Thank you for the opportunity to present the results of the CheckMate 577 study. The reason we did this study was that neoadjuvant chemoradiation followed by surgery is a widely used standard of care for patients with resectable, locally advanced oesophageal cancer or gastroesophageal junction cancer but unfortunately only about 25-30% of patients achieve a pathologic complete response to that regimen and so the risk of recurrence remains high, especially those patients who do not achieve a pathological complete response. There is no established adjuvant treatment post-operatively with chemotherapy not being shown to be beneficial.
So we did this study because nivolumab has been demonstrated to show superior survival in the advanced setting so CheckMate 577 is the first global randomised double blind phase III study to evaluate adjuvant checkpoint inhibitor after trimodality therapy for patients with oesophageal cancer and gastroesophageal junction cancers.
Can you go into more detail on the study design?
The study design, this is a global randomised, double blind, placebo-controlled trial. The key entry criteria were patients needed to have stage 2 or 3 oesophageal cancer or gastroesophageal junction cancer, either adeno- or squamous carcinoma histology. All patients had to have neoadjuvant chemoradiation followed by an R0 surgical resection but then on pathology report they could not have a pathological complete response. So we really picked out those patients with poor biology who had residual pathologic disease greater than ypT1 or ypN1. The stratification factors were histology, pathologic lymph node status and tumour cell PD-L1 expression.
In total we randomised 794 patients in a two to one manner with 532 receiving nivolumab and 262 receiving placebo which, as I said, is really the standard of care. The primary endpoint was disease free survival and the interim analysis was presented at ESMO after a median follow-up of 24.4 months. The secondary endpoint of overall survival is still ongoing and we hope to have that in the future.
What were the results?
Overall the study was well-balanced: in terms of tumour location 60% had oesophageal cancer, 40% had gastroesophageal junction cancer. In terms of histology 71% of the patient population had adenocarcinoma, 29% with squamous cell. In terms of pathologic lymph node status it was approximately 60% of patients. Tumour cell PD-L1 expression was 17% in the nivolumab arm and 15% in the placebo arm but it’s important to note we used tumour cell PD-L1 expression rather than the combined positive score.
Overall patients tolerated treatment very well. 89% of patients receiving nivolumab received a dose intensity greater than 90% with the median duration being 10.1 months on treatment. The primary endpoint was disease free survival and in this study we met the primary endpoint with the median disease free survival in the nivolumab arm being double that of placebo. So placebo was 11 months and the median disease free survival in the nivolumab arm was 22.4 months which had a hazard ratio of 0.69 equating to a 31% reduction in the risk of recurrence or death. The p-value was 0.0003.
So overall the treatment was very well tolerated. We didn’t see any undue toxicities that we hadn’t seen in previous trials. If you look at disease free survival according to subgroups we saw an efficacy in the adenocarcinoma or the squamous cell group according to whether a patient was lymph node positive or negative. Efficacy was seen irrespective of PD-L1 expression.
What are the next steps?
The overall summary of the study, I would say, is that nivolumab is the first adjuvant therapy to provide a statistically significant and a clinically meaningful improvement in disease free survival versus placebo. As I said, we saw a 31% reduction in the risk of recurrence or death and a doubling in median disease free survival from 11 months to 22.4 months. We saw disease free survival across multiple pre-specified subgroups. Will we look at CPS rather than the tumour PD-L1 expression? That could be something done in the future.
Nivolumab was well tolerated with an acceptable safety profile. We do need to wait for overall survival so, to answer your question of what’s next, the study remains ongoing. We’re blinded to the overall survival, that will happen when we reach pre-specified endpoints. But, in summary, really this is the first trial in the adjuvant setting, after melanoma, which has shown a benefit to the use of adjuvant checkpoint inhibitors. So from that point of view it’s extremely novel, very impactful. We’ve never really had gastric or gastroesophageal junction cancers or oesophageal cancers leading the field in terms of response to checkpoint inhibitors. So here we’re just the second subgroup of patients after melanoma to show an efficacy signal so that’s very exciting.
What are the potential impacts of this study?
Like everything in the checkpoint inhibitor world or the immuno-oncology world, there are a lot of other studies ongoing. This particular study took many years, it’s a very challenging patient population to study. As you know, an oesophagectomy is one of the hardest oncologic operations to recover from and so it was very exciting to see a benefit when the primary endpoint here was disease free survival. So we’ll wait to see what overall survival is in this study but there are other trials looking at the neoadjuvant space – can you give checkpoint inhibitors with chemoradiation? There are also, as you mentioned, combination studies looking at combining a PD-1 inhibitor with a CTLA-4 inhibitor. We’re even looking at the definitive setting, so the inoperable patients – can we use chemoradiation plus PD-1 inhibitors?
We need to make sure, though, that we don’t get ahead of ourselves because there are no guarantees those studies will work; we have been disappointed in the past in other tumour types. So we just take this as a very promising study; it’s really a game-changer in that we’ve never had a trial in early stage disease in oesophageal gastro cancers to show any benefit. So this is the first one so it’s really, I hope, the start of a whole new era but we’ll have to see how those other trials pan out in the future.
Is there anything you would like to add?
I really wanted to point out, this was a global study. This was done in 27 countries over 165 sites. If you look at all of the practice changing trials over the last couple of decades they’ve come from single countries. So you might have a study from the United Kingdom or Holland or Germany or Japan. This is one of the first trials now in these early stage diseases that has looked across the entire globe. We had five continents in this study and we’ve shown a benefit. So that is a very important point for me to drive home, that a global trial taking account of different races, different backgrounds, different surgical techniques and we showed the benefit. So I think that’s a very exciting step forward for us.