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Nexavar (Sorafanib) with Chemo in Front Line Advanced NSCLC Fails to Improve Survival
I’ll get back to the storyline of our growing understanding of the differences of individuals based on pharmacogenomics very soon. But I wanted to give people some breaking news that just came out. The first line ESCAPE trial of chemo with the anti-angiogenic and multi-kinase inhibitor nexavar (introductory post here) or placebo is apparently negative according to a press release, and it even shows a harmful effect of the study drug in patients with squamous cancers, who were included in the trial.
The trial was designed very similar to the ECOG trial with avastin that led to its subsequent FDA approval. Over 900 first line, previously untreated patients with advanced NSCLC were randomized to receive standard carbo/taxol chemotherapy IV every three weeks for up to six cycles, with either nexavar (introductory post here) by mouth twice daily or a placebo on the same schedule. As in the avastin trial, patients who did not progress after six cycles of chemo continued on “maintenance” nexavar or placebo until progression or prohibitive side effects. The trial design is summarized here:
(Click on image to enlarge) Continue reading
Duration of First-Line Chemo in Advanced NSCLC: 4 vs. 6 cycles
Although I’ve previously written about the question about optimal duration of therapy for first-line chemotherapy in advanced NSCLC (post here), these conclusions have been based on a limited number of trials. One study randomized patients to three or six cycles of rather old chemo and found no significant differences (abstract here). Another more recent study randomized patients to four cycles of carbo/taxol compared with treatment until progression or prohibitive toxicity, with some patients going for more than 12 cycles, also demonstrating no significant differences in survival (abstract here). Based on the rather modest data, the current guidelines of the American Society for Clinical Oncology (ASCO) are to treat for no more than four cycles in non-responders, and no more than six cycles in patients who demonstrate a response to first-line treatment.
Most US-based oncologists follow a practice of treating up to either four or six cycles, although a reasonable minoriity in the US, and a higher proportion in other parts of the world, still treat beyond six cycles and up to the time of progression. Our current clinical trials, developed to include current best treatment practices, incorporate either four or six cycles of chemotherapy, with no consensus. The ECOG 4599 trial that established the role of avastin with carbo/taxol gave six cycles of chemo and avastin together, followed by maintenance avastin (abstract here). On the other hand, multiple trials that have focused on the maintenance portion or timing of second-line therapy have stopped at four cycles (see prior posts here and here). What’s really the best approach?
A trial by Park and colleagues from Korea that was just reported in the Journal of Clinical Oncology tried to address this question (abstract here). As shown in the schema below, 452 patients with previously untreated advanced NSCLC were treated first with two cycles of cisplatin-based chemo, and then responses were measured. One third who showed progression or toxicity problems came off the trial, leaving 314 who experienced stable disease or a response to be randomized to either four more cycles (total of 6) or two more cycles (total of 4) cycles of the same chemotherapy:
(Click on image to enlarge)
Patients were then followed, received a CT every three months after chemo ended, and in most cases received subsequent chemo (off protocol) at that point.
The results demonstrated that the patients who received a total of six cycles had a significantly longer progression-free survival, but both groups had the same overall survival, as shown here:
Differences in side effects weren’t very different between the two arms, with a little more toxicity in the patients who received more chemo, as you’d expect. Quality of life was also measured, and while there were no overall clear differences, a few parameters favored the shorter treatment arm, and none favored the longer treatment arm.
The results are noteworthy for a number of reasons. The authors make the point that the survival is quite favorable, and if the numbers you see look especially good, that is largely because the numbers reflect survival of a group of patients who remained after the third who had progressed or otherwise done poorly came off the study — the only ones randomized were those with stable disease or better after two initial chemo cycles. Second, more than half of the patients on the trial received iressa, and we know that Asian patients are more likely to do particularly well with EGFR inhibitors. At the same time, however, some trials that compare results in Japanese vs. North American trials that used the exact same chemo in the same setting produced more favorable results in the Japanese population. It is possible that patients in Japan do better because something about the supportive care is better, they have more responsive disease, or some combination of factors.
I don’t get a clear answer to the question of whether four cycles or six cycles is a better choice, and frankly I don’t think it matters much. I think that if patients tolerate chemo well and are still demonstrating stable disease, it’s perfectly great to continue to six cycles, but four is going to get people to pretty much the same place. I think the main reason for this is that there’s a dilution of any differences with second line and often third line treatments. An advantage of stopping after four cycles is that it may deliver more patients to later therapies with a good performance status and “bone marrow reserve” — the capacity to have the bone marrow make more blood cells quickly after subsequent chemo. Overall, I wouldn’t have any hesitation about participating in a trial that includes four cycles, nor would going to six cycles be a problem, as long as a patient continues to feel OK on chemo. With several later treatment options available now, and a real possibility (and I’d even say probability) of more new treatments emerging as 2nd, 3rd, or even 4th line options for advanced NSCLC, subtle differences in what happens in first line treatment are increasingly likely to get washed out over time.
