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Maintenance Avastin after First-Line Chemo/Avastin: A Controversial Standard of Care
I’ve recently received some questions about the advantages and disadvantages of maintenance Avastin as a single agent for patients after completion of 6 cycles of first line chemo and avastin together for avastin-eligible patients. While this is generally considered to be a standard of care, many oncologists question whether it should be done. It’s worth looking at how that standard came about and the strength of the evidence for it.
The trial that led to the FDA approval of avastin was called ECOG 4599 (NEJM abstract here), and in that trial 878 patients with previously untreated advanced NSCLC (limited to those with nonsquamous cancers, no brain metastases, no history of coughing up blood, and not on coumadin or other blood thinners) were randomized to carbo/taxol for six cycles or the same chemo with avastin 15 mg/kg every three weeks. For the patients who didn’t show progression of their cancer after six cycles of chemo, the protocol had patients stop the chemo and continue on “maintenance” avastin every three weeks, until they showed evidence of progression of their disease. The trial design is as shown here:
(Click to enlarge)
Described in more detail elsewhere, the trial was positive, with a significantly higher response rate, progression-free survival, and overall survival seen in the recipients of chemo with avastin:
Based on the overall survival benefit, the FDA approved avastin in this particular population, to be given with carbo/taxol, then followed by maintenance avastin. How much of the benefit was from the chemo and Avastin combination, overlapping for 6 cycles, and how much of a contribution was from the maintenance avastin? We don’t know. We just know that if you give avastin the way it was done on the ECOG trial, survival is improved, so that’s the way most experts advocate doing it. We don’t have trial results in which avastin is given with chemo but then there’s no maintenance therapy.
For what it’s worth, 53% of the patients on the trial had no progression of disease after 6 cycles of chemo/avastin and went on to receive maintenance avastin every three weeks. Half of those patients went on to receive more than 5 cycles of avastin before progressing. Importantly, some of the problematic side effects of the chemo/avastin combination, most notably the significant drops in blood counts and the associated risk of infection, pretty much went away when the chemo ended. Importantly, while we haven’t seen responses of lung cancers (or really other cancers) to avastin as a single agent, we have seen patients who had prolonged lack of progression. In a smaller trial that led to the development of the larger ECOG trial (abstract here), patients who were assigned to a chemo alone arm could cross over to high-dose avastin (15 mg/kg IV every 3 weeks) after they progressed. Of the 32 patients on the chemo alone arm, 19 received avastin. They didn’t show tumor shrinkage, but five of them went more than 6 months before showing progression, and one patient went twice as long on avastin alone without progression as he did on chemo as first line therapy before progressing (120 vs. 60 days). Here’s a survival curve in which the horizontal lines at the bottom represent the length of time that cross-over patients remained on avastin without progression:
Overall, in both the smaller phase II and the larger phase III experience, some patients went a remarkably long time before progressing, far more than you’d expect with chemo alone, yet these patients stopped chemo after 6 cycles and were maintained on avastin alone.
But what we don’t have is results of a trial in lung cancer in which patients received chemo/avastin and then no maintenance, to be compared with patients who went on to maintenance avastin (there was a European trial in colon cancer in which maintenance avastin was not included; the trial had less impressive results than expected, so some people extrapolate that the lack of maintenance avastin could be the reason). There are several potential downsides to ongoing avastin. First, there’s the cost, which if you have a significant co-payment to make, can really add up. Then there’s the safety risks, and while the decreased blood counts and infectious risks go down after chemo ends, risk of bleeding, high blood pressure, and other potentially problematic side effects can continue. And there’s the open question of whether it would be better to stop avastin after the chemo and then restart it with a new chemo or tarceva once a patient moves to a new line of treatment. Does a cancer become completely resistant to avastin, or might avastin modify the activity of many different anti-cancer drugs it’s given with? If the latter, it could be beneficial to continue it from one line of treatment to the next, the way oncologists routinely continue Herceptin for certain patients with breast cancer as they move from one chemo to another. But we have no data to answer these questions.
There are risks, there are costs, and there are potential benefits. Many oncologists are skeptical of the benefits of the maintenance avastin and think that the trial design for ECOG 4599 set up a convenient way to increase longer-term use of the very expensive avastin. It would be great to have a head-to-head trial of chemo/avastin without maintenance avastin to chemo/avastin followed by maintenance, but such a trial isn’t coming anytime soon. Until then, the majority of experts are advocating treating patients the way they were treated in the ECOG trial. But it’s possible that maintenance chemo doesn’t add much, especially if it’s restarted when a patient moves to their next line of therapy.
