One of the abstracts in lung cancer that I noted as being particularly noteworthy before ASCO 2008, but which I haven’t managed to mention since, is a trial of a monoclonal antibody known as CP-751,871 that targets and inhibits insulin-like growth factor receptor-1(IGF-1R), a molecule that appears to be involved with cell growth, balance of programmed cell death, and likelihood of metastatic spread (abstract here):
This was a rather complex study, presented by Dr. Dan Karp from MD Anderson in preliminary form last year (abstract here), in which patients with previously untreated advanced NSCLC were randomized two to one to receive either carbo/taxol alone or the same chemo combination with this IGF-1R antibody at either of two doses, IV every three weeks. After randomizing 150 patients and seeing especially encouraging results in patients with squamous cancers, they then enrolled a few additional patients with squamous cancers to all receive chemo with the higher dose of the IGF-1R antibody.
Someone recently asked a question about a recommendation she had received about being treated with a first-line combination of gemzar (gemcitabine) and navelbine (vinorelbine), because we have focused so much on doublets of either cisplatin or carboplatin with a newer drug like taxol (paclitaxel), taxotere (docetaxel), gemzar, navelbine, or most recently possibly alimta (pemetrexed). Why don’t we pair the partners of the platinums and perhaps do even better?
In the early 2000s, that was a timely question, as we wondered whether the platinum drugs might be more of a “legacy” component of the combinations we used — perhaps these newer drugs could combine to form their own doublets like taxol/gemzar, taxotere/gemzar, and gemzar/navelbine. One early trial completed in Greece (abstract here) randomized previously untreated advanced NSCLC patients to receive either taxotere/cisplatin or taxotere/gemzar. It looked at response rates as the primary objective, showed remarkably similar results overall, and a significantly higher response rate with taxotere/cis for patients with non-adenocarcinoma tumors and taxotere/gem for patients with an adenocarcinoma:
One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.
Obviously, the response rates and side effects didn’t change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:
It’s worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.
I think one of the most important lead stories from ASCO 2008 got buried. Nobody’s really talking about it yet, but they should.
Amidst the results that led to an arguable role for erbitux and more compelling evidence to move second line chemo to bridge first and second line chemo together, we also received what I would consider to be very convincing clinical evidence that we can identify populations of lung cancer patients who are far more or less likely to benefit from alimta (pemetrexed), one of our most commonly used drugs in advanced NSCLC. Although alimta is considered a conventional chemo and not a targeted therapy, we’re getting increasing evidence of how to target our convention chemo (such as by using ERCC1 levels to predict sensitivity to cisplatin, as discussed in a prior post). The new data from the JMEN trial of maintnenance alimta vs. placebo provides what I’d consider to be downright convincing evidence that alimta is a quite effective treatment for patients with non-squamous NSCLC and also appears to be far less effective or even simply not effective for patients with squamous cell NSCLC.
There was some evidence that patients with adenocarcinomas received a little more benefit with erbitux than the patients with squamous cancers, as shown in the table below (which also highlights the race-based difference)
(click on image to enlarge) Continue reading →
Within the lung cancer community, the biggest story from the ASCO meeting was the long-awaited plenary session presentation (abstract here) of the FLEX trial of chemo with or without the EGFR monoclonal antibody Erbitux (cetuximab) that we knew was statistically significantly positive for an overall survival benefit as far back as September of last year (see prior post for details of trial and that initial press release). However, we had received no further information since that time but knew that if it showed a survival benefit, erbitux would have earned a place as a player in our considerations for treatent of lung cancer, at least first line treatment of advanced NSCLC. But we really needed to see more details to determine how to integrate it our current strategies.
FLEX was a European trial that enrolled 1125 previously untreated patients with advanced NSCLC who were all screened and found to have expression of the EGFR protein on their tumors (because that’s what the monoclonal antibody binds to). There are various levels of stringency for the amount of protein expression, but this trial was as lenient as you could get, with evidence of the protein by immunohistochemistry (IHC) on just one single cell being considered enough to get waved into the trial. A total of 15% of patients who were screened didn’t have any EGFR expression by IHC, which may be a reason why this trial was positive for a survival benefit but the results from the BMS-099 trial have been less clearly favorable (a rumor last month of it being positive for survival was wrong and based on miscommunication — we don’t have any survival data yet for that).
