EOR: Hello everybody, I am Eileen O’Reilly. I am a GI medical oncologist from Memorial Sloan Kettering Cancer Center and I’m delighted to be here from ESMO 2019 here with Dr Ian Chau, consultant medical oncologist from the Royal Marsden Hospital. We’re going to be talking for the next ten or fifteen minutes on pancreas cancer and the updates from the meeting. So, Ian, I think it’s been a good meeting so far. What comes to mind in pancreas cancer in terms of important information for our audience?

IC: Yes, I think there’s certainly some very exciting data coming out from this year’s ESMO; we can probably group it in different categories. Probably I would start with talking about some locally advanced pancreatic cancer because there have been two abstracts and two studies which were presented by the  European groups which really give us some more insight about how we manage locally advanced pancreatic cancer. The first study was actually presented by a German group looking at a randomised study where every patient up front had two months of gemcitabine plus nab-paclitaxel. Then they were then randomised to continue with gemcitabine nab-paclitaxel or FOLFIRINOX. Another important aspect of this study was that all the patients according to protocol have an exploratory laparotomy to see whether they can resect the pancreatic cancer after the induction chemotherapy. What they found in this study is that after the first two cycles of induction whether the patient continued to have gemcitabine nab-paclitaxel or whether they actually switched to FOLFIRINOX they actually have a very similar rate of able to go to surgery. Although probably numerically it did actually favour FOLFIRINOX but that was not statistically significant. Perhaps the good take-home message from that is close to 30-35% of the patients were able to have a resection of the pancreatic tumour. They were able to show that for those who actually underwent resection the survival, as you would expect, was much better than those who did not resect. What this highlights is perhaps, yes, you have the induction chemotherapy, whichever regimen may not matter as much, but if you’re then able to undergo surgery that would be the main aim to be able to increase the survival.

EOR: Yes, I think you’re right. This is a very important point – we’re not very good at predicting up front, based on the imaging, who is actually ultimately able to undergo an operation with locally advanced disease. These data were pretty impressive that a third of patients were able to get resected. Obviously this is expert surgeons and multidisciplinary centres that look after individuals with this disease but it resonates with other data that has emerged in the locally advanced setting. So that was one key study, do you want to comment on the other trial?

IC: Yes, the second study came from Italy so it’s called the GAP study. This study randomised between gemcitabine alone versus gemcitabine plus nab-paclitaxel, again in locally advanced pancreatic cancer. This study was able to show that really you need at least a doublet, gemcitabine nab-paclitaxel, that significantly improved the progression free as well as the overall survival. Now, in this study rather than follow on by surgery, patients who had not progressed were actually followed on by chemoradiation. So after they finished the gemcitabine-based treatment they then have capecitabine based radiotherapy. Again it highlights the fact that in the optimal management of locally advanced pancreatic cancer we do need to start with systemic therapy because of a high risk of metastatic spread but then we really have to think about local regional treatment, whether it’s surgery or chemoradiation. As you highlighted, a multidisciplinary approach is really necessary to manage locally advanced pancreatic cancer.

EOR: I think this study also is important for another context. It really tells us that single agent therapy is essentially a past era except, perhaps, for poor functional status individuals or individuals with comorbidities who really need combination approaches. But it’s an open discussion in the locally advanced setting as to which regimen is the preferred choice. I would say increasingly edge with FOLFIRINOX perhaps.

IC: And in your practice do you think that would be your preference to use FOLFIRINOX?

EOR: Yes. We’re waiting for data in the borderline resectable or in the resectable setting in the US. We have the co-operative group which looked at nab-paclitaxel and gemcitabine perioperatively and the other arm was modified FOLFIRINOX perioperatively. As you know, we don’t have any data in metastatic disease directly comparing them but this will give some insights. We certainly look forward to that. But I think they’re both good active options and to some degree it depends on the individual – preference, ports, infusions, alopecia and the toxicity differences. And maybe picking up that theme we had a number of abstracts on the issue of quality of life in pancreas cancer. As physicians we probably don’t pay enough attention to this, right? We’re always looking for the oncologic endpoints. But it’s critical for our patients so do you want to walk us through what data we had from the POLO study in quality of life and any other comments just on this theme in general?

IC: Yes. Again in ESMO this year they presented quality of life from the pivotal study, the POLO study. Perhaps just to remind everyone the POLO study was a randomised study for patients who have germline BRCA mutated pancreatic cancer. They all received up front platinum-based chemotherapy. Again, for those who are controlled or had a response to platinum-based chemotherapy were then randomised to either olaparib or placebo in a three to two randomisation. We already heard, and we know from the publication in The New England Journal of Medicine, that there was a significant progression free survival. So of course now we are very, very interested to know what is the quality of life with these patients. Because from the toxicity profile we know that olaparib has some toxicities but generally patients are able to tolerate it on a long-term basis. It is not like chemotherapy, you really can take it for months and sometimes years in some patients.

Now, in the quality of life data that was presented, what they found was the quality of life was certainly not compromised by taking olaparib compared to placebo. So there was no detriment in the quality of life when they’re taking the drugs. Also when you talk to patients there’s another way to look at that. You need to think about that. Yes, this drug is going to keep your disease under control for longer, you’re going to have some side effects, your quality of life is okay but it’s not necessarily better than taking nothing. So that is that balance that one will need to discuss that with patients.

