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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:
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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
Single-Agent Zactima/ZD6474 in Advanced NSCLC
As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I’ll focus on the research that gave it as a single agent and where it has led us in terms of current trials.
As I mentioned in my previous post, an early phase I trial just trying to establish an optimal dose showed some activity zactima as a single-agent, as 4 of 9 patients with NSCLC in a Japanese trial showed significant tumor shrinkage on zactima. From there, Dr. Ron Natale at Cedars-Sinai Medical Center in Los Angeles led a randomized phase II trial (abstract here) that compared zactima as a single agent at the higher dose of 300 mg by mouth per day, pretty close to the maximal feasible dose, to iressa at 250 mg by mouth daily. The trial was designed to allow cross-over to the other drug after patients experienced either progression or problematic side effects. So the design was as shown here:
(click to enlarge) Continue reading
Zactima (ZD6474) in NSCLC: Part I
In prior posts I’ve described the idea of combining targeted agents like Tarceva and Avastin, but there are also some single agents that inhibit multiple targets within cancer cells. I’ve described sorafenib/nexavar in a prior post. Today I’ll focus on another multi-targeted agent, known previously as ZD6474, and with a marketing name of Zactima. Similar to the combination of avastin and tarceva, this single oral drug is anti-angiogenic and also blocks EGFR. Although less well studied, it also blocks a protein called RET and can inhibit cell proliferation that way.
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To be more specific, whether Zactima has anti-EGFR activity depends on the dose: it is primarily an anti-angiogenic drug at lower doses, such as 100 mg per day. At higher doses starting around 300 mg, it inhibits EGFR as well. 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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