Comparison of Iressa to Single Agent Chemo in First Line treatment for Elderly Advanced NSCLC Patients: The INVITE Trial
In addition to a direct comparison of iressa to chemo in the second line setting for advanced NSCLC (see recent post on INTEREST trial), as conducted with the INTEREST trial I described in a recent post, a very similar comparison of Iressa to chemo was also performed in another setting where single-agent chemo is also the treatment of choice. Specifically, the INVITE trial evaluated iressa vs. navelbine as a single agent in previously untreated advanced NSCLC (abstract here).
(Click to enlarge)
As discussed in one of my early posts, there is room to debate whether single agent approaches or older patients should receive single-agent chemo or standard platinum-based doublets (particularly carboplatin-based instead of the more challenging cisplatin doublets). Among the most commonly used single chemo agents in the elderly population is navelbine (also known as vinorelbine), based on it being proven to improve survival compared with supportive care alone in the memorably named ELVIS trial (Elderly Lung Cancer Vinorelbine Italian Study – paper here). We’ve seen the results of a trial in which tarceva was compared to the chemo doublet of carbo/taxol in patients with a marginal performance status (not the same population as elderly), and as I described in a prior post, the recipients of chemo fared better than those who received tarceva. So did the INVITE trial show similar results for gefitinib in the elderly compared to a single chemo agent? Continue reading
The INTEREST Trial of Chemo vs. Iressa as Second Line Treatment for Advanced NSCLC
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 don’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.
(Click to enlarge)
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
Cisplatin vs. Carboplatin for Advanced NSCLC
The question of whether to use cisplatin or carboplatin in our “platinum-based chemotherapy doublets” that are the most common treatment for the first-line treatment of NSCLC has been a smoldering debate in lung cancer for more than a decade. Although at this point carboplatin is by far and away more commonly used than the generally less tolerable cisplatin, whether these are completely identical in their efficacy isn’t entirely clear. Nobody questions that they’re very close. And the reason most oncologists feel that carboplatin is the best choice is that if there is a difference, it’s a slight one, felt to be more than offset by the toxicities and inconveniences of cisplatin compared to carboplatin, including considerably more nausea and vomiting, increased risk of kidney damage, as well as risk of hearing loss and peripheral neuropathy (nerve damage with numbness/tingling). Another factor that is important to many people is that cisplatin is administered over many hours, with lots of IV fluid support, so it usually requires either long days in the outpatient infusion center or a night or two in the hospital, while carboplatin is typically just a one-hour outpatient IV infusion.
Let’s start with one figure that is perhaps the best summary of a bleak 5 year period of lung cancer research:
(Click to enlarge)
This figure of overall survival, from the ECOG 1594 trial led by Dr. Joan Schiller (abstract here), randomized over 1200 patients with previously untreated advanced NSCLC to any of 4 platinum-based chemo doublets, 3 with cisplatin and the 4th being carbo/taxol. As you can see from the figure, the survival curves for each of the four chemo combinations performed identically, with completely superimposable survival curves. This image is what oncologists think of when we consider the differences among the different platinum-based chemo doublets. They all get you to the same place.
But there have always been nagging questions about whether cisplatin may be just a shade more active. One well-publicized trial, known as TAX 326 (abstract here) and conducted by Aventis (now Sanofi-Aventis), the makers of taxotere, was very similar to ECOG 1594 in that it randomized 1219 previously untreated first-line patients with advanced NSCLC to cisplatin/navelbine, cisplatin/taxotere, or carboplatin/taxotere:
The news from this trial was that the overall survival with cisplatin/taxotere was significantly better than the “control arm” of cisplatin/navelbine. Having one doublet do significantly better than any other is pretty rare, so that’s why some people would perhaps consider the cisplatin/taxotere doublet to be among the most active combinations for NSCLC, albeit by a small margin. The carboplatin/taxotere doublet was also compared to cisplatin/navelbine and wasn’t significantly different, which isn’t a great surprise. The issue, though, is that if you try to actually compare cisplatin/taxotere to carbo/taxotere, which the trial doesn’t formally do because it was designed to just compare each of the taxotere-containing arms to cisplatin/navelbine, the carbo/taxotere arm appears notably worse: median survival of 11.3 vs. 9.4 months and one year survival 46% vs. 38%. However, this has never been highlighted.
