The ABOUND trial was designed a while ago before immunotherapy really had emerged as a now standard part of first line non-small cell lung cancer treatment. The idea was pretty simple – could you take a therapy like nab-paclitaxel, which was showing efficacy in the first line squamous setting, and extend that into a maintenance setting. We knew that pemetrexed found its place in the first line setting and has become an established standard of care for non-squamous lung cancer where it’s given with platinum therapy, usually for four cycles, and then in a maintenance fashion indefinitely. So we don’t have similar data for squamous lung cancer. Squamous lung cancer usually historically has been platinum and gemcitabine, platinum and docetaxel, platinum and paclitaxel or platinum and nab-paclitaxel, usually for 4-6 cycles and then stopping. We got close with gemcitabine, some old data suggested you could continue that in a maintenance fashion and patients could benefit. But that was really the goal of ABOUND was could you take patients who were getting, in this case, carboplatin and nab-paclitaxel up front, patients with advanced squamous lung cancer newly diagnosed, and then randomise them to maintenance nab-paclitaxel or to supportive care alone. That was, in its simplest form, the goal of the study. It wasn’t designed to be a registration trial, a phase III trial, it was a phase II study to look for a signal for progression free survival.
The study was set up pretty simply, it enrolled just under 500 patients who were newly diagnosed and they received four cycles of carboplatin and nab-paclitaxel. Then if they didn’t have progressive disease after four cycles, so either a response or stable disease and they were otherwise doing well from a toxicity standpoint, they then got randomised to nab-paclitaxel by itself and it was given in a different regimen where it’s 100mg/m2 days 1 and 8 every 21 days or supportive care, it was not a placebo-controlled trial.
The study actually took off to a great start and then hit a little bit of an enrolment delay as immunotherapy found its place in the second line setting and then trials opened up in the first line setting. So a decision was made to close the study early for futility because of the slow enrolment and probably the inability to achieve a statistical result as time continued to pass and patients continued to receive immunotherapy. At its early stopping point here’s what we found: statistically no advantage for the nab-paclitaxel arm over the control arm for progression free survival, however there was a trend; overall survival was a secondary endpoint, similarly no survival advantage but a bit of a trend. What was interesting, though, as we suspected, a lot of patients were receiving immunotherapy and when we removed those patients from the analysis there’s a suggestion that patients do benefit from nab-paclitaxel but when you have a negative trial, a trial that stopped early, these kinds of subsets don’t mean anything, they perhaps generate other questions.
But the world has moved on, we now give… actually just as of the last few months trials like KEYNOTE-407 teach us that if you give a drug like nab-paclitaxel and platinum or carboplatin and pembrolizumab that’s going to be a new standard of care for squamous lung cancer and those patients will just maintain the immunotherapy and taxane indefinitely. So this study just got trapped in this time where perhaps had nab-paclitaxel been approved and a drug that came into lung cancer many years ago, like pemetrexed it could have been a maintenance agent but importantly we’re moving on to hopefully more impactful therapies and regimens for our patients.
Maybe, like you say, in another world, in another life.
Yes, well that’s why we research, it’s also why we don’t expose patients to ongoing therapy if we think there’s better options that are going to be available. Some have asked me, ‘Boy, David, if we didn’t stop the trial early maybe you would have found a true advantage,’ a lot of maybes. If the trial had enrolled faster maybe that would be true but we’d still be in an era today, even if the trial were positive, where we’re probably doing it anyway with trials like KEYNOTE-407 where we’re giving maintenance nab-paclitaxel. So I’m not sure keeping the trial open made a lot of sense. We learn what we can from the study that was done but importantly move on to other regimens.
