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.