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. One key trial that is coming out in the next year is called the AVAiL trial, being done in Europe. Similar to the trial that I described earlier (known as ECOG 4599) in a prior post, the AVAiL trial compares chemo alone to chemo with Avastin. The differences between this trial and the ECOG 4599 trial is that the chemo is cisplatin and gemcitabine, probably the most commonly used chemo combination in Europe. This will also have three arms of about 350 each, for a total of 1050 patients. One will be chemo alone, one will be the same chemo with Avastin at a lower dose of 7.5 mg/kg, and the last arm giving chemo and Avastin at 15mg/kg as was tested in the US-based ECOG trial. So this trial will be important to confirm that Avastin improves survival in another big trial, to check whether you need the higher dose or whether a lower (and cheaper) dose works as well and/or is less safe, and also to ensure that women get a benefit, which remains somewhat controversial in reviewing the results of the ECOG 4599 trial. We will also be able to assess the safety, specifically the bleeding risk, in another large trial. We hope to know the answers to these questions within the next year.
Another interesting combination is to combine targeted therapies together. This is an appealing concept because targeted agents with different targets may combine to be particularly effective, and potentially with very favorable and modest side effects. For example, the combination of Avastin and Tarceva can target both the tumor itself and its blood supply, as shown in the figure below.
(click to enlarge)
This combination was tested in an early small study by investigators at MD Anderson Cancer Center and Vanderbilt University and looked very promising, with more than half of the previously treated patients living more than a year and nearly one in five patients showing a significant tumor response (50% shrinkage or better). There were no severe bleeding complications. However, with only 40 patients, all treated at an excellent tertiary cancer center, it is not possible to say that these encouraging results were not due to the fact that these were selected patients who do not represent a “real world” experience.
The results of a larger trial were presented at our major US oncology meeting, ASCO (American Society for Clinical Oncology) in June, 2006. This trial included 120 patients who had received just one line of prior platinum-based chemotherapy, and it excluded patients who would have been ineligible for the ECOG trial, so no patients with predominantly squamous cancers, or brain metastases, or on blood thinners, or with a history of coughing up blood (hemoptysis) were allowed to participate, and nobody could have received prior avastin. Patients were then randomized to one of the two FDA approved second-line chemo options (taxotere or alimta) alone, or the same chemo with avastin 15 mg/kg IV every three weeks, or a third arm with the targeted therapy combination of avastin and tarceva with no chemo.
Although the trial is not big enough to show conclusive answers, the two arms that received avastin had a higher response rate, a notably longer time before progression than the chemo alone arm, and a better overall survival than chemo alone. Both the chemo/avastin arm and avastin/tarceva arms had very similarly encouraging results. Importantly, there were rare fatal side effects of treatment in all groups, including chemo alone, including bleeding events in both of the arms that got avastin. Overall, the avastin/tarceva combination had fewer side effects, with 10% of patients stopping treatment due to side effects vs. about 25% in both the chemo/alone and chemo/avastin arms.
So the available results suggest that while avastin can have rare serious or even fatal side effects in previously treated patients (although no prior treatment with avastin), there is a good suggestion that it can improve outcomes in avastin-eligible patients. The combinations of avastin and second-line chemo and avastin/tarceva seem to come out similarly, with perhaps a suggestion of better tolerability in the non-chemo combination. Further studies, many likely to become available in the next couple of years, will give us more answers on how avastin combines with a range of current treatments in advanced NSCLC.
posted by Dr. West @ 10:17 pm link to this post
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November 20th, 2006 at 10:02 am
Dr. West,
Thank you very much for this forum. It is a great help.
I wanted to ask why Avastin cannot be used in squamous cell. I understand there is some problems with bleeding but why is that different for squamous vrs other nsclc’s
Thanks Donna
November 20th, 2006 at 10:52 am
avastin is being used as maintenance therapy for nsclc. Sutent has been approved for kidney cancer and gist and works by a similar mechanism but is an oral agent. It is also cheaper than avastin; would it be worth trying sutent for maintenance?
