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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
Biologic and Molecular Correlates of Clinical Benefit in French Trial of Iressa in BAC
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:
(Click to enlarge)
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.
France Weighs in on EGFR Inhibitor Therapy for BAC; Mucinous vs. Non-Mucinous BAC
I reviewed a couple of presentations on bronchioloalveolar carcinoma (BAC) at ASCO 2007, including one by Cadranal and colleagues in which patients with advanced BAC received single agent Iressa (abstract here). This study enrolled 88 eligible previously untreated patients with advanced BAC or adenocarcinoma with BAC features, about 55% women/45% men (typical for BAC trials to have slightly more women than men, unlike other types of lung cancer) to receive Iressa at 250 mg daily. They did a repeat CT scan three months after starting Iressa and looked at the disease control rate (DCR), the combination of responses and stable disease, in patients at that point. The response rate of 13% and disease control rate of 29% were just a little lower than other trials of EGFR inhibitors in BAC (one of Iressa at 500 mg daily in the US that I led (abstract here), and another of Tarceva at 150 mg daily that was led by Drs. Vince Miller and Mark Kris at Memorial Sloan Kettering (abstract here)). While the French group didn’t report a median survival, they did report a one-year survival of 52% that was right in line with my earlier US-based study, so it didn’t appear that a lower dose of Iressa was associated with a worse outcome. Here are the available efficacy results for the three similar trials, side by side:
(Click to enlarge)
As we’ve seen as a recurring theme, in all of these trials women did somewhat better than men, never-smokers did better than former or current smokers, and the people who developed a rash also did better than the ones who didn’t develop skin toxicity.
One way in which the French study moved things along in the world of BAC was by noting differences in outcome between the half of patients with mucinous BAC vs. those with non-mucinous BAC, among the 65 who had tissue available for study. They found that the folks who had non-mucinous BAC did considerably better on the Iressa trial than those with mucinous BAC:
That would perhaps just be an interesting curiosity, except that we saw the same significant difference, with significantly better results with Iressa in the patients on our SWOG trial who had non-mucinous instead of mucinous BAC (reported in a separate abstract here):
We haven’t seen any analysis like this yet from the Memorial Sloan Kettering trial with tarceva, but with the two trials that have looked at this issue showing the same exact finding, it does seem that Iressa, at least (and I’d suspect it’s the same with Tarceva) is particularly helpful with the non-mucinous form of BAC. Interestingly, the small study of taxol (infused slowly over four days; abstract here) actually showed that the responses were in patients with mucinous BAC, and that there were no responders with non-mucinous BAC, although the actual number of patients who had tumor tissue available for analysis was very small. This remains an open question, but it’s possible that mucinous BAC may be more responsive to chemo and that non-mucinous BAC is more responsive to the EGFR inhibitors like iressa and tarceva.
We’ll be studying this a lot more in the future, but at this point we might actually want to begin to subdivide BAC into different groups to see if we can refine best treatment plans by whether patients have the mucinous or non-mucinous subtype. They appear to actually be somewhat different diseases.
Risk of Complications when Avastin Combined with Chest Radiation
After Avastin was found to produce a survival benefit when combined with chemo in advanced NSCLC, it became increasingly appealing to try to see if adding Avastin in earlier stages of lung cancer, both SCLC and NSCLC, where it might increase the cure rate. I’ve described how it’s being studied in a trial with post-operative chemo (prior post here), but another place where it’s being studied in the potentially curative setting is locally advanced NSCLC and LD-SCLC. However, a trial of Avastin combined with chemo and radiation for LD-SCLC was actually stopped early due to the appearance of an unusual and serious complication that may be a real problem, leading to a great deal of caution in this line of research.