I’ll let you know if we learn anything more. At this point, I’m continuing with avastin and not continuing the avastin after patients have progressed and are moving on to second-line therapy.
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:
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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:
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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
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.
Emerging Results with Avastin: AVAIL Trial Press Release
Last week, Genentech had a press release in which they disclosed some potentially important information about a large randomized trial being done in Europe with Avastin. This study, known as the AVAIL trial, enrolled just over a thousand first-line patients with advanced NSCLC to receive their most common standard chemotherapy, cisplatin and gemcitabine, alone or in combination with Avastin at either of two dose levels, 7.5 mg/m2 and 15 mg/m2. The basic design is as shown in this figure:
(click to enlarge)
Just as in the ECOG 4599 trial (NEJM abstract here), the patients who go through 6 cycles of chemo wihout progression continue to maintenance avastin, until the time of progression, if they received it with chemo. As in the ECOG trial, the patients on the trial was not the entire NSCLC population, but the subset who don’t have squamous cancer, brain mets, problematic high blood pressure, or a need to be on blood thinners. Unlike the ECOG trial, the AVAIL trial also excluded patients who had “central” tumors, out of concern that the location of the tumor was important for bleeding risk. Thus far, we have concentrated on the histology (microscopic appearance) of the NSCLC tumor as more important than the location. In fact, most squamous tumors are also central. Continue reading
Avastin Studies Beyond its Current FDA Approval
As mentioned in prior posts, the anti-angiogenic monoclonal antibody Avastin (bevacizumab) is now approved in first-line treatment of advanced NSCLC in combination with carboplatin/paclitaxel chemotherapy. Among the very interesting questions is whether Avastin should be added with other active drugs for NSCLC. Most of us in the field strongly suspect that the survival benefit from Avastin will also be the case with other types of therapy, but we’re only starting to get the evidence to address this. Continue reading
Where do we go from here with Avastin?
Although Avastin has been approved for first-line treatment of advanced NSCLC, at this point it cannot be universally employed. Patients with squamous cancers account for something in the range of 30% of patients, while patients with brain metastases amount to about 10-15% of patients. Another 5-10% may have hemoptysis, or the symptom of coughing up blood, and many others are on therapeutic blood thinners for a history of blood clots or atrial fibrillation. The trial of Avastin in lung cancer (called ECOG 4599) also did not include patients who had a marginal performance status, defined as being able to care for oneself but not able to work, and patients moderately limited in how active they can be, whether due to fatigue or shortness of breath or other issues, account for a lot of patients in the real world. We also still have trouble predicting which patients will have bleeding complications that can be serious or even fatal, even if only patients who meet the eligibility criteria are given Avastin. We are somewhat concerned about the risk of bleeding in patients with cavitary lesions (with an empty space in the middle, shown below)
and those with central cancers near major blood vessels, but those patients would be eligible for Avastin according to the trial and the approval guidelines. Finally, while most oncologists expect that Avastin would give similar benefits if added to different chemo regimens, we don’t have proof of that yet, nor do we know with certainty that it is safe when combined with other chemo agents.
So trials are now being done to clarify whether Avastin can be given safely to patients with hemoptysis who have received radiation to treat that issue, and to patients who have squamous cancers who may have received prior treatment with radiation to minimize bleeding risk. Other trials are evaluating Avastin in patients with treated brain metastases. Multiple trials are carefully assessing whether the patients with central cancers or cavitating tumors are at significantly greater risk for bleeding, and also will clarify whether women show a benefit with Avastin outside of the ECOG trial. Multiple ongoing trials are combining Avastin with other chemo drugs to ensure that it is safe in other regimens.
Avastin with Chemo: Standard of Care for a Subset with Advanced NSCLC
Avastin (bevacizumab), an antiangiogenic agent that works by blocking the blood vessel stimulating factor vascular endothelial growth factor (VEGF), has already been FDA approved and commercially available for colon cancer, but it has now been approved by the FDA for first-line treatment of non-squamous NSCLC in combination with standard chemo of carboplatin and paclitaxel (taxol). This is because the combination of chemo and Avastin was found in a large randomized trial publsihed in the New England Journal of Medicine (abstract here) that the combination improved survival when combined with chemo alone for patients with advanced/metastatic NSCLC who hadn’t received chemo before. This trial, with nearly 900 patients, compared carboplatin and paclitaxel (Carbo/Taxol) alone to the same two-drug chemo with Avastin every three weeks, and people who went through six cycles of chemo and Avastin without having progression of disease went on to receive Avastin alone as maintenance therapy until their cancer showed progression:
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