An interesting trial presented at ASCO 2008 came out of Japan, asking the question of whether there is an advantage to continuing first line platinum-based doublet chemo for up to six cycles or whether it might be better to give just three cycles and then switch from chemo right to the EGFR inhibitor iressa in Japanese patients with advanced NSCLC (abstract here). I haven’t mentioned it before because the trial, although interesting and with some provocative findings, didn’t clearly provide conclusions that would lead to obvious management changes.
For trial 0203, the West Japan Thoracic Oncology Group (WJTOG) enrolled 600 patients with previously untreated advanced NSCLC, with asymptomatic brain metastases permitted. Unlike North American NSCLC patients, among whom 10-15% are never-smokers, 31% of the patients in this Japanese trial were never-smokers; about 78% had adenocarcinomas (a higher proportion than in North America or Europe). They were randomized to receive chemo for six cycles vs. three followed by Iressa. The chemo could be carbo/taxol or cisplatin with gemcitabine, taxotere, navelbine, or irinotecan, all comparable in activity.
The European Society for Medical Oncology (ESMO) Congress, similar to ASCO but based in Europe, has been going on in Stockholm, where the results of a study called the First Line Iressa versus Carboplatin/Paclitaxel in Asia Study (taking some liberties to force it into the acronym “IPASS”) was presented in the Presidential Symposium by my friend and Hong Kong-based colleague Tony Mok. This study, as shown in the schema below, randomized 1217 Asian patients with advanced NSCLC who had not received prior systemic therapy to either the oral EGFR inhibitor iressa (gefitinib) or the standard chemotherapy carboplatin/taxol (paclitaxel):
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.
One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people. And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.
A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients. Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials. More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups. We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo. But how well do older patients do with tarceva, independent of performance status? This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70. A couple of trials help shape our thinking here.
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 →
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.
In a recent issue of the Journal of Clinical Oncology, Dr. Vince Miller and colleagues published the results of an important trial of the EGFR inhibitor tarceva (erlotinib) in the unusual NSCLC subtype bronchioloalveolar carcinoma, or BAC (abstract here). This work was predicated on the observation, also by Dr. Miller and his colleagues at Memorial Sloan Kettering Cancer Center in NYC, that EGFR inhibitors, and specifically gefitinib in the earliest clinical experience, appeared to be most associated with great responses in patients with adenocarcinoma and particularly BAC, and also in never-smokers (abstract here). Over the past several years, much of our greatest interest in drugs like iressa and tarceva has focused on BAC, including a trial with iressa that I led with the Southwest Oncology Group (SWOG) and subsequently published (abstract here), and also the trial with tarceva that Dr. Miller ran with collaborators at Vanderbilt-Ingram Cancer Center in Nashville and MD Anderson Cancer Center in Houston.
Over several years, these investigators enrolled 101 patients, most of whom had adeno/BAC and not the pure form of BAC (see prior post for discussion of this spectrum), which is representative of the eligibility of most or all of our current trials that we say are for “BAC“: the majority, and sometimes the vast majority, are BAC mixed with some invasive adenocarcinoma. In truth, different pathologists, even great ones, differ in their definitions of what is BAC, what is adenocarcinoma with BAC features, and what is BAC with focal invasive adenocarcinoma. Continue reading →
Member Sandra recently asked the question that several other people have asked in one form or another: how do we choose among the treatment options for second line therapy in NSCLC. I’ve covered in several posts and a huge number of responses in the Q&A Forum the leading options we generally consider for second line therapy for NSCLC. I’ve consistently stated that there are three agents that are most commonly used — taxotere, alimta, and tarceva — because they’ve all been pretty well studied, and they’re all approved by the US FDA for this setting based on the evidence available. Moreover, they also have what appears to be very comparable activity: taxotere and alimta have been compared head to head and shown to have remarkably similar efficacy, and while we don’t have data yet for direct comparisons of tarceva vs. one of these chemo options, we do have data from the large INTEREST trial (post here) that showed that iressa, which the preponderance of evidence would say is the slightly weaker EGFR inhibitor vs. tarceva, had the same efficacy as taxotere in a huge worldwide trial.
So we’ve got these three leading options (and it’s also reasonable consider others, even if they aren’t as well studied), and how do we choose among them? My first question is whether I’m inclined to recommend chemo or an EGFR inhibitor as second line therapy. And the two leading factors I’d consider are prior response to chemo in first line, and smoking status. To me, they both count pretty similarly. The main principles are that if someone responded well to chemo in first line, they’re more likely to respond well to second line chemo. On the other hand, someone who progressed after the first two cycles is not someone I’d be especially optimistic about for a better response to second line chemo. So the better the first line outcome with chemo, the more inclined I’d be to recommend more chemo; conversely, the more disappointing the outcome, the more inclined I’d be to recommend EGFR inhibitor therapy with tarceva, although in this case I’m selecting it as the “not more chemo” choice more than because it’s an EGFR inhibitor. I’d consider it more of a wild card, and a wild card is good when you’re expecting a bad outcome with what you’ve already got (for instance, more chemo), but it’s less appealing if you’re expecting a good outcome with what you’re holding.
