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Survival Benefit in Another Erbitux Trial for Advanced NSCLC Reported
Although it’s only a leak from a “reliable source”, news came yesterday (link here) about a new lung cancer development from a financial source (yet another example of us learning oncology from Wall Streeters). Specifically, we heard that the BMS-099 that I described in a prior post is actually demonstrating a significant benefit in overall survival (OS). To summarize the BMS-099 trial, it’s one that compared standard chemo of carboplatin/taxane (either taxol (paclitaxel) or taxotere (docetaxel) at the physician’s discretion) with or without the EGFR inhibitor Erbitux (cetuximab), which is an IV monoclonal antibody and “targeted therapy” in a population of patients with previously untreated advanced NSCLC. The schema is as shown here.
Randomized Phase II Trial with Erbitux Looks Favorable
The antibody to the epidermal growth factor receptor erbitux (cetuximab) (introductory post here) has been used as an effective treatment for colon and also head and neck cancer for several years, but its role in lung cancer has yet to be defined. Early work in lung cancer was not especially impressive (prior post here), but in September, 2007, a press release reported that the FLEX trial, a European randomized study for first line advanced NSCLC that gave cisplatin/navelbine with or without erbitux, was positive with a statistical survival benefit (prior post here). Several months later, we’ve got no more information than that press release, but we do know that the trial was designed to require a survival benefit of at least 20-25% (I’ve never gotten a firm answer on this) from chemo/erbitux compared with chemo alone to be positive, so presumably it achieved a pretty impressive result that should be clinically relevant, offering a survival benefit in the same range as adding avastin to chemo for first line advanced NSCLC.
In the setting of mixed results and unreported positive trials, additional signals that can validate positive results are particularly helpful. A randomized phase II trial by Dr. Charles Butts and colleagues that enrolled first-line advanced NSCLC patients to receive either platinum-based chemo alone or with erbitux was presented at ASCO this year (abstract here), and the results were provocative, but the trial was small, with just 131 patients, and in the absence of a larger trial demonstrating the benefit of erbitux, it didn’t blow me away.
The full manuscript was just published in the Journal of Clinical Oncology (abstract here), and while it’s still a small study that won’t change the world, it now corroborates the positive FLEX trial and therefore has a new significance, to my eye. The schema was that previously untreated patients would be randomized to receive platinum (cisplatin or carboplatin) with gemcitabine on three week cycles, either alone or with weekly erbitux:
(Click on image to enlarge) Continue reading
Erbitux in Context: BMS 099 and other Trials Before FLEX
In my last post, I noted that the FLEX trial of cisplatin/navelbine with or without the EGFR monoclonal antibody erbitux was reported to be positive, demonstrating a significant survival benefit. That’s definitely going to have major implications, since our track record for phase III trials of chemo with or without new drug X was very poor for most of the last several years, until the negative streak was broken by the ECOG 4599 trial with Avastin added to carbo/taxol. Here’s the older scorecard we had:
(Click to enlarge)
Not so good. EGFR inhibitors have been pretty well tested, including both Iressa and Tarceva each in two trials of more than 1000 patients randomized to chemo with or without the EGFR inhibitor, and those trials failed to show a survival benefit overall. But those agents are EGFR tyrosine kinase inhibitors, working on the inside of cancer cells, while erbitux is a monoclonal antibody that works on the outside of the cell against the same target of the EGFR molecule:
FLEX Trial of Chemo +/- Erbitux Shows Survival Benefit
Merck KgAA, the company developing cetuximab/Erbitux, the monoclonal antibody against EGFR, reviewed here) outside of the US, has announced that their pivotal FLEX trial (for First-Line Trial for patients with EGFR-Expressing Advanced NSCLC) is positive, demonstrating a signficant improvement in overall survival, as indicated here. I mentioned it as an important study to define any role for Erbitux in NSCLC, especially since a recent randomized trial I described in a prior post was reportedly negative.