As described here, a trial in LD-SCLC that combined carboplatin, irinotecan, and avastin with radiation stopped after 29 patients were enrolled, because two confirmed cases of tracheo-esophageal (T-E) fistula (a connection between the trachea (windpipe) and esophagus) were confirmed, of whom one died, and a third patient also died with a suspected but not confirmed T-E fistula. So if there were about 10% of patients with a life-threatening or fatal side effect, that’s a red flag, and this led the manufacturers and the FDA to issue a warning about it. The official packaging information will also reflect information on this issue in the future. At least six other cases of T-E fistulas associated with chemo or radiation, have been reported to the company, and others may come as this information becauses available. In the lung cancer conference I co-chair here, my colleagues and I presented a patient who was treated elsewhere and had received prior chemoradiation, then chemo and avastin, and developed an enormous fistula that was sent to our center to manage. Our surgeons noted that this was the largest T-E fistula they had ever seen in their careers, so at our meeting we publicized the case and raised the question to our participants whether thay had seen similar cases (they hadn’t). So the closure of that trial didn’t come out of left field for me. We suspected that avastin could be related to development of fistulas in patients who received radiation, but one case doesn’t make a trend. We’re providing details of our case to the company. Continue reading
Integrating Avastin into Treatment of SCLC
In a talk at ASCO 2007, I was asked to present some commentary on a couple of phase II, single arm trials of patients with ED-SCLC that were reported by two different cancer cooperative groups in the US, each adding the anti-angiogenic agent Avastin (bevacizumab) to standard chemotherapy options in this setting. One trial, CALGB 30306 by Ready and colleagues (abstract here), added Avastin (15 mg/kg) every three weeks to a chemo regimen of weekly cisplatin and irinotecan (camptosar, CPT-11), each given two weeks out of a three week cycle, for up to 6 cycles, with no “maintenance” avastin alone after stopping the chemo. The second, ECOG 3501 by Sandler (the same Alan Sandler who led the advanced NSCLC trial ECOG 4599 that led to the FDA approval of Avastin in lung cancer) and colleagues (abstract here), combined Avastin at the same dose every three weeks with cisplatin and etoposide, stopping the chemo after four cycles, but continuing with maintenance avastin alone until patinets showed progression. Interestingly, these exact regimens, including the same schedules and doses of the chemo drugs, were compared to each other in a study by Nasser Hanna and colleagues that was published in 2006 (abstract here), so the performance of these chemo regimens in this phase III trial (that showed no significant differences in activity) can serve as a benchmark of what we should expect the chemo to do without avastin. Here’s a summary of the two trials side by side, along with the general profile of the patients in each trial:
(Click to enlarge)
As is typical for other lung cancer trials, patients with a history of coughing up blood (hemoptysis) or with evidence of brain metastases were not eligible for these studies. Each enrolled a little more than 60 patients. Continue reading
New Trial Starting, Studying Avastin with Adjuvant Chemo
At long last, and after years of planning, a new large phase III randomized clinical trial is getting underway to determine whether adding avastin to chemotherapy as post-operative (adjuvant) treatment for early stage NSCLC provides added benefit compared to chemotherapy alone. This trial, led by the Eastern Cooperative Oncology Group (ECOG) and with the principal investigator Heather Wakelee of Stanford, is designated E1505 and will randomize 1500 patients with stage IB (tumors of 4 cm or larger only) or stage II or IIIA NSCLC to receive four cycles of any one of three chemo regimens alone or with avastin, and the avastin arm will also receive ongoing avastin for up to a year:
(Click to enlarge)
Avastin is of great interest in this setting because adding avastin to chemo improved survival for eligible patients with advanced NSCLC by a couple of months (post here), and perhaps a better result in post-op treatment for early stage, surgical disease would translate to a significant increase in the actual cure rate for NSCLC. Continue reading
Trial Testing PCI for NSCLC Closing Early
In a previous post I described the open question about whether patients with locally advanced NSCLC should receive prophylactic cranial irradiation (PCI) after completing chemo and chest irradiation. The benefit of PCI for LD-SCLC is established, and it is a standard of care in that setting, and a new report from ASCO 2007 that I described in a recent post also highlights the value of PCI for patients who respond to chemo for ED-SCLC. Why is this approach tempting for locally advanced (stage III) NSCLC? Because we see 20-40% of patients go through chemo/radiation and then have recurrence in the brain first, or brain only, because the brain can be a sanctuary site where our chemo can’t effectively get in and eradicate micrometastatic disease our scans can’t pick up. But the few previous trials that have evaluated PCI in NSCLC haven’t shown any real benefit, although they weren’t large enough to say anything meaningful either way; given the possibility (small, but real) of real detrimental effects that can be long-lasting from PCI, most oncologists have not been inclined to recommend PCI routinely in this setting.
The Radiation Therapy Oncology Group (RTOG) has been trying to answer this question with the clinical trial designated RTOG 0214, which I described in a prior post, but basically randomizes patients to either PCI or observation after standard treatment for locally advanced NSCLC. Unfortunately, I just learned that this trial will be closing early, due to slow accrual (a common problem for trials that randomize patients to treatment or no treatment, which patients often don’t want to go on) with about 350 patients enrolled thus far. It was designed to enroll over 1000 patients, so that it could detect a difference in survival, but at the lower enrollment of around 350 patients should still be able to detect an improvement in rate of development of brain metastases, and it may also still show survival differences. If we see just trends, though, it likely will not be enough to change our treatment practices, and we may have missed our best chance to answer this question definitively and potentially improve patient outcomes for locally advanced NSCLC.