The second big factor is smoking status. We’ve spoken mostly about never-smokers, and as I’ve mentioned all over the website, never-smokers appear to have a distinct biology (post here) and are consistently more likely to do well with EGFR inhibitors like tarceva (post here). So in my mind, never-smokers should receive tarceva early: many experts consider it to be an appropriate first line treatment (I’d consider myself in that camp), but if not used first line, I’d almost always advocate to use it second line. And I wouldn’t wait for someone to have major progression on first line chemo. If a never-smoker’s scans looked convincingly worse, even if the difference didn’t technically meet criteria for progressive disease, I’d almost certainly move them to tarceva ASAP. But the important point is that while that’s a neat answer for the 10-15% of lung cancer patients who never smoked, what about the other 85-90%? And the point is that it isn’t ALL or NOTHING, ever-smoker or never-smoker. People who smoked relatively little (say, less than an average of a pack per day for 10 or 15 years) and who quit smoking 20 or 30 years before diagnosis often have the molecular and treatment characteristics of the never-smoker population (as described in one of the referenced posts above, on different response to treatment in never-smokers). Some of our current trials on smoking status also include remote, light smokers in addition to never-smokers. We don’t know if they will do as well as never-smokers, but in the real world, the less a person has smoked and the longer they’ve been off of tobacco, the more likely I think it is that they’ll get an impressive benefit from tarceva. However, I don’t want to completely overstate this association. There are never-smokers who don’t benefit, and there are smokers who do well with tarceva as well. Smoking status is just a useful predictive tool, not a guarantee.
So putting this together, I’d definitely advocate chemo for someone who responds well to first line chemo and has a significant smoking history. And I’d strongly favor tarceva second line for someone who either has a minimal/remote smoking history or progressed quickly through chemo. What is someone is a remote and/or light prior smoker AND responded pretty well to chemo? Either choice is very reasonable, so I talk with the patient about whether they’d prefer IV chemo or an oral targeted therapy, discuss the different side effect profiles, and then make a decision or flip a coin (kidding — hasn’t happened yet). And most of the time, whichever we didn’t do second line is going to remain a feasible third line option, so it’s more choosing the order of treatment than which treatment they’ll get. We don’t need to burn bridges, unless a person declines too quickly to tolerate more therapy.
In terms of which chemo, either is very appropriate, but I and many other oncologists have come to clearly favor alimta. If patients haven’t lost their hair, most would prefer not to lose it (which occurs far more commonly on taxotere). Alimta was approved by the US FDA based on its modestly more favorable toxicity profile overall vs. taxotere, and although the differences weren’t striking, my clinical experience, and that of many of my oncology colleagues, is that the toxicity of alimta is appreciably less than taxotere, overall. Of course, there are patients who have a hard time with it, just as with any cancer medication.
In patients who are strong enough for long enough, it’s possible to give first line therapy and then all three of these agents at some point, and sometimes more. But beyond these general principles, I largely individualize my treatment plans with patients, as most oncologists do.
I’d be interested in learning how Dr Laskin approaches second line therapy. She may have a similar approach, or she may have a different perspective, working in a system that, from my vantage point, has more rigid guidelines in place. There’s plenty of lattitude for differing views, but at the present time, this is how I approach my patients after they have completed first line therapy.
In a post several months ago, I described the results of a trial from Japan, designated V-15-32, that directly compared Iressa to Taxotere as a second line therapy. Although overall comparable, the study showed that Japanese patients receiving Iressa had a higher response rate, but despite that had a lower median and one year survival. Although Iressa overall has not shown the same degree of clinical benefit as the very similar drug Tarceva, these results were perhaps a bit surprising because EGFR inhibitors have been most effective in Asia, where a higher proportion of lung cancer patients are never-smokers and/or have an EGFR mutation. But the Japanese trial had the problem that more patients randomized to Taxotere received a potentially effective therapy (different agent with potential activity in previously treated patients) after the trial drug than patients on the Iressa arm.
