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Integrating Alimta and Cetuximab in Locally Advanced NSCLC
As a follow-up to my last post on the appeal of developing new regimens for combining with radiation in treatment of locally advanced unresectable NSCLC, I wanted to highlight work being done by the Cancer and Leukemia Group B (CALBG), one of the major cancer cooperative research groups in the US. As I mentioned previously, we’ve had difficulty developing widely accepted alternatives for the few chemo regimens commonly used in combination with concurrent radiation — primarily cisplatin/etoposide or weekly carbo/taxol. Some experts feel that weekly carbo/taxol has a shortcoming in that it is given at a more frequent but lower dose than the “full dose” every three week regimen, and the lower dose may have very little activity against micrometastatic cancer cells traveling throughout the bloodstream. For that reason, it may be preferable to give full, “systemic dose” chemo at least at some point during treatment for locally advanced NSCLC, and giving it during radiation could allow you to treat a person for both local cancer in the chest(disease you can see and treat directly, with radiation, while chemo bolsters the radiation — called chemosensitization) and distant disease outside of the radiation field. But there are relatively few chemo regimens that can be given safely at full “systemic” doses with radiation concurrently. The CALGB lung cancer committee has been working on a new regimen that incorporates a regimen of carboplatin and alimta one day every three weeks at full dose, with radiation, an approach that could potnetially be enthusiastically adopted in the lung cancer community as a newer and more convenient alternative if it looks as good or better than our older standards.
Now that there is evidence from early safety/feasibility studies that chest radiation can be given along with full dose alimta every three weeks along with carboplatin (abstract here) or cisplatin (abstracts here and here), CALGB developed a trial to test the activity and safety of carbo/alimta/RT followed by alimta “consolidation”, or the same strategy with erbitux added throughout, both during the radiation and afterward, with the alimta consolidation (abstract here). The trial design is as shown here:
Alimta Disappointing in Small Cell Lung Cancer (SCLC)
As described in my last post, one of the interesting points we’ve seen from the recent trial of maintenance alimta vs. placebo after first line chemo for advanced NSCLC is that alimta’s beneficial effects appear to be concentrated on the 2/3 of patients with non-squamous cancers, while the patients with squamous cell NSCLC did no better with alimta than with placebo. That post also described how sensitivity to alimta may be associated with low levels of a relevant target enzyme for alimta, called thymydylate synthetase (TS), and that TS levels are relatively high in squamous cell NSCLC, and also in SCLC.
Unfortunately, the results of a large trial in extensive SCLC (abstract not yet available on ASCO website) clearly confirmed that alimta isn’t an improvement as a treatment for SCLC. This trial was designed to directly compare the regimen of carboplatin/alimta to carboplatin/etoposide, which is a standard regimen for this setting. It was designed to enroll 1820 patients (!) and look for a significant improvement in survival. The study had enrolled 733 patients when the “Data Safety Monitoring Board”, which reviews results during the conduct of a trial to ensure that one arm isn’t doing so remarkably well or poorly that it would be unethical to continue to randomize patients, found that the carbo/alimta arm was doing so poorly that it was not possible that it would ever emerge as superior. It was closed, and Dr. Socinski presented the results.
In pretty much every measure, the carbo/alimta arm fared worse than the arm receiving standard carbo/etoposide. Median progression-free survival was 3.7 vs. 5.3 months, and the survival curve shows the dramatic difference:
The other measures supported the same conclusion. The median overall survivals with carbo/alimta vs. carbo/etoposide were 7.3 vs. 9.6 months, and response rates were 25% vs. 40%. Even side effects, usually a very strong suit for an alimta regimen, didn’t look better than carbo/etoposide, and in some measures like degree of anemia and need for transfusions, the carbo/alimta regimen was significantly worse.
There isn’t too much more to say about it, except that it was remarkably convincing that there was nothing to recommend alimta in the setting of SCLC. It certainly deserved to be tested, and this regimen had looked promising in smaller earlier trials in SCLC, but it was one of the most definitive answers you could ever see. While we’ve become quite impressed with its value in NSCLC, and from now on perhaps particularly in those patients with non-squamous cancers, I would say that alimta doesn’t have much of a future in SCLC. On the other hand, the results looked favorable enough for the regimen of carbo/etoposide, which is reassuring to see when we’d like to consider it as a kinder, gentler alternative to cisplatin/etoposide for ED-SCLC. So perhaps there was still some positive that came out of this otherwise disappointing trial.
Alimta and Lung Cancer Histology: Targeting Conventional Chemo Effectively
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.