The press release includes no details, just a glimpse of the trial, with a progress report last presented at ASCO 2006 (abstract here). This is a European phase III randomized trial with just over 1000 patients with previously untreated advanced NSCLC that had to have EGFR protein expression by immunohistochemistry (IHC), which is present on about 60-80% of NSCLC tumors. So there was a modest degree of selection of these patients, but a majority of patients would likely be eligible. All patients received doublet chemo with an “old school” combination of cisplatin and navelbine. This is a fine regimen but not commonly used in advanced NSCLC in the US (but still favored as a very good choice in the post-operative setting, since the majority of the best data in this setting is with cisplatin/navelbine). At the time this trial was developed, European oncologists were most commonly giving cisplatin, often with navelbine and gradually giving way in recent years to gemcitabine. Continue reading
Is there a Group That Does Particularly Well with Erbitux in NSCLC?
I wrote in a post several months ago about the ongoing study of the monoclonal entibody against EGFR erbitux (cetuximab) in lung cancer, where it’s role is still up in the air. Unlike the EGFR tyrosine kinase inhibitors (TKIs) iressa and tarceva, which showed no benefit when given concurrently with standard chemo, erbitux has a different mechanism and may still be useful when given along with chemo. As I mentioned in my last post, a phase III trial of carbo/taxane chemo with or without erbitux failed to show any improvement in progression-free survival, but it did actually show a higher response rate in the group that received chemo with erbitux. But perhaps there are particular patients who are likely to gain a lot more with erbitux than others, just as we’ve found that certain groups, such as those with EGFR mutations and never-smokers benefit most consistently from the EGFR TKIs.
I previously described the early results on SWOG Trial 0342 (abstract here), in which over 200 patients with previously untreated advanced NSCLC were randomized to two arms. The sequential treatment arm received 4 cycles of carbo/taxol chemotherapy followed immediately by weekly erbitux until progression of disease, while the concurrent arm received the same 4 cycles of chemo along with concurrent weekly erbitux, then followed by weekly erbitux alone. The schema is shown here:
(Click to enlarge)
The early results (abstract here) suggested that perhaps the concurrent arm did a little better, but neither arm did spectacularly, and it was worth debating whether the results were promising enough to commit to larger future studies. This year, Dr. Roy Herbst from MD Anderson Cancer Center presented more updated results (abstract here). With longer follow-up, the two arms converged together, both looking pretty good, with a median progression-free survival (PFS) of 4 months and overall survival (OS)of 11 months. You can see that the survival curves for the two groups are basically on top of each other:
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
Single-Agent Erbitux Studies in NSCLC
Yesterday I reviewed a series of studies of the EGFR monoclonal antibody cetixumab, or Erbitux, combined with chemotherapy. Overall, these trials are modestly encouraging, without what I would consider to be a potential antagonistic effect when chemo and EGFR tyrosine kinase inhibitors (TKIs) like Iressa or Tarceva. However, we still don’t have studies big enough to establish any role for erbitux. Today, I’ll cover the very limited experience of single-agent Erbitux in advanced NSCLC. Continue reading
EGFR Monoclonal Antibody Therapy in NSCLC: A Focus on Erbitux
Most of the discussion with about inhibiting the EGFR axis in lung cancer has focused on the orally available tyrosine kinase inhibitors (TKIs) that work inside the cells. However, another way to inhibit the cells is by giving an IV “monoclonal antibody” which is a protein that attaches to the outside of the cell at the EGFR target and can block activity. A figure of the two approaches is shown here, with the antibody circled in red:
(Click to enlarge)
Cetuximab, or erbitux, is by far the most studied in cancer. This agent, you may recall, is the one that Martha Stewart was indicted over:
It’s now approved in colon cancer and also in head and neck cancer, but it’s been the subject of much less research in lung cancer than the EGFR TKIs like Iressa and Tarceva. Continue reading
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