The Role of Anti-Angiogenic Therapy in Lung Cancer - Episode 3
In lung cancer, bevacizumab was initially tested in combination with carboplatin and paclitaxel. The ECOG 4599 trial enrolled nonsquamous non-small cell patients with advanced cancers and randomized them to the control arm of carboplatin and paclitaxel versus the same chemotherapy plus bevacizumab. Bevacizumab was given at 15 mg/kg. The protocol allowed for up to six cycles. However, the bevacizumab was allowed to be continued until evidence of either disease progression or unacceptable toxicity. Now, back when 4599 was designed, we called that “treatment to progression.” In modern times, we call that “continuation maintenance therapy,” and that’s a new term since 4599.
Now, adding bevacizumab to carboplatin and paclitaxel in ECOG 4599 led to an improvement in overall survival, which was the primary endpoint. It also more than doubled the objective response rates from 15% to 35% in the two arms and significantly improved the progression-free survival (PFS). Adding bevacizumab to carboplatin and paclitaxel is associated with greater toxicity, although I believe it is acceptable toxicity. You have to be aware of hypertension and proteinuria. It increases the rates of neutropenia and fever neutropenia, although the rates were very low to start with. So it does increase the risk of treatment, but I do think that the survival, response, and PFS benefit outweigh the potential risk. It does remind us that we should be selective in our patient choices in terms of who we recommend this drug for in this particular setting.
Now, since 4599, there have been a couple of trials to be aware of. We had a couple of confirmatory trials, which used PFS as the endpoint, which were also positive. These trials also showed enhanced response rates. ECOG 4599 did not allow patients with brain metastases to be enrolled. Brain metastases are very common. Following ECOG 4599, the PASSPORT trial looked at the safety of bevacizumab, and treated and controlled brain metastases was acceptable. The primary endpoint of that trial was central nervous system hemorrhage, and there was basically no serious hemorrhage seen in that particular trial. And so we proved in that particular trial that if brain metastases are treated and controlled, that the use of bevacizumab is safe in that population.
One of the exciting areas recently about bevacizumab has been a trial out of Japan in an epidermal growth factor receptor (EGFR) mutation-positive trial. What these investigators did is randomize patients with a known EGFR mutation to receive either erlotinib as monotherapy—which is the standard of care—versus the combination of erlotinib plus bevacizumab. There was a very striking benefit in PFS. The curves for PFS are actually quite remarkable. This trial has been published. We don’t have any long-term overall survival data. It really does change the game for EGFR mutation—positive patients, though. In this population, these patients typically take a pill once a day. We see them every six to 12 weeks depending on how stable they are. Committing them to a course of bevacizumab adds the intravenous treatment, with bevacizumab being administered every three weeks, so they’re tied to coming to the doctor every three weeks, and it adds the potential toxicity. Even though in an EGFR-mutant population—which tends to be female, predominantly never-smokers, almost all adenocarcinoma, and a generally a healthier population—there is still the risk of toxicity with bevacizumab. So it’s an interesting observation. There are a couple of trials ongoing, both in the US as well as Europe, to confirm that Japanese observation. I personally don’t think it’s the standard of care at this point. It’s interesting, certainly provocative, but I think we need a second trial before we embrace it as a routine strategy for EGFR mutation–positive patients.
The other important thing about bevacizumab is that bevacizumab is a first-line choice in lung adenocarcinoma. It is not indicated in second- or third-line. There are really no compelling data to use it in second- and third-line. One of the questions that often comes up is should bevacizumab be continued through multiple lines of therapy. For instance, if you progress after carboplatin and paclitaxel and bevacizumab, should you continue bevacizumab, say with docetaxel, in the second-line? We don’t know the answer to that. There is an ongoing trial. I think it’s completed its accrual; patients who were on bevacizumab and stable are randomized when they progress to either continue bevacizumab with subsequent lines of therapy or to stop bevacizumab. So that question of bevacizumab use through multiple lines of therapy has been addressed. We look forward to seeing those data.
Transcript Edited for Clarity