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Dr West

Where do we go from here with Avastin?

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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)

Cavitary lesion illustration

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 is also being tested in first-line, untreated small cell lung cancer, combined with cisplatin and etoposide, a combination commonly used in this setting. Importantly, we know that the small cell trial, also being done by ECOG, has not needed to be closed early due to safety problems. This helps us understand more about Avastin and bleeding risks, since small cell lung cancers are almost always very central. Because there is apparently no obvious increased bleeding risk when Avastin has been given with small cell lung cancer, it suggests that central location may not be as important as squamous subtype.

In mesothelioma, the combination of cisplatin and gemcitabine (Gemzar) has been studied with and without Avastin. The trial has closed for new patients and we anxiously await the results, which could make the addition of Avastin to chemo an appealing option for mesothelioma as well.

One important large trial that Is being done in Europe and near completion is called the AVAIL trial. This one, also for patients who have advanced NSCLC and received no prior chemo, gives cisplatin and gemcitabine with or without Avastin. There are actually two different dose levels of Avastin being studied, including the higher dose used in the US trial by ECOG, and a lower dose that is half of the higher dose. When the AVAIL trial results are presented in the next year or so, we should clarify whether we need the higher dose, whether women get the same degree of benefit as men, and whether Avastin is as safe and beneficial, or perhaps better, than with carboplatin and taxol.

I am leading two national trials through the SouthWest Oncology Group (SWOG) that combine Tarceva (erlotinib) and Avastin, one for never-smokers with any lung adenocarcinoma, and the other for patients with BAC (can have smoked) that should become nationally available in the next few months. Most of the patients will probably get this as their first or second treatment, since Tarceva is often used very early for BAC and never-smokers because this agent appears to be so helpful for these patients.


6 Responses to Where do we go from here with Avastin?

  • Rodney says:

    Will you be posting the results of your Tarceva/Avastin trials on this website or do we have to go looking for them on the web?

  • Dr West
    Dr West says:

    I won’t be allowed to tell results before they’re publically available, presented at an oncology meeting. However, you can be sure I’ll give details as soon as I can. In the meantime, I will write a post in the next few days on Avastin in the second-line setting, combined with Tarceva or chemo, from trials that have already been presented.
    -Jack

  • hubbie says:

    My wife had a complete response to Avastin, Taxol, Carboplatin and Zometa. She was stage 4 with many small tumors or nodules throughout the right lung. She is a neversmoker. After about 6 months she developed a malignant pleural effusion. Her oncologist wanted to treat her with Alimt and Avastin but the insurance company has refused to pay for Avastin again. In the meantime she has been prescribed Tarceva. She is apparently not eligible for any clinical trials as she has no measurable disease. What are your thoughts on use of Avastin as part of secondline therapy, especially in a case like my wifes that responded so well to prior treatment? I realize Avastin is only approved for first line treatment but trials to extend its use will probably take years that my wife probably doesn’t have.

  • Dr West
    Dr West says:

    The evidence suggests that avastin can be similarly beneficial in patients receiving it as second-line therapy as it has been shown to be as first-line therapy (although not as well studied beyond first-line). The bigger question is whether avastin provides benefit in second line if patients have already received it and progressed on it. That’s a completely open question for which I don’t know of any evidence to say anything one way or another. I think if someone had clear evidence of progression relatively early on an avastin-containing regimen, I wouldn’t be inclined to include avastin in a second line approach. On the other hand, if a patient had only subtle progression after many months of effective therapy that included avastin, I’d be much more inclined to include it. But at this point, all of the second-line trials have not included patients who have previously received avastin. In general, in oncology we don’t continue a patient on a therapy on which they’ve shown progression, but this is an area where it certainly makes sense to consider making an exception.

    -Dr. West

  • ortizbazurto says:

    Dr. West:

    I just read today the preliminary results of the AVAIL trial that you mentioned in your post. Cisplatin and gemcitabine with Avastin yields the same benefit as carboplatin/paclitaxel + Avastin. More importantly, I think, is that the patients that got the lower dose of Avastin (half to the dose in the original U.S. trial) did as well as the full dose patients in progression free survival.

    Here is the link to one of press release:
    http://www.made-in-switzerland.com/News/index.php?p=1000

    Hopefully, this means that the Avastin + chemo therapy will be less expensive and also with less side effects, right?

    Best wishes,

    Carlos

  • Dr West
    Dr West says:

    Yes, the lung cancer world is abuzz about these preliminary results. We need to see overall survival benefit, because all we have is a small glimpse of what the trial will tell us. However, I suspect that even just the preliminary data showing a progression-free survival benefit in both the 7.5 mg/kg and the 15 mg/kg group will lead some, and perhaps many, oncologists to move to a lower dose approach. We do need to weigh the risks against benefits, and lowering the safety risks at a lower dose would be great if it preserves the same survival benefit. And the cost savings at a lower dose is also an important factor if the benefits are still comparable. However, I wouldn’t be inclined to change my practice patterns YET based on the very limited information we’ve received thus far.

    -Dr. West

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