The Argument For A Non-Surgical Standard of Care for Stage IIIA N2 NSCLC
In my last post I covered much of the controversy about whether patients with stage IIIA, N2-node positive NSCLC should be treated with induction therapy (chemotherapy or chemo/radiation) followed by surgery, or an alternative approach of chemo along with radiation delivered at a definitive dose (curative, not just the supplemental, lower doses used in induction therapy). In fact, while there are some flaws in the analysis that suggests that patients who require a lobectomy do better with surgery vs. without it, I really didn’t disagree with Dr. Swisher, the surgeon who provided the pro-surgical view, that a subset of stage IIIA patients are particularly well served by receiving the most aggressive approach, including surgery.
My main counterpoints were these:
1) The patients viewed as most likely to benefit from surgery are currently the ones who respond very well to induction chemoradiation or chemo, specifically the ones who clear their mediastinal lymph nodes. I’ve described this issue in a prior post, and some of the highlight slides/figures are reproduced here:
(click to enlarge; mediastinal clearance after chemo alone was as important as whether the tumor was completely resected in predicting overall survival)
(in another trial of induction chemoradiotherapy, survival was remarkably better for the patients who had mediastinal sterilization before surgery). Continue reading
The Great Debate: Should Surgery be the “Standard of Care” for Stage IIIA NSCLC with Mediastinal Nodes?
It’s over, and I won (did you doubt me?). As I mentioned in a recent prior post, today I spoke at the Eighth International Lung Cancer Congress, where I was assigned the topic of speaking in favor of chemo/radiation as the more appropriate standard of care, with the opposing view, that surgery is the standard, taken by the esteemed Dr. Stephen Swisher, thoracic surgeon (and actually Chair of the Department) at the MD Anderson Cancer Center in Houston.
Now in truth, we didn’t differ very much in our perspectives. One key point we agreed on completely is that the stage of IIIA N2 NSCLC is a very heterogeneous group, ranging from some patients with just microscopic involvement of a single lymph node in the mediastinum (mid-chest, between the lungs) to multiple lymph nodes at multiple areas of the mediastinum that are enlarged and even bulky (more than about 2 or definitely 3 cm). In fact, within that range, outcomes are very different, with the group who have a single area of non-enlarged lymph nodes that have cancer involvement just at the microscopic level having a much better prognosis than those with enlarged nodes or with more than one mediastinal area involved:
(Click to enlarge) Continue reading
Chemotherapy for Mesothelioma
For many years, patients with malignant pleural mesothelioma (MPM) were often not offered treatment. Surgery was offered to rare, selected patients who tended to be much younger and more fit than a typical patient with MPM, but we’ll talk about surgery later. Chemotherapy was only very inconsistently offered to the vast majority of unresectable patients with MPM, because it was not felt to clearly be beneficial. This is pretty similar to the view of advanced NSCLC until the mid- to late-1990s. Fortunately, studies over the past several years have clarified that chemotherapy can improve survival for MPM.
Up until Alimta was approved, the regimen that was most commonly used for MPM was cisplatin and gemcitabine. This combination was reported in a trial of 21 patients with advanced MPM (abstract here) to produce an objective response rate of 48%, median response duration of about 6 months, and a median survival of about 9 month — not amazing, particularly in overall survival, but the best we had. In fact, several later trials suggested lower response rates and not as impressive results overall, but we used it because we wanted to help and patients needed treatment, and there had never been any reasonably large trials undertaken for MPM, so we really didn’t have any good evidence for or against the value of treatment. That changed when a large study evalauted the utility of cisplatin and alimta together.
At ASCO 2007, Nick Vogelzang and colleagues presented a plenary session abstract on mesothelioma (here) that was subsequently published as a full publication in 2003 (abstract here). The first major MPM trial ever, it enrolled 456 patients from 114 sites in 19 different countries. It had a straightforward design, randomizing patients to the likely minimally active cisplatin alone in one arm, and cisplatin/alimta in the other arm:
(Click to enlarge)
It was a plenary session presentation because the combination of cisplatin and alimta led to a significantly higher response rate (41% vs. 17%, p < 0.001), but also a significantly higher median survival by 3 months (12.1 vs 9.3 months, p < 0.02), as well as a nearly two month difference in median time to progression (5.7 vs. 3.9 mo, p < 0.001). The differences are shown here, with pretty striking differences (gaps) on the survival curves:
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