EOR: That was actually a little bit surprising. That’s comparing an active agent which was clearly active, it had a response rate, it had progression free survival advantage, compared to placebo that there wasn’t a difference. Just one point for our audience is that for both groups the quality of life levels as measured by EORTC, the QLQ-30, were good to start and that may be part of the reason. Then there was attrition in terms of the number of patients who were eligible for assessment over time. So it’s a little limiting.

IC: I think you highlight a point which is very important in cancer therapy trials is that they collect quality of life when they’re on treatment. But once they progress, which is probably when they become much more symptomatic, they stop collecting the quality of life data. So the time when it actually matters most, when you think there is the biggest difference in quality of life, is actually when they stop collecting those data. So these studies, you might say, ‘Well, how come we’re not seeing the quality of life differences?’ It’s because probably when they have the biggest difference it’s not the collection time points for the quality of life data. So maybe in the future when they design clinical trials, especially nowadays a lot of these patient reported outcomes are done electronically, whether they’re smartphones and tablets, maybe we should continue to say post-treatment rather than just collecting the 30 day end of study quality of life questionnaires we should continue to ask patients to submit their quality of life outcomes to the study.

EOR: Yes, I think our tools are somewhat crude in terms of collecting quality of life. We’re looking at a snapshot at a point in time and you wonder how representative that is of the daily swings that everybody experiences. That’s also part of the challenge. But I would say there wasn’t a negative signal for an active drug which is also reassuring, looking at it the other way. So more to come, right, on that very important topic.

IC: Because on the POLO study, which obviously you’re one of the key investigators and probably looked after a few patients, a number of patients, on it, they also talk about… in ESMO they presented some data about the time to the next treatment and even the treatment after next. Eileen, can you maybe walk us through some of those data?

EOR: Sure. The POLO study, as you’ve highlighted, is two selected groups of people – people of a germline BRCA mutation who have had four months of platinum-based therapy, stable responding disease, and then randomised to olaparib or placebo. The important observations here, beyond the quality of life data, were for those that were randomised to olaparib the time to their next treatment was significantly delayed compared to the placebo. That makes sense because the control of cancer was better for longer on the intervention arm. So one of the other issues that we’ve been struggling to understand with POLO is the lack of apparent overall survival signal and what does that mean. Part of it is because of two factors – that for both groups there was active therapy at the time of progression and most patients went on to a platinum-based treatment, as you might expect. And to some degree there may have been a little bit of contamination by the crossover that wasn’t permitted in the study but that some individuals went on to receive a PARP inhibitor on the placebo arm. That makes it a little harder to interpret the overall survival. But pretty clearly the time to the next treatment was delayed for those who received the PARP inhibitor. We hope that this will be enough to support access to this drug in this setting in pancreas cancer.

IC: Absolutely. While we’re talking about overall survival in pancreatic cancer, maybe we’ll just switch gear a bit and think about the adjuvant setting which of course there was this big study that was presented at ASCO, the APACT study looking at neoadjuvant gemcitabine versus gemcitabine plus nab-paclitaxel which again in the survival endpoint there’s quite a bit of discussion about it. Maybe if you can just recap?

EOR: Sure, the APACT trial was an important follow-on study after we had the PRODIGE modified FOLFIRINOX study in 2018. This trial evaluated gemcitabine nab-paclitaxel compared to gemcitabine in 860-odd patients who had resected pancreas cancer. The primary endpoint was disease free survival as adjudicated by blinded independent central review. This turned out to be challenging, that clearly we’re not very good in isolation looking at imaging in terms of evaluating cancer control. That investigator adjudicated with the benefit of the person in front of you and seeing how they’re looking and feeling and doing and the CN99 trends clearly provide important information. So a negative trial but nonetheless there is an intriguing signal in terms of overall survival for the combination over gemcitabine. The hazard ratio was about 0.8 or so and we’ll hopefully have an updated final analysis on that dataset in the not too distant future.

Also a hint that certain subsets of individuals who had an R1 resection etc., node positive, may do better. So the more poorly acting group might benefit a bit more from the combination. That makes sense, at least intuitively. So we need to see the maturation of this to understand whether there is a role in the adjuvant setting. Right now we have to say, based on the primary endpoint, the answer is no but more to come on this.

IC: Absolutely. In the end the more mature results of the overall survival is very important in thinking about whether adjuvant gemcitabine nab-paclitaxel would be one of the options to use. Because again at ESMO this year they presented some quality of life data on that study. What they were able to show, as you would expect, when they’re on treatment, when they’re on that six months of adjuvant treatment, the addition of nab-paclitaxel in some aspects of the quality of life is worse than gemcitabine alone because we know that there are some additional side effects from the nab-paclitaxel. But that detriment to quality of life was temporary and is really just along the time of the treatment period, for that six months and maybe slightly beyond. When they’re able to follow these patients on the longer term, which probably is different to the metastatic setting, in the adjuvant setting you’re really able to follow patients on a longer term, it looks like the quality of life really comes back towards those patients with gemcitabine so that there is not really any long-term detriment of quality of life with having nab-paclitaxel.

EOR: Yes, I know. Thank you. I think we probably need to wrap up here in terms of our discussion on pancreas cancer. Thank you very much for joining us from ESMO, Eileen O’Reilly and Ian Chau, and we look forward to the next session.