Jennie
November 20th, 2006 at 1:57 pm
I was interested in any information concerning the use of Avastin for maintenance for nscl cancer. That is the recommendation I am receiving. I have tried to find something even regarding longer term use with colon cancer, but cannot find anything. Also, was trying to find if there are any known parameters of who this drug works for. Thanks so much for the information. It is great to have something that is current and reliable.
Myrtle
November 20th, 2006 at 11:13 pm
In response to Donna’s question, the issue with avastin in squamous cell cancers is safety. In a smaller trial that was conducted before the bigger ECOG 4599 trial, they allowed patients with squamous cancer and found that 4 of 13 patients (31%) had fatal or near fatal bleeding complications, vs. only 2 of 53 patients (4%) with non-squamous cancers. We don’t know the details of why, but because of the risk of bleeding, patients with squamous cancers were excluded from the later trial, the FDA approval does not include patients with squamous NSCLC. Further clinical trials are carefully assessing the safety in previously treated patients who have peripheral (near the outer edge of the lung, since the major blood vessels are in the center of the chest) squamous cancers. I would not treat patients who have squamous NSCLC with Avastin outside of a clinical trial to carefully evaluate it, given the risk of serious bleeding complications.
Myrtle asked about maintenance avastin, which remains a controversial issue. The ECOG trial on which the FDA approval was based gave maintenance avastin to patients on the avastin arm who didn’t have cancer progression after 6 cycles of chemo with avastin (6 cycles is pretty much the outer limit of what we’d consider the point of diminishing returns with first-line chemo). 21% of the patients on that arm were still on maintenance avastin without progressing one year after starting the trial. It was only 9% for the patients who received 6 cycles of chemo alone and no maintenance avastin.
In the earlier, smaller trial of Avastin in NSCLC, the patients who got chemo alone could switch over to single-agent avastin after progressing on chemo alone. They didn’t have any significant tumor shrinkage with avastin alone, but several patients were on avastin alone for many, many months before progressing. However, given the cost and potential for side effects, the question of the added value of maintenance avastin is still controversial.
Finally, Jennie asked about sutent. Oral antiangiogenics like this and AZD2171 may very well be additional tools, and they could potentially improve on avastin by either improving survival more, being usable in a broader population, having a lower risk of complications such as serious bleeding, or just being as good as avastin but cheaper. Right now, sutent has been tested in previously treated patients with NSCLC and had a pretty encouraging response rate of 10%, but it had some toxicity problems, including a few patients who had fatal bleeding complications. I definitely think it’s worht studying further, and in fact I’m running a trial at my center of sutent in patients with BAC or never-smokers with adenocarcinomas (starting very soon, I hope). But I wouldn’t use it yet outside of clinical trials, when there is a higher level of evidence in favor of other drugs.
I hope that helps. Thanks for your interest.
November 28th, 2006 at 11:46 am
Thank you Dr West for your reply. Do you know if any studies are planned to investigate why bleeding occurs with SC or is it assumed that because its central that it likely involves major blood vessels unlike the more peripheral cancers?
My mom died of squamous cell in 2003 and I’ve read of the strong hereditary link between 1st degree relatives and SC. I am also a former smoker. Doesn’t hurt to stay informed about the latest treatments
Donna
November 28th, 2006 at 4:51 pm
Donna,
There’s plenty of work being done to see if we can minimize the risk of bleeding with squamous cell by radiating the tumor first, or monitoring for cavitation (hollowing out of the center of tumor). So far, it seems to not just be the central location, because we haven’t seen much bleeding thus far with other central tumors like small cell lung cancer. It seems to be a combination of location and how responsive the cancer is to avastin (it seems to respond extremely well, but potentially opening up a wall of a nearby blood vessel as it responds - NOT GOOD).
I’m glad you’re a “former” and not current smoker. That’s already the best thing you can do to minimize your risk. I think it’s great for you to stay informed, but I hope you never need these treatments.