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And Another One Bites the Dust: Avastin in Small Cell Lung Cancer
Fri, 10/16/2009 - 13:37
Author
Dr Pennell

Keeping with the weekly theme of small cell lung cancer (SCLC), I thought I would comment on a newly published study by the Eastern Cooperative Oncology Group (ECOG), ECOG 3501.

As Dr. Sanborn so aptly described earlier this week, small cell lung cancer has stymied the oncology establishment for decades. This horrible disease is treated today almost exactly the same way it was treated 20 or even 30 years ago, with only minor advances being made in decreasing toxicity of treatment and with prolonging survival with radiation. The only blessing during this period has been that the incidence of SCLC continues to fall in developed countries, although my guess is that the rise in smoking in developing countries like China and India will keep those of use who treat SCLC in business for a long time.

As Dr. Sanborn pointed out, the lack of advancements is not for lack of trying. Numerous combinations of chemotherapy and novel, targeted agents have been tested in this disease and have uniformly been disappointing. Small cell has destroyed more careers than Jessica Simpson (thank you, folks, I’ll be here all week).

Perhaps one of the reasons “targeted” therapies have not worked well to date is the lack of a good target to aim at. Whether it be p53, hedgehog, matrix metalloproteases, or bcl-2, there is no lack of upregulated genes in SCLC that sound promising on paper. However, I have yet to see a single gene, protein, or pathway that, if inhibited, would have major impact on the disease. If cancer oncogenes were represented as a graphic equalizer on a stereo, then SCLC has turned all the knobs up to 11, making inhibiting one of those pathways unlikely to do much.

graphic_equalizer_studio_2005_2718

So on the surface, testing a drug like Avastin (bevacizumab) in SCLC makes a lot of sense. Avastin is an antibody against vascular endothelial growth factor (VEGF), and is commonly used in combination with platinum chemo in non-small cell lung cancer (as well as in breast, colon, kidney, and brain cancer). In my opinion, much of the activity of Avastin against cancer comes from its ability to “normalize” tumor blood vessels so that chemotherapy can reach more of the cancer and thus can be more effective. Avastin rarely has much activity by itself.

So, by using a targeted agent that targets tumor blood vessels rather than the cancer cells themselves, perhaps Avastin would break the streak of disappointing results in SCLC. There have already been a few small trials looking at the role of Avastin in this disease. Two trials have added Avastin to chemotherapy and radiation in limited stage SCLC, but both seemed to indicate that there was an unacceptably high rate of tracheoesophageal fistula formation, a potentially life threatening connection between the esophagus and the lungs that will likely halt this line of investigation.

Avastin has also been tried in phase II trials in combination with chemotherapy for extensive stage SCLC, which brings me back to ECOG 3501. In this trial, published online this week in the Journal of Clinical Oncology, 63 patients with extensive SCLC were treated with cisplatin and etoposide (the standard chemotherapy for this disease for a long time) plus Avastin. The primary endpoint was the percentage of patients alive and without disease progression (PFS) at 6 months, aiming to beat what would be expected for this group of patients historically. Given how consistent the survival is with extensive SCLC (typically 9 to 11 months in large trials), historical controls are actually pretty reliable for this disease.

The addition of Avastin had minimal increases in toxicity over what one would expect with chemo alone, which is important to show since one hallmark of Avastin is that it does seem to increase the side effects of chemotherapy. There is also a concern with Avastin about serious pulmonary bleeding, and only one patient had serious but non-fatal bleeding in this sample. There were no episodes of TE fistulas in this trial without radiation. The overall PFS in this trial was 4.7 months, the 6-month PFS was 30.2%, and the overall survival was 10.9 months in this group.

The authors argue that these numbers are better than historical controls and that this combination deserves further investigation. I myself am unimpressed. Phase II trials are expected to have better numbers than phase III trials, and an 11 month survival is not unheard of in SCLC trials using chemotherapy alone, so in my mind this is hardly a sign of great promise. Nonetheless, these will be a randomized trial done comparing chemo to chemo plus Avastin in SCLC based on these results.

Why didn’t Avastin have a greater effect? There is no way to say for sure, of course, but one possible reason is that chemotherapy is already quite effective in this disease. Most patients will get a good response to chemo initially, and adding Avastin probably doesn’t change this. The problem is the residual cancer cells which develop resistance to chemo and inevitably relapse. Perhaps adding better penetration of the chemo to these cells does not alter their underlying resistance. I guess we’ll have to wait for the randomized trial to know for sure, but I for one will keep looking for other targets that might make a bigger impact on this disease.

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