One of the trials presented at the Presidential Symposium at the recent World Conference on Lung Cancer in Seoul, Korea, was called the INTEREST trial (I donâ€™t remember what the acronym stands for, except that it was a major stretch), led in North America by my friend Ed Kim from MD Anderson Cancer Center. This trial (abstract here) had almost the exact same design as the Japanese study, again randomizing previously treated patients to either Iressa 250 mg daily or Taxotere IV every three weeks.
The INTEREST trial was run around the world, accruing 1466 patients from 149 centers in 24 countries, making it the largest trial in previously treated patients with NSCLC that has ever been conducted. The Taxotere dose was also 75 mg/m2 every 3 weeks, the FDA-approved standard in the US based on a proven survival benefit in North American trials, while the Japanese V-15-32 trial used 60 mg/m2, which is the standard in Japan and appears to be a dose with the same general toxicity and effectiveness as a higher dose in North American/European populations. Otherwise, the INTEREST trial asked the same question as the Japanese trial but in a broader audience. Specifically, one of the reasons it was so big is that it was looking to see whether the two approaches could be proven to have the SAME survival/clinical benefit, which requires more patients than showing that one is better than another. The trial was also designed to look at whether patients with EGFR gene amplification as measured by the FISH test. Continue reading →
The study I was just discussing, the French trial of Iressa at 250 mg daily for advanced BAC (abstract here), provided interesting clinical information, especially when viewed in the context of previous work on EGFR inhibitors in BAC. But in 2007 we’re also interested in the next generation of questions, including trying to identify which patients are more or less likely to benefit from Iressa or other EGFR tyrosine kinase inhibitor therapy. In addition to the clinical portion of the trial, the French investigators evaluated several clinical, pathologic, and molecular variables that were associated with disease control (DCR: response or stable disease) vs. progressive disease (PD) in a separate reported part of the study (abstract here).
From the 88 eligible patients enrolled on the BAC trial, they had tissue submitted from 65, of whom the expert pathologists felt that 50 had BAC or adenoBAC, evenly split between mucinous (M) and non-mucinous(NM) BAC, while the others didn’t have tumor tissue in their submitted specimen or had an adenocarcinoma that the experts didn’t think could be called BAC (this is typical — expert reviews of pathology submitted as “BAC” from various hospitals often show high rates of disagreement, with a less strict definition in the “real world”). Not suprisingly, the patients with tissue submitted, like those on the trial in general, had a higher rate of non-smokers (>40%, and from France, no less!), and more than half of the BAC patients were women (pretty much the only lung cancer setting where we see this). The tumor tissue was tested for EGFR by protein expression (immunohistochemistry, or IHC), gene amplification (by a process called FISH, and another called CISH), and also for EGFR mutations; they also checked for ras mutations, which I described in a prior post as being likely associated with a lower likelihood of benefit on EGFR inhibitors. Finally, they checked for thyroid transcription factor-1 (TTF-1), which is a marker of thyroid and lung tissue that helps us determine whether a cancer is actually from the lung or thyroid vs. another part of the body (they can tell the difference between lung and thyroid from other protein stains in the unusual cases where there’s a question between those sites as the primary tumor site). About 70% of lung adenocarcinomas express TTF-1.
First, the investigators compared the M-BAC to NM-BAC tumors and found differences in several regards. Although there were no gender differences and never-smokers were found in similar proportions between the two types of BAC, NM-BAC was much more likely to be associated with TTF-1 expression, EGFR protein overexpression (by IHC; about 35%) and gene amplification (by FISH and CISH; 10% range)) and EGFR mutations (12% of the population) than M-BAC tumors. They didn’t differ in their frequency of ras mutations (about 1/4 of both groups). So they have some differences that might explain differences in how the different types of BAC tumors respond to EGFR inhibitor therapy.
And when they looked at the characteristics of the patients who achieved disease control vs. those who showed PD, they saw that the patients who had stable disease or better were significantly more likely to be women, never-smokers, have NM-BAC, have a tumor that expresses TTF-1, and also a higher likelihood of having an EGFR mutation. In contrast, those with ras mutations were more likely to be the ones who showed progression. Here’s the summary:
This isn’t a large enough study to say anything definitive, but it’s a step forward in giving us hints about biological differences between M-BAC and NM-BAC, and it also helps provide some insight about why people with NM-BAC may be more likely to respond better and have longer survival on Iressa and Tarceva trials. In addition, this biological information may be useful outside of BAC. Perhaps the patients with TTF-1 positive tumors are the ones more likely to respond to EGFR inhibitors. We’ve never really looked at that, but that marker is a routine part of testing lung tumors. It’s readily available everywhere, and it doesn’t take days or weeks to obtain, unlike the mutation work. There are several other interesting leads here, so we need to follow up and see what holds up in other studies of EGFR inhibitors.
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