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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”?
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.
Cancer Care in the Canadian System, by Dr. Laskin
Is the grass greener?
I have noticed that a number of the participants on this site are Canadians, which is only one reason I always keep my extra Canadian “u”s in my posts. There have been a few issues that have come up that might be different on the other side of the border, but for the most part, cancer is cancer and the questions are universal. However, a recent question on second line therapy prompted Dr West to wonder what happens in our more regulated health care system so I thought I’d provide a bit of a commentary. If you read my bio you will already know that I did all of my medical training in Canada but I did have the pleasure of spending a year in Nashville, Tennessee at the Vanderbilt-Ingram Cancer Center and University Medical Center. I spent this year in a lung cancer research fellowship that included at least 2 days a week in the clinics. So, although limited, I do feel that I have some sense of the similarities and differences in cancer care, at least in an academic setting.
Rather than get trapped in a debate about which country has a better system let’s just agree that there are good things and bad things about each one. Both could use some improving, neither is perfect, and both will need to evolve over time.
Access is usually the issue in Canada. We often seem to be “behind” the United States in terms of access to new drugs. Although we pay close attention to the rulings of the FDA, our own Health Canada carefully considers the evidence, data, and trials available for each new chemotherapy. And, even if a drug is approved for use in a given disease state, each province will have to decide if the drug will be paid for or not. If it is available then it is provided free, to everyone. If it is not covered by the province but it is approved by Health Canada, then patients can usually get access to it by paying for it themselves or sometimes through any additional health care insurance programs an individual patient might have. Additional health insurance is certainly not the norm, but it is relatively common. For example, pemetrexed (Alimta) is approved for use in the second line setting for advanced NSCLC, but most provinces do not pay for it (except in mesothelioma). It is paid for/covered in British Columbia, which is why I use it more than docetaxel (Taxotere) (mainly because of the hair loss issue), but I had no problem using the equally effective docetaxel before and I do not think that the other provinces are providing inferior treatment because they do not have it available.
There is a similar issue with erlotinib (Tarceva), which is covered by almost every province (and being reviewed by the territories) for use in second line if someone cannot take a taxane and for third-line treatment for any NSCLC. This approval is based on the trial (BR21) that demonstrated benefit in this particular group of people. It is not approved in first-line because the results for the studies that are testing that haven’t been released yet. I agree, it is tempting to give it a try first-line – why not? If it works later why shouldn’t it work first, right? Well, I’m not so sure, and I think looking before you leap might be wise sometimes.
For example, erlotinib works by itself, we saw that from the phase II studies in the 1990s. Chemotherapy agents seem to work best when we combine them together – carbo/taxol or gem/cis so it must be that all 3 together would work even better. Right? Except when this concept was tested on over 4000 people there was no benefit to adding in the erlotinib (or gefitinib). Good thing we tested it rather than just adding it in automatically.
That’s not to say I haven’t used erlotinib first line. In fact I have a clinical trial open right now that is testing this exactly, with a solid rationale and a thorough ethics review. Beyond trials, I must admit it makes me nervous, though in individual cases I think it is worth considering.
Yes, I admit that it is sometimes incredibly frustrating that I cannot have access to every new drug that comes up in any creative combination for as long as I want to use it for. But this is supposed to be an evidence-based practice; the people I’m treating deserve a rationale for what I prescribe. And I believe that as responsible physicians we do need to put some thought into the cost of what we’re recommending. There is not an endless health care budget, in Canada but also in the USA. Even at a patient level, is it worth spending the last few months of your life struggling to go to work so you won’t lose the insurance that pays for your $200,000 of chemotherapy that maybe only adds 2 weeks to your survival?
Someone will ask about Canadian waitlists – yes, this can be a problem. Sometimes it takes 2 weeks to get a CT scan or 2 weeks to book an appointment for palliative chemotherapy. That waiting can be very anxiety-provoking for patients and families. From a biological point of view, it’s hard to know how much difference a week or two makes. When it does make a difference, in a curative situation or in a medical emergency, there is no waiting.
So of course there are differences. Having worked in both countries, I see that there are a lot of misconceptions about the other’s systems and there is a huge amount of variability for individual situations. Hopefully we can learn from each other.
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