Impressions on the Trial of “Maintenance”/Early 2nd Line Alimta vs. Placebo
A couple of weeks ago I described in a prior post the design and general results of a trial coded as JMEN by the sponsor company, Eli Lilly. This study randomized patients to either maintenance/early second line alimta (pemetrexed) or a placebo after four cycles of initial platinum-based doublet chemo with a drug other than alimta. The randomization was only for the patients who didn’t progress after the first four cycles of chemo, and as described in the prior post, there was a very highly statistically significant improvement in progression-free survival with maintenance alimta, and while the overall survival benefit wasn’t quite statistically significant, it was a very respectable difference of nearly three months (9 vs. 12 months) that was arguably quite clinically signficant and was associated with a “p-value” of 0.06 (meaning there was only a 6% chance that the difference could be by chance alone, while the standard cut-off we use is a p-value of 0.05, or a 5% or less probability of a difference being by chance alone) .
Combined with the results from a pretty similar trial of immediate vs. delayed second-line treatment with taxotere (docetaxel) that was presented at the ASCO meeting last year (see prior post), we now have two recent large studies that show major improvements in progression-free survival and a nearly significant improvement in overall survival. Taken together, these results are arguably enough to change our standard approach to moving second line treatment to right after first line, effectively blurring the edges so that non-progressing patients transition straight to maintenance therapy after 4 cycles of first line chemo (or possibly 6 as a variant that wasn’t used in these two trials, but you’d likely have many patients show progression between the 4th and 6th cycles). Continue reading
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
Carboplatin/Alimta for Mesothelioma, or NSCLC
So far, I’ve only written a few introductory posts on mesothelioma, but there were some interesting presentations at ASCO 2007 about the topic. One described the results of an expanded access protocol (EAP), which is when a company gives free access to a drug that is not yet commercially available (generally in exchange for participation in a data-collection study). This EAP was for Alimta (pemetrexed) as a treatment for malignant pleural mesothelioma (MPM) in Europe (abstract here). On this EAP, patients with mesothelioma from 13 different European countries were enrolled and could receive cisplatin/alimta (the combination approved by the FDA after being studied in a large randomized trial (abstract here)), carboplatin/alimta (carbo being a popular substitution for cisplatin in many settings because it is associated with considerably less nausea, risk of kidney damage, hearing loss, and some other side effects), or alimta alone. All patients received B12 and folate supplementation with their chemo. Over 3000 patients with MPM had data collected on how they tolerated treatment and how well they did on therapy, with just over 2000 of them receiving this treatment as their first chemotherapy. The report described the experiences of the 1704 patients who received alimta with either cisplatin or carboplatin, rather than alimta alone, and compared the results. The groups were almost evenly split between the two combinations (843 getting cis/alimta, 861 getting carbo/alimta). The two groups were quite comparable except that the median age of patients getting carboplatin was about 66, vs. 62 for recipients of cisplatin. This isn’t especially surprising, because the younger, presumably a little healthier patients would likely be selected to receive the more rigorous treatment.
The results showed that the two groups performed remarkably similarly in just about every way. The median number of cycles was 5 with cis/alimta vs. 6 with carboplatin/alimta, but otherwise, both groups had the same general response rate in the 25% range, the same disease control rate (stable or responding) of 75-80%, median time to progression of 7 months, and one-year survival rate of 60-65%. Looking at the numbers and the survival curves, it’s impressive to see how overlapping they really were:
(Click to enlarge) Continue reading
Alimta: A Newer Chemo with Increasing Utility
As I mentioned in prior posts on the topic of second-line therapy, taxotere was the first treatment approved for second-line treatment of NSCLC. Back in 2000, first-line chemo with platinum-based doublets was becoming increasingly established as demonstrating a consistent survival benefit of several months for previously untreated patients with advanced NSCLC, and then a couple of trials came out that demonstrated a modest survival benefit that for second-line taxotere, compared to either supportive care alone or compared to alternative chemotherapy (navelbine or ifosfamide). However, even after these trials demonstrated a survival benefit and taxotere was approved by the FDA for treatment as second-line therapy, only a minority of patients were getting treated in this way. A large part of this was the concern about the challenging side effects of treatment with taxotere every three weeks. Although taxotere is clearly among the most active and effective agents available for treatment of NSCLC (and many other cancers), it can cause a lot of fatigue and decreased blood counts and other problematic adverse effects. Over the last few years, the alternative approach of Alimta (also known as pemetrexed) has become available and approved by the FDA for second-line treatment of NSCLC, and it is being studied in more and more treatment settings as a potentially appealing option in lung cancer.
Alimta, or pemetrexed, is a form of standard chemotherapy that is a newer version of old standard chemo like methotrexate. These drugs are called antifolates, and they inhibit the production of critical components of DNA that growing cells need to survive. Because cancer cells are growing faster than other cells, they are particularly susceptible to the damaging effects of antifolates and can lead to death of cancer cells. The “MTA” at the end of the name Alimta stands for multi-targeted antifolate, because, as its name suggests, it actually has several targets that are critical in DNA and protein formation (too complicated and not interesting enough to go into here). In truth, the distinctions between what is called standard chemotherapy and “targeted therapy” are actually not very clear. Even regular chemo is targeted, but we have generally had a better idea of the target for the newer molecular therapies. Continue reading
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