), and a similar magnitude of improvement in PFS but not reaching statistical significance in a smaller, less “well-powered” (to show a statistically significant difference) trial adding Zactima to Alimta (pemetrexed). The head to head comparison of Zactima to Tarceva showed equivalent activity.
Searching for Low-Hanging Fruit: Identifying Critical Targets in Lung Cancer
One of the most pressing issues in lung cancer research is in identifying patients who could benefit from a particular drug, both to increase their chances of having a good outcome and to spare everyone else from an ineffective drug with unnecessary toxicity. There have been some exciting advances in this field, but before I elaborate I want to give some (simplified) background on how drugs are traditionally developed. Classically, potential cancer drugs are tested on cancer cell lines in a Petri dish, and if the drug appears to kill the cells, it is then tested in animals. If the animals don’t die the drug may eventually be tested on small numbers of humans with advanced cancer as part of a phase I trial. The drugs are normally given to patients with no regard as to how likely the drug is to work on that type of cancer, and the results are generally predictable. If the patients are able to tolerate the drug, and some of them have shrinkage of their tumors, the drug can then be tested on larger groups of patients with the same kind of cancer as the patients from the phase I trial who seemed to benefit.
However, if none of the patients in the phase I trial respond the drug is usually abandoned. Rarely, a drug will jump through all these hoops and lead to an approved chemotherapy drug, usually over a period of a decade or more. However, even “effective” drugs typically work only in a minority of patients. Drug companies are typically more interested in developing drugs that work on ever larger numbers of patients rather than on identifying why the minority of patients who responded did so.
When the effectiveness of this process plateaued with the current stable of chemotherapy drugs, companies began to focus more on “targeted drugs” like Gleevec, Herceptin, and Tarceva. These drugs were designed to affect only a single (or small number of) proteins such as the platelet-derived growth factor receptor (PDGFR), Her2, or the epidermal growth factor receptor (EGFR). The best example of this is Gleevec, which turns off the single protein that drives chronic myelogenous leukemia (CML) cells (bcr-abl), and has revolutionized the treatment of CML. In lung cancer, the best examples are the EGFR inhibitors Tarceva and Iressa, which can cause dramatic tumor responses and prolong survival in about 10% of Western NSCLC patients. It has been shown that the tumors in these patients are “addicted” to signaling through mutated EGFR, and shutting off this signal kills the cells. In the other 90%, however, there is either no benefit at all from Tarceva or some stabilization of disease, probably because EGFR is important to these tumors but not to the same extent as in the EGFR mutants.
Serum Test Being Launched to Test for Likelihood of Benefit from Oral EGFR Inhibitors
About 18 months ago, I wrote a post about a new technique being developed that looks at the pattern of proteins in the blood of a patient in order to determine whether a patient is likely to do well or poorly after receiving an EGFR tyrosine kinase inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. This work was the product of collaborative work among folks at Vanderbilt University, the University of Colorado, and a Colorado based company called Biodesix.
At the time that I wrote the original post, there was a general plan to bring this test to commercial use. Earlier today, I met with some of the folks at the company, who told me that this plan is now moving forward, with a plan to launch the test, now known as Veristrat, in early March. While they didn’t have additional published or formally presented information to highlight, they told me that they have continued to do studies of the serum from patients from all over the world that has validated what their test is trying to do. Here’s the idea:
The Subtleties of Progressive Disease: Why Some Oncologists Continue EGFR Inhibitors (or Other Agents) after Progression
One of the basic concepts of oncology is that you treat patients with different drugs once they’ve shown progression on a treatment, rather than continue that a patient has presumably become resistant to. However, there are some exceptions to this: many or most women with breast cancer continue the antibody herceptin (trastuzumab) even after progression, adding it to one chemo and then the next, and the same is often done with avastin in colon cancer and sometimes lung cancer as well. In the past few years, there has been interest in whether the patients who respond well to an EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) should continue on it for a while or even forever after showing the first evidence of progression on an EGFR inhibitor.
It may help for us all to take a step back and remember that the goal of improving survival and slowing the progression of a tumor may occur not only if the cancer is shrinking or even if it’s holding steady. If the cancer might potentially be growing quickly, even slowing the progression may translate to an improvement in how a patient does. In the lab, basic scientists examine the growth of a cancer in lab animals and consider it beneficial if the cancer progression is slower over time when a new treatment is added, compared with a placebo or some alternative approach. But in the grading system oncologists use, we don’t discriminate between slow progression and faster progression — it’s just considered a disappointment and time to move on.
