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FLEX Trial of Chemo with or without Erbitux in First Line NSCLC Data Available
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.
More Disappointing Results with EGFR/COX-2 Combination
When I first started OncTalk, there was a lot of buzz about celebrex (celecoxib) as a cancer drug, but almost all of it was among patients talking about it on the internet: oncologists watching the field hadn’t been impressed by the early returns, including this one (despite the fact that some of my earliest work in lung cancer was on cyclo-oxygenase-2, or COX-2, the target of celebrex). I must admit that part of the idea of me providing commentary here was to provide a filter and a dose of healthy skepticism to keep people from being swept up by a tide of irrational exuberance about an unproven and largely untested drugs and approaches. Just over a year ago, I wrote a prior post about studies combining EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) with celebrex or vioxx (rofecoxib); I wasn’t very impressed, overall, although some early work by Dr. Karen Reckamp at City of Hope Cancer Center looked promising, with more work combining tarceva and celebrex ongoing.
But another article was published (abstract here) on the combination of celebrex (at a pretty high dose of 400 mg twice daily) and iressa (at a typical dose of 250 mg daily) as a first line therapy for advanced NSCLC, in an unselected population (not chosen by smoking status, EGFR mutations, COX-2 protein expression on the tumor, etc.). This study was conducted by the Hoosier Oncology Group (affectionately known as HOG) in Indiana, who enrolled 31 patients. They found that there was certainly activity, but the response rate of 16% and median survival of 7 months was on the low side for what you’d expect in a group of patients with advanced NSCLC who started with the standard approach of platinum-based doublet chemo (with or without avastin). Another concerning issue was that 2 of these 31 patients developed fatal interstitial pneumonitis, and inflammation of the lungs, a complication that can rarely occur with EGFR inhibitors, but I’ve never had a life-threatening or fatal case occur in the well over 200 patients I’ve treated with iressa or tarceva in the past 5-6 years, so having this occur in 2 of 31 patients, or 6%, is pretty concerning for the possibility that there is a danger to this combination.
It’s possible that the results would have been better if they only enrolled patients who never smoked, or who had EGFR mutations or high expression of the COX-2 protein on their tumors. We can’t say that this combination wouldn’t be good for anyone, but this trial was a clear disappointment to the investigators and corroborates my belief that there is definitely no reason to deliberately combine these drugs in hopes of improving the impact as a lung cancer treatment outside of a clinical trial.
Dose Escalation with Tarceva? Dosing to Rash?
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.
Maintenance Alimta in Advanced NSCLC Shows Significant Improvement in Progression-Free Survival
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
Stable disease is just fine, thank you.
At the 1st ESMO-IASLC Lung Cancer Conference in Geneva last week I saw a presentation that I thought would interest this general readership. The study, presented by Dr Grossi, from Italy, is a retrospective review of 61 patients with advanced NSCLC of all subtypes treated with either Tarceva (erlotinib) or Iressa (gefitinib) in the 1st or 2nd line setting.
The groups were similar, remember this was not a randomized prospective study; the median age was 65 for those receiving Tarceva and 74 for those on Iressa. About 26% of the whole group were never/former smokers. They all were pretty physically fit (ECOG PS of 0 or 1), and most of them (55-58%) had adenocarcinoma.
There were no complete responses and the rate of partial response was 6% and stable disease of 26% for the people on Tarceva and 13% partial response and 29% stable disease for those on Iressa. These figures, although low, are entirely in keeping with previous study results for both drugs given to unselected patient populations.
What was interesting was that for the people who had a partial response the median survival was 9.7 months, but it was 9.1 months for those who had stable disease, and only 3.7 months for those who progressed on treatment. This was a trend noted in other studies and one I certainly see in my clinic, but it was reassuring to see it reproduced. And hopefully reassuring to anyone who might have “only” stable disease. Dare I say “size isn’t everything”?
Arguing Against Molecular Testing for EGFR in NSCLC
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.
Just another negative trial, or a worrisome trend?
Last week, the preliminary results of interim analysis the ESCAPE (Evaluation of Sorafenib, Carboplatin, And Paclitaxel Efficacy in NSCLC) trial were presented by Dr. Scagliotti at the 1st IASLC (International Association for the Study of Lung Cancer)-ESMO (Eurpean Society for Medical Oncology) Lung Cancer Conference in Geneva, Switzerland. This was a randomized, placebo-controlled, double-blind phase III study for patients who have not yet had chemotherapy for advanced NSCLC. Patients were treated with a standard course of chemotherapy (carboplatin and paclitaxel) and were randomized to receive sorafenib or placebo along with chemo. As you may recall from other posts, sorafenib (also known as nexavar) is an oral multitargeted tyrosine kinase inhibitor which primarily acts to block the VEGF receptors thus inhibiting tumour angiogenesis (blood vessel growth and development). Dr. West previously noted in a prior post that this trial was reportedly negative, but I was able to see the first presentation of the actual results.