Another trial that did directly compare cisplatin to carboplatin in a doublet with a mutual partner was conducted by Rafael Rosell and colleagues in Spain (full article here). In this trial, 618 first line NSCLC patients were randomized to cisplatin/taxol or carboplatin/taxol, and the results showed a significant survival benefit with cisplatin:
As noted in the slide on the right, there was more nausea/vomiting and kidney toxicity with cisplatin, and more of a problem with low blood counts with carboplatin. In this trial, they also measured quality of life and didn’t see any significant differences.
So as we sometimes do when we have a complex mix of studies that show varying results, a meta-analysis was performed by Ardizzoni and colleagues (abstract here) in which the investigators pooled together the results from 9 different trials that included 2968 patients who were randomized to a cisplatin- or carboplatin-containing arm of the same trial. These meta-analyses are done to give us a summary sense of what’s going on when you look across several studies that may be too small individually to detect real differences. Pooling the results of all of these cis vs. carbo studies together, the response rate with cisplatin combinations was higher (30% vs. 24%), and the overall survival benefit was 7% better with cisplatin, although that survival difference wasn’t statistically significant. In the figure below, the size of the squares represents the size of each included trial, the horizontal lines to the sides of the boxes represents the variability in the data (so long lines means very inconsistent results), and the position of the square to the right or left of the vertical line represents whether each trial showed a survival benefit for cisplatin or carboplatin, respectively:
Looking at different subsets, though, the patients with non-squamous lung cancers and those treated with the most modern chemo agents as a partner for the platinum (like the taxanes, gemcitabine, or navelbine) had a survival with cisplatin that just reached statistical significance:
Maybe that really means something, but we always want to take subset analysis with a grain of salt, because those subset analyses are sometimes done when the orignical question didn’t give you the answer you wanted, so you ask the question again 10 different ways. As the saying goes, “if you torture the data enough, eventually it’ll tell you whatever you want.” There may be something to these subsets, but the overall results are that the differences are right on the cusp of being statistically significant.
The real issue is whether the differences between cisplatin or carboplatin are clinically significant even if they are on the border of statistically significant. Some of the trials suggest a difference of perhaps a month, while others suggest less than that, in a setting where we know treatment isn’t curative. As an increasing number of drugs become available and effective in improving survival in the second and third line setting, the small differences would be expected to be diminished further: later treatments after first line chemo should be an equalizer. Now that we have the opportunity for several lines of treatment for advanced NSCLC, I am partly thinking about preserving something for round 2 and round 3 as I make recommendations for first line treatment, rather than completely beat people down by making first line treatment more toxic than it needs to be. Finally, these trials have generally included very few older and/or sicker patients, so they tend to evaluate a population that is not always representative of a “real world” patient population that would likely tolerate cisplatin as well. But perhaps these considerations sound more like rationalizations to some people.
My perspective has been that I do recommend carboplatin-based chemo for the majority of my patients in the advanced disease setting, where cisplatin can’t increase the cure rate, and the differences in efficacy are relatively small and, from my vantage point, offset by the often problematic toxicity of cisplatin, and that with the vast majority of my patients receiving later treatments, the differences in first-line treatment shoudl be smaller still. Finally, now that avastin is approved and well tested with carbo/taxol and shown to confer a significant survival benefit, this is the regimen I use for appropriate patients, and we don’t have a hint of a cisplatin combination with avastin being superior. While the combination of cisplatin/gemcitabine with avastin has been shown to be feasible and associated with an improvement in progression-free survival compared to cisplatin/gemcitabine alone (abstract here), we don’t have any data yet on overall survival with this combination, and definitely no hint it’s better than carbo/taxol/avastin.
However, I do believe in my heart of hearts that cisplatin is marginally superior, and I think this actually matters much more in the setting of curative treatment, such as adjuvant chemo after surgery or as multi-modality treatment with radiation and/or surgery for stage III NSCLC. I think if a patient can tolerate it, pushing hard and accepting greater short term (and perhaps also long-term) side effects if it can translate to a cure rate that is even a few percent higher is likely worth it. It’s possible that carboplatin-based chemo regimens are equally effective, and I’m sure they’re close, but I tend to be conservative and offer the most aggressive option that makes sense in the curative setting.