Regardless, the FLEX trial randomized patients to either cisplatin/navelbine alone or the same chemo with erbitux weekly, and patients who didn’t progress after 6 cycles would receive erbitux weekly as a maintenance therapy until progression or serious problematic toxicity. It was reported in the plenary session because it was only the second trial that has shown a significant survival benefit from adding a targeted agent to chemo (the first being avastin), and this is the first that applies to a much broader patient population, since it included patients with a marginal performance status and didn’t exclude patients with squamous tumors, on blood thinners, unlike the trial of avastin (although the FLEX trial also excluded patients with brain metastases). But the overall difference in median survival was only 1.2 months, or 5 weeks — 10.1 months in the chemo alone arm, compared with 11.3 months with erbitux. There was only a 5% difference in one-year survival between the two groups, although both groups did better than we’ve seen in older studies (42% vs. 47%). The trial just barely met the pre-defined criteria for what would be considered a statistically significant improvement in survival, and many in the audience, both general oncologists and also the lung cancer specialists, were largely left struggling with the question of whether the difference was really large enough to be considered clinically meaningful. Continue reading →
There’s a single lung cancer trial being presented 6/1/08 at ASCO’s Plenary Session, at which the most important cancer studies of the year are presented. This is on the FLEX trial that I described in a prior post, and which was already reported to be positive, at a press release all the way back in September of last year. We’ll actually see the full data at the presentation, but the abstract just became publically available (here) and provides some additional information.
Some financial analysts have already described the findings and potential financial implications (here), but I’ll give you an oncologist’s perspective, and a sense of what my colleagues feel about the strength or weakness of the results and what they’ll mean to the changing standards for lung cancer treatment, after the session Sunday.
As I’ve described in a prior post, there is some evidence that patients who develop a rash on tarceva (erlotinib) have an improved survival compared to patients who experience no skin toxicity on tarceva. The key question is whether this is an issue of under-dosing some patients, or if it’s just a correlate of overall immune function or constitution in a person, in which case increasing the dose won’t improve the outcome.
The best evidence we have to address this issue is a trial by the Eastern Cooperative Oncology Group, ECOG 3503 (abstract here), in which 137 patients (118 eligible) with previously untreated advanced NSCLC were treated with first line tarceva, starting at the typical dose of 150 mg daily. But the dose was then escalated by 25 mg every two weeks until patients developed either grade 2 rash (scattered bumps or spots or general skin redness with itching or other symptoms) or significant other side effects that precluded dosing up to a maximum of 250 mg per day.
Only half of the patients (60 of 118) ended up pursuing the dose escalation, presumably because the other half already had enough of a rash or other side effects that increasing tarceva dose wasn’t feasible. Only 15 (13%) were escalated up to 250 mg daily. The overall response rate was only 7% (8/112, with one complete response), and the overall survival wasn’t any better than you’d expect.
This trial was actually presented at ASCO last year, but it’s one that we heard almost nothing about. It hasn’t been published as a full manuscript (that’s not unusual, as it can easily take many months or a year or more to get a full paper drafted and accepted in a journal), but I suspect that this information hasn’t gotten out there into the world because the results were pretty disappointing.
But they do make an important point. So to recap, this trial showed that with aggressive dose escalation of tarceva, the response rate was less than was seen in the larger trial with 150 mg and then dose reduction as needed (abstract here); survival was also no better than you’d expect. So this really suggests that there isn’t any incremental benefit to escalating dose. Patients who don’t benefit on tarceva don’t appear to be underdosed. The standard dose of 150 mg per day seems to be adequate, and there doesn’t seem to be an incentive to increasing side effects. This isn’t especially surprising for me, since I see that some of the patients who do very well on tarceva also do it on a reduced ongoing dose of 100 mg or sometimes lower when they’re experiencing toxicity. You don’t need to experience pain to receive the gain.
Last year, a provocative trial was presented at ASCO that compared early vs. later taxotere as second line therapy. I described that study here, and it showed a very significant improvement in progression-free survival (PFS) and a near significant improvement in overall survival (OS) for the recipients of taxotere immediately after four cycles of first line chemo for advanced NSCLC. These results were impressive enough that it would make us consider switching to a “maintenance” approach of giving second line treatment, in this case with taxotere, immediately after 4 cycles of first line chemo in non-progressing patients.
