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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
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
Avastin in Older Patients: Survival Benefit Not Seen
As described in one of my first posts, Avastin was approved by the US FDA for the first line treatment of advanced NSCLC in patients with non-squamous cancers, no history of coughing up blood, and no brain metastases, based on the positive trial ECOG 4599 (abstract here) that demonstrated a survival benefit for carbo/taxol/avastin compared with carbo/taxol alone. The trial included only active patients with a good performance status, and we saw that while patients lived longer on average with avastin, they also had increased side effects. This leaves us with some open questions about whether sicker and/or older patients would be well served by the combination of chemo with avastin. This year at ASCO we learned something about the value of avastin in an older population.
A friend of mine, Dr. Suresh Ramalingam from the University of Pittsburgh Medical Center, presented data from the ECOG 4599 broken down by patient age (abstract here). To review, the trial divided about 878 patients between carbo/taxol and carbo/taxol/avastin for up to 6 cycles, and then the patients on the avastin arm received maintenance avastin if they didn’t show progression after 6 cycles of chemo/avastin:
(click to enlarge) Continue reading
ASCO Update on Avastin and ED-SCLC Issues
The AVAiL trial in first-line advanced NSCLC, based in Europe, was designed to confirm the role of avastin with chemo using a different regimen of cisplatin and gemcitabine with a placebo or Avastin at 7.5 or 15 mg/mg every three weeks (the European trial was placebo-controlled, unlike the US-based Avastin trial with carbo/taxol). I described it in a prior post that described a glimpse of the results that were reported in a press release a few months ago, but we received more information at ASCO. The presentation noted that both groups receiving avastin had a significantly longer progression-free survival than the folks who received a placebo. The trial wasn’t designed to compare the two doses, but it’s hard not to, because we need to choose just one of them. The hazard ratio (describing the total improvement over time) was more favorable at the lower dose, and I’d say that the curves showed more separation at the 7.5 mg/kg dose. Importantly, there were no clear differences in safety issues between the lower and higher dose, so side effects weren’t obviously dose-dependent. We didn’t see any survival data, which was considered to early to present, but we should see that in the next year, I’d suspect. In the meantime, it appears that there’s a lot of reason to debate whether we should be using the lower dose of avastin that appears to offer the same benefit as a higher dose, or whether we should continue to use the 15 mg/kg dose that has the proven survival benefit with carbo/taxol and that is approved by the FDA.
A couple of other trials also combined avastin with standard chemo options for first-line treatment of ED-SCLC, and we saw that this is generally safe and feasible, with no episodes of pulmonary hemorrhage (coughing up blood), and the results from each of these trials were modestly encouraging, but didn’t hit the ball out of the part. Some of the cancer cooperative research groups are considering moving forward with a larger trial of chemo with or without avastin in the first-line treatment of ED-SCLC.
Another trial in ED-SCLC, out of Europe, compared carboplatin and irinotecan to carboplatin and etoposide, noting a modestly better survival for patients who received carboplatin and irinotecan. Of note, the results with carboplatin and etoposide were a little on the low side, but carboplatin/irinotecan certainly looked like a fine option, and it’s a regimen that I have also used in a clinical trial in SCLC and found that patients generally tolerated quite well and had done similarly to other common regimens. Importantly, most of the more encouraging results we’ve seen with irinotecan in SCLC have come out of Japan, where the drug was developed, and it just so happens that the Asian population has genetic features that are associated with a better ability to tolerate irinotecan compared to those of European or African descent. So seeing a trial in which irinotecan does well outside of Asia is particularly notable, as we are recognizing that there are good reasons to repeat trials with different populations to check if the best treatments in Asia are truly the best treatment in North America or Europe or elsewhere.
The most interesting work on the ED-SCLC front was the finding from a European cancer cooperative group, the EORTC, that prophylactic cranial irradiation (PCI) significantly improved survival for patients who had either a complete or even just a partial response to first-line chemo.
I’ll add more highlights soon.
EGFR inhibitors (Tarceva, Iressa) and Stomach Acid
Several members have raised questions in the last several weeks around the question of whether antacids like garden variety Rolaids or Tums, a class of drugs called histamine H2 blockers like zantac and tagamet, and also proton pump inhibitors (PPIs) like prilosec (the “magic purple pill”), protonix, nexium, etc. that effectively shut down stomach acid may actually be problematic if taken in combination with Iressa or Tarceva (I’m going to focus primarily on Tarceva here, since that’s the drug marketed in the US right now). This issue isn’t one that has been highlighted in the general research and teaching about these oral agents. We do know that absorption is variable, but the reason it is recommended that they be taken on an empty stomach is that it’s more predictable in that setting. Taking these agents with food tends to increase absorption, but unpredictably, so the best way to have a good idea of what’s going into the body is to take the recommended amount (or a dose reduction, as needed) on an empty stomach.
It’s certainly understandable that the absorption from the stomach and gastrointestinal tract be moderated in part by stomach acid or lack thereof, since it’s the job of stomach acid to help digest food (it’s not just to cause heartburn), but there has never been any instruction on having antacids and/or PPIs be considered contra-indicated medicines (advised to not be taken at the same time). In fact, the Iressa package insert does mention that zantac and sodium bocarbonate (antacids), given to keep the pH above 5 (outside of the highly acidic range, which is the low numbers like 1-2), reduce Iressa absorption by 44% in one of the studies by the manufacturer (AstraZeneca). Member NeilB was kind enough to e-mail me this link to a chart in a summary article about the EGFR inhibitors, which notes some of the key drug interactions observed with EGFR tyrosine kinase inhibitors like Iressa and Tarceva. Another official document summarizing extensive pharmacologic information on Tarceva tablets (here) also documents that tarceva absorption appears to be diminished in the absence of an acidic stomach environment and suggests that “caution should be exercised when these medicinal products are prescribed with erlotinib” (Tarceva) (page 19 of this pdf document). Continue reading
Survival and Quality of Life (QoL) in Advanced Lung Cancer: A Devil’s Bargain?
A member recently asked me whether treatment in the second-line or later setting for advanced lung cancer would potentially improve survival at a cost of quality of life, or whether patients can benefit not only in terms of how long they live but also how they live during that time. Since advanced lung cancer, both NSCLC and SCLC, aren’t generally able to be approached with curative intent, it’s important for the treatment not to be worse than the disease. Ideally, patients will even feel better with treatment, rather than have to choose between quality of life (QoL) and quantity of life. However, it’s important to note that the oncology community has not focused on QoL measures nearly as much as survival measures. Partly, this has been because measuring QoL requires expensive and time consuming surveys and/or other measures, and they have not been perceived as enough of a key to FDA approval, patient focus, or physician interest. So here’s a few leads. Continue reading
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