In recent years the idea to combine antiangiogenesis agents with chemotherapy has become very popular, and this strategy was further encouraged by the positive results of the E4599 study that demonstrated a two month survival advantage when the monoclonal antibody to circulating VEGF, Avastin (bevacizumab), was combined with carboplatin/paclitaxel. Unfortunately, we have also recently learned that a similar trial with cisplatin/gemcitabine plus Avastin (AVAiL) failed to confirm this survival advantage (prior post here). What the future of this combination looks like is now unknown, at least for the countries who have not funded chemotherapy plus Avastin based on E4599.
In any case, the ESCAPE trial enrolled 926 patients over approximately 18 months (Feb 2006 – May 2007). The demographics of this population were very similar to other studies, about 62% male, medically fit for chemotherapy (ECOG performance status (PS) of 0 or 1), and no brain metastases at the time treatment started. Approximately 25% of patients had squamous cell carcinoma, the majority having adenocarcinoma: this is all very typical for phase III studies in advanced NSCLC. The toxicities were fairly predictable, and the median number of cycles of chemotherapy was 5 for the chemo alone group and 4 for the chemo plus sorafenib group. The response rates were also standard for the chemo alone arm with response rates of 5% complete (no evidence of residual cancer), 23% partial response, and 51% with stable disease. The chemo plus sorafenib arm was very similar with 1% complete, 30% partial response, and 46% with stable disease.
The progression-free survival was 5.1 months in the chemo alone arm and 5.4 months in the chemo plus sorafenib arm. The median survival was similar in both arms: 10.7 and 10.6 months in the control and experimental arms, respectively. Neither of these reached statistical significance. Thus, this trial did not meet its primary endpoint, which was to improve survival by the addition of sorafenib.
One interesting feature that came out of this study was the subgroup of patients (25%) who had squamous cell carcinoma. In this group the median survival for those who received sorafenib was worse than the control arm, 13.6 versus 9.8 months. In the non-squamous carcinoma group, the median survivals were similar at 10.3 and 11. 5months for the control and the sorafenib arm, respectively. The toxicities were not particular different for the patients with squamous cancers, though more patients died of progressive disease on the sorafenib arm (33%) than the chemo alone arm (25%). Overall, the reason this possible worse outcome for squamous patients on sorafenib plus chemo remains unknown — however, the 13.6 month survival for the squamous arm is longer than one would expect from previous studies, so perhaps there was some biological imbalance that was not evened out by the randomization process.
The results of this study, although I stress that these are only the preliminary results, are troubling for a number of reasons. Of course it is disappointing that this strategy did not make a significance difference in survival. But more than this, I am concerned that this might be a trend, and this is particularly worrisome after the early closure of a very similar study (BR-24, run by the NCI-Canada) with carboplatin/paclitaxel with or without AZD2171 (cediranib, with the trade name Recentin), another oral multitargeted tyrosine kinase inhibitor of VEGF receptors. Although no results have been released from this study (it will likely be presented at the ESMO meeting in Sept 2008), it is troubling that it was stopped early after an interim analysis that showed it could not meet its primary endpoint to improve overall survival with the chemo-AZD2171 combination. There are rumours that that there were toxicity issues rather than a lack of efficacy, but still it is something of a disappointment.
The potential failure or problems with tyrosine kinase inhibitors of angiogenesis with chemotherapy reminds me of the earlier failures of the combinations of chemo and the oral EGFR inhibitors (INTACT 1 and 2, TRIBUTE, and TALENT; described in a prior post here). And now with the lack of improvement in survival in the AVAiL trail (cisplatin/gemcitabine with or without Avastin), perhaps lung cancer investigators, myself included, have to at least consider the possibility that this strategy isn’t working. Or it isn’t working for all types of NSCLC. Of course all of these studies have a solid foundation in basic (lab-based) research, with tumour models suggesting this is a successful strategy making the results in people all the more frustrating and disappointing.
To me, this reinforces the need to collect human tumour tissue and work closely with our colleagues in the labs to figure out some of the differences among various lung cancers. Perhaps it stimulates other questions out there.
As always, I’d be interested to hear your thoughts.
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