There were a few limitations to that work. First, some prior, generally smaller studies didn’t clearly support the conclusion that maintenance or early second line chemo is definitely superior. Because of that, most experts felt that it would be helpful to get another study that supported maintenance chemo before we declared it a standard of care. Second, the prior trial waited a full three months before doing a repeat scan that would trigger a start of chemo in the delayed chemo arm — and about 1/3 of the patients on that arm were too sick to get chemo by the time they were found to have progression. That’s too long, in my opinion, to wait before checking for progression, which is often found radiographically before a patient gets too sick for chemo. With so many people in the delayed chemo arm not getting it, the trial was in some ways a study of everyone getting immediate chemo vs. 2/3 getting delayed chemo — not fair.
But yesterday there was a press conference sponsored by ASCO to highlight the results of a trial sponsored by Eli Lilly and being presented at the oral presentation on advanced lung cancer at ASCO in two weeks (abstract here), and this result added to the prior study will likely change the standard of care, in my opinion. The new trial, called JMEN by Lilly (every common has their own cryptic coding for trial names, and I don’t know if ANYONE really knows what JMEN refers to — it’s not an acronym), asked a very similar quesiton to the one from last year — does maintenance chemo (or early second line chemo, depending on your point of view) improve progression-free survival, the time before someone shows cancer progression and needs to change treatment plans? Continue reading →
So I’ve been invited to be on the faculty of a lung cancer conference in Kauai next month (yes, a good gig, but this is the first year that the flights are so expensive that I can’t bring my family to this normally very family-friendly event), and my topic is to argue in a debate about whether molecular testing for EGFR should be routinely used in clinical practice.
In the initial draft of the agenda, I had been assigned the “Pro” side of the argument, to say that we should be ordering EGFR mutation and/or FISH tests on patients routinely to determine whether and when we should be using EGFR-based therapies. I think this was an attempt to be provocative, since they would probably know that I am not a proponent of this approach. I called the organizers and requested that I trade positions with Dr. Roman Perez-Soler from Albert Einstein College of Medicine in NYC, who is not militant but I think far more in favor of molecular testing than I am. We all agreed it made sense to switch positions, which is fortunate because I was otherwise going to present the data from the standpoint of trying to convince myself that there were strong arguments to be made in favor of routine molecular testing, then show that I couldn’t convince myself this was a good idea even when I needed to, and therefore still argue the “Con” side. Then there would be actually be two arguments against molecular testing, which is fine with me.
I’m putting together my thought process and my slide set now (we need to submit slides weeks before the meeting so that they can be printed in a syllabus book to be distributed at the meeting). First, I thought I’d outline some areas where I think there is pretty clear consensus. First, though immunohistochemistry for EGFR is the most widely available test, this approach is also done in many different ways and is the least reliably associated with better or worse outcomes with EGFR inhibitors. Second, EGFR activating mutations (in the DNA of the EGFR gene) are very highly associated with tumor shrinkage, although not in everyone with EGFR mutations and there is not a clear improvement in survival – that is, patients with EGFR mutations may live just as long with or without an EGFR inhibitor. Third, the technique of EGFR fluorescence in situ hybridization, or FISH, which measures the number of copies of the gene in the cancer cells, is less clearly associated with response than mutations have been, but this test may be useful in predicting survival for the EGFR oral agents (called tyrosine kinase inhibitors) like tarceva (erlotinib) and iressa (gefinitib), and the EGFR FISH test may be especially promising in predicting who will benefit from the EGFR monoclonal antibodies, IV drugs like erbitux (cetuximab) (see prior post).
At this point, the major oncologist groups that put out guidelines don’t recommend routine molecular testing, but the real question is whether there is enough evidence to support it that they should. My answer is no, for now, because I’d like to see at least one of the following criteria be met before I’d say there is good reason to do this testing as a standard approach.
1) A negative test should preclude there being a clinical benefit from getting the drug – otherwise, it makes more sense to give it to everyone
2) A positive test would need to produce a greater benefit if given early vs. later, if later is the standard
3) A positive test would lead you to give an EGFR inhibitor to people in a different clinical setting, such as before or after surgery, or along with chemo and radiation for locally advanced lung cancer
I’ll discuss all of these points in some detail, but my sense of the literature right now is that none of these is true. At the same time, there are a couple of additional factors, including the added time delay and cost of the tests, and the fact that we often don’t have adequate biopsied tissue to do molecular testing.
We’ll cover these topics more thoroughly, and I’ll be very interested in hearing people’s assessments. Your questions and objections will help me to sharpen my thought process in anticipation of the actual debate. More later.
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