I’m changing the polling question now to see whether people would favor a more aggressive, toxic treatment for marginally better activity in the curative setting, in any setting, or whether they would prefer to accept a better balance with potentially a little less efficacy but a considerably better side effect profile. I’d love to hear what people think of this issue, not only in their poll answers, but also with any comments people have. Oncologists have been debating these issues for many years, to the point that it’s become like a “Coke vs. Pepsi” debate, but we haven’t really heard from the patients and family members most directly affected.
Trial of Chemo with or Without Erbitux in Advanced NSCLC Negative
It’s a little sad that you can get more cancer information from the business websites than from the medical ones, but if you checked a story on Forbes.com today you learned that Bristol-Myers Squibb (BMS) provided a press release that one of their important Erbitux (cetuximab) trials didn’t meet its primary endpoint of improved progression-free survival for chemo with Erbitux compared with the same chemo alone.
Erbitux is another inhibitor of the epidermal growth factor receptor (EGFR), similar to Iressa and Tarceva, but unlike those oral pills, Erbitux is an IV drug that is actually a monoclonal antibody to the part of the receptor that is on the outside portion of the cancer cell (extracellular). Erbitux definitely has activity in some cancer types: it’s FDA-approved in treating colon cancer and head and neck cancer. But there have been some negative studies with Erbitux as well in other tumor types, including a large trial of chemo with or without Erbitux in pancreatic cancer that showed no benefit to the Erbitux combination (abstract here). It’s also been studied in lung cancer, primarily in NSCLC, with some modestly encouraging results, but definitely not a slam dunk. I’ve described some of this work in a prior post. Continue reading
Maintenance Therapy in Advanced NSCLC? ASCO Update
I had previously mentioned in prior posts that there have been a few studies in advanced NSCLC that indicate that about 4 cycles provides as much treatment benefit as continuing first-line chemo until progression. I also noted that the ECOG 4599 trial (abstract here) gave up to 6 cycles of chemo (with carbo/taxol) and avastin, followed by avastin alone as a maintenance therapy until progression of the cancer. We haven’t had much information, though to guide us on whether to follow with immediate second-line chemo after completing the typical 4-6 cycles of chemo in the first-line setting, but a trial by Fidias and colleagues at ASCO this year was provocative and suggested a potential benefit to going straight from first to second-line treatment. Continue reading
Chemo Combinations for Advanced NSCLC: A Regimen of Choice, or a Choice of Regimens?
We’ve come along way over the past decade. In the first half of the 1990s, the value of treating metastatic NSCLC was debated and not clear. A “meta-analysis” that pooled the results from 11 chemotherapy trials, 8 with cisplatin, and nearly 1200 patients demonstrated a modest but convincing improvement in survival compared to supportive care alone (article here). The figure summarizing the improvement by adding chemo is shown here:
(click to enlarge)
Although the difference now seems pretty convincing to me, and probably to you, at a time when treatment for advanced NSCLC was otherwise not felt to be beneficial, these results didn’t take the world by storm. Fortunately, several new drugs emerged for lung cancer that were often well tolerated and had clear activity in lung cancer as single agents:
Single-Agent Zactima/ZD6474 in Advanced NSCLC
As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I’ll focus on the research that gave it as a single agent and where it has led us in terms of current trials.
As I mentioned in my previous post, an early phase I trial just trying to establish an optimal dose showed some activity zactima as a single-agent, as 4 of 9 patients with NSCLC in a Japanese trial showed significant tumor shrinkage on zactima. From there, Dr. Ron Natale at Cedars-Sinai Medical Center in Los Angeles led a randomized phase II trial (abstract here) that compared zactima as a single agent at the higher dose of 300 mg by mouth per day, pretty close to the maximal feasible dose, to iressa at 250 mg by mouth daily. The trial was designed to allow cross-over to the other drug after patients experienced either progression or problematic side effects. So the design was as shown here:
(click to enlarge) Continue reading
Does Age Matter? Treating Older Patients with Advanced NSCLC
We know far too little about the best way to treat older patients with NSCLC, that lung cancer, like many other cancers, is a disease highly related to advanced age. First, how do we define an older, or elderly, population in cancer treatment terms? Beyond the joke that it increases as the person answering gets older, in the US it’s usually around 70, occasionally defined as 65, generally outside of the US. Despite the fact that the average age for patients newly diagnosed with lung cancer is in the late 60s, trials done in lung cancer far disproportionately enroll younger patients. It’s only been in the last few years that trials have been done specifically looking at older patients, or including them in large enough numbers in broader trials to ask meaningful questions about whether they should be treated identically or differently than younger patients. Continue reading
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