(Click to enlarge)
The point is that imperfect brakes is better than no brakes. In fact, in some settings of especially effective treatments for other cancers, some investigators noticed that patients who were progressing slowly on a previously very effective treatment showed a rapid rebound progression when they stopped the treatment (as if they jumped from the blue line to the yellow line in the figure above). So a few years ago, the folks at Memorial Sloan Kettering Cancer Center (MSKCC)studied a small number of patients with either EGFR mutations or a prolonged response to EGFR inhibitors who were showing some progression (abstract here). They did CT scans and PET scans right before and right after patients took a planned three week break from their EGFR inhibitors, and they also assessed how these patients were feeling. After restarting their EGFR inhibitors and repeating scans and checking patient symptoms, they added another novel agent called everolimus, an mTor inhibitor (see prior post for discussion of the novel agent approach of mTor inhibitors alone and combined with EGFR inhibitors). For the more visually oriented, this is the overall design of the complicated trial:
A New Look at Maintenance Treatment after First-Line Chemotherapy in NSCLC
With the recent publication of the Eli Lilly-sponsored phase III trial of immediate versus delayed Taxotere (docetaxel) after the completion of first-line chemotherapy in patients with advanced NSCLC (abstract of paper by Fidias and colleagues here), I think the time has come to critically evaluate this as a potentially practice-changing concept. Call it whatever you want: maintenance therapy, sequential treatment, or early/immediate second-line therapy, but whatever you do, don’t call it a fluke. The idea behind maintenance is simple: after finishing your initial 4-6 cycles of platinum-doublet chemotherapy, you move immediately on to more treatment rather than stopping and waiting for the cancer to progress. In the last year and half, we have seen four major phase III trials test some version of maintenance treatment with chemo or Tarceva, and all have generally supported a benefit. The Fidias paper is the first of these to be published, so let’s take a closer look at the design:
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In this trial, 566 previously untreated patients with metastatic NSCLC were all initially treated with carboplatin and gemcitabine. Those that finished four cycles without progression were randomly assigned to either receive Taxotere immediately and continue it for a maximum of 6 cycles, or to be followed and receive Taxotere once their cancer started to progress. The trial was designed to be large enough to see a 4 month improvement in overall survival (OS), which in retrospect seems ridiculously ambitious. To give you a comparison, the ECOG 4599 trial, which led to the approval of Avastin in lung cancer, only showed a 2 month improvement in OS.
In any case, the trial did not quite make the 4 month improvement, missing it by a little over a month (OS 12.3 months for immediate Taxotere versus 9.7 months for delayed; p=0.085), but it did have an impressive improvement in progression-free survival (PFS; 5.7 versus 2.7 months; p=0.0001), which is a measure of patients still alive without progressive cancer. Essentially what this means is that patients who started immediately on Taxotere delayed the progression of their cancer by 3 months compared to those who waited, and lived an average of almost 3 months longer. This is a pretty clinically significant improvement, although there are some important things to point out about this trial. First, only 309 patients (out of the original 566) made it to the randomization, so these were already the patients who were doing very well after first-line chemo. Second, 37% of the patients (58 of 156) who were designated to receive the delayed Taxotere never got it (as opposed to only 8 patients in the immediate arm), about half of them because their cancer progressed so much that they were unable to get more treatment. So it is unclear if the benefit of immediate Taxotere was truly better effect, or just the results of most of the patients in the immediate Taxotere group actually getting the chemo.
Tarceva Dose Escalation in Current Smokers: Could Higher Doses Improve Results?
We have long noted that there is a clear association of smoking history with effectiveness of oral EGFR tyrosine kinase inhibitors (TKIs). Part of this is because never-smokers have a high incidence of carrying activating EGFR mutations, but also potentially because current smokers actually metabolize EGFR TKIs faster (see prior post). We’ve seen a consistent association of rash development with better outcome (see prior post), and current smokers have been disproportionately likely to develop little or no rash. A recent study just coming out in the Journal of Clinical Oncology from a group in the UK has studied blood levels with dose escalation of tarceva (erlotinib) among current smokers (abstract here) and suggests a possible value in giving higher than standard tarceva dosing among current smokers, so that they can achieve the same blood levels as never-smokers or former smokers. Will this lead to better results for these patients?
ATLAS: Another Trial Shows Benefit for “Maintenance”/Early Second Line Therapy
A press release today informs us that the ATLAS trial of maintenance avastin (bevacizumab) combined with tarceva (erlotinib) vs. avastin with placebo was positive for a significant improvement in progression-free survival (PFS). We had already learned that the very similar SATURN, of maintenance tarceva vs. placebo in patients who weren’t on avastin was also positive for an improvement in PFS (see prior post), though we don’t have details yet. Here’s the design of these two trials:
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What we’ve learned so far about the ATLAS trial is that an interim planned analysis of safety and efficacy showed that there was a significant improvement in progression-free survival that led to the stopping of the trial and disclosure of these early results of more favorable PFS in the recipients of tarceva combined with avastin. It had already enrolled 1157 patients, which was its goal, and these patients received avastin with any of several different platinum-based chemotherapy doublets (carboplatin/gemcitabine, carboplatin/paclitaxel, carboplatin/docetaxel, cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine). If patients hadn’t progressed after four cycles of this combination, they would be randomized to avastin maintenance with either tarceva or a placebo pill. The results apparently showed no evidence of any unexpected safety problems, which is important both for broadening our experience of different chemo agents with avastin and because patients with therapeutic doses of blood thinners were able to be enrolled, as were patients with more peripheral squamous cancers that were far from the center of the chest (a minority of squamous cancers).
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