IC: Welcome everyone. Thank you for joining us for an ecancer education session from Chicago ASCO 2019. I’m very, very honoured to be able to be joined by two other international experts from France and the US. My name is Ian Chau, I’m a medical oncologist from The Royal Marsden Hospital in the United Kingdom.

MD: My name is Michel Ducreux, I am a GI oncologist in Gustave Roussy Cancer Centre in Paris.

VS: I’m Vaihab Sahai, I’m also a GI medical oncologist at the University of Michigan, Ann Arbor.

IC: So, as we know, this year’s ASCO we have some exciting data and perhaps we will start with asking Michel in patients where we have a resectable pancreatic cancer can you maybe tell the audience what is our current management for patients who have a resectable pancreatic cancer?

MD: Yes, as you know twenty years ago after resection of pancreatic cancer there was nothing to do and we were just waiting for a recurrence. After that it has been proven that chemotherapy could be active in these patients and the first type was gemcitabine. Recently it has been published, a British trial, ESPAC-4, showing that the combination of gemcitabine and capecitabine could be a little bit better than gemcitabine alone. More recently during the last ASCO meeting and it has been published in December the French and Canadian trial showed that a huge combination of FOLFIRINOX, using 5-FU, irinotecan and oxaliplatin in these patients after resection of pancreatic cancer, was able to clearly improve the overall survival of the patients. This is where we were before this ASCO 2019 meeting.

IC: Good. So it sounds like we’ve got two effective options as adjuvant therapy, as you said, gemcitabine plus capecitabine and FOLFIRINOX. This year at ASCO we have the large phase III study, APACT, being reported. Maybe can you outline the results, what it shows and, probably most importantly, what it means to you?

MD: Yes, as you know, gemcitabine plus nab-paclitaxel was shown to be better than gemcitabine in metastatic disease. So we were hoping that this combination could be active also in the adjuvant setting and this APACT trial is a well done trial evaluating the whole of gemcitabine versus gemcitabine plus nab-paclitaxel. Unfortunately the trial is considered to be negative because it did not meet its primary endpoint. This primary endpoint was disease free survival evaluated by a central review and we can discuss that, maybe this is a mistake because if you look at the results in terms of disease free survival evaluated by investigators the trial is slightly positive and the same for overall survival. But at the end the main endpoint is negative so we have to consider that this is a negative study and I would say that this is a pity.

IC: Just let us know, obviously overall survival in pancreatic cancer is a very important endpoint because patients still have a relatively dismal prognosis. Maybe can you expand a bit more about the overall survival result that has been reported so far for APACT?

MD: Yes, the fact is that the difference in terms of overall survival is statistically significant. The difference is not very important and if you compare to the difference that has been observed with FOLFIRINOX I would say that FOLFIRINOX, in my opinion maybe because I am French, but FOLFIRINOX, in my opinion, remains clearly now the standard of care. But FOLFIRINOX can be considered only in very fit patients and we are speaking about patients that sometimes are more than 70 years old and after a huge surgery because surgery of pancreatic cancer is something that is not so easy. So we may imagine that patients that are less fit could benefit from a less aggressive regimen. At this time there could be two candidates – gemcitabine plus capecitabine that has been published and that is positive, or this gemcitabine nab-paclitaxel, again, even if the main endpoint is not fit in the trial.

IC: Vaihab, maybe if I can ask your opinion about this. Michel has already said a few times this primary endpoint may not be correct. So compared to this other pivotal study that we just mentioned, the FOLFIRINOX as adjuvant study, how is this primary endpoint compared to the primary endpoint as used in other studies.

VS: The primary endpoint, as Michel mentioned, was central review for this particular trial and it has not been used previously in studies. In ESPAC-4 and in the FOLFIRINOX trial it was only per investigator review. In this trial the gemcitabine control arm median progression free survival was similar to that reported with ESPAC-4 and the FOLIFIRNOX. So it gives us an idea that perhaps that is a more realistic endpoint that should have been considered for this trial and that is a secondary endpoint for this trial, unfortunately. We are looking forward to perhaps consideration of gemcitabine nab-paclitaxel along with gemcitabine capecitabine in patients who are not fit for FOLFIRINOX, as Michel mentioned.

IC: Okay, so really you’re saying when you’re faced with a patient tomorrow and you think that gemcitabine nab-paclitaxel could be a potential option to consider, especially when they’re not fit enough for FOLFIRINOX?

VS: I think so. I struggle with just using the central review as the primary decision when it comes to my patient. If you look at the overall survival of 40.5 months that is still, perhaps, better than the overall survival reported by the gemcitabine capecitabine ESPAC-4. Perhaps that is a consideration for us to use gemcitabine nab-paclitaxel.

IC: Now, currently there are a number of clinical trials looking at moving some of this adjuvant therapy to the neoadjuvant setting. Maybe in light of what we’ve seen with APACT maybe if I can ask both of you, but one by one, what do you think are the implications with the neoadjuvant treatment strategy? So Michel, maybe I’ll start with you. First of all do you believe a neoadjuvant strategy is a reasonable strategy to test and how do you think the current results will influence what we do?

MD: Yes, I totally believe in this strategy and when you consider, especially for a quite aggressive chemotherapy regimen, when you consider, as you already said, to give that after pancreatectomy it is sometimes very difficult. So to put the chemotherapy before surgery is clearly a nice idea. It has to be verified and in France at this moment we are trying to evaluate the role of FOLFIRINOX as a neoadjuvant treatment versus post-operative use of FOLFIRINOX in resectable pancreatic cancer. There is also this SWOG trial that is very interesting with gemcitabine nab-paclitaxel neoadjuvant, surgery and then followed by gemcitabine nab-paclitaxel versus the same schedule but with FOLFIRINOX and then pick the winner. This is a very interesting trial too.

IC: Yes, so Vaihab, maybe on the US studies is there anything you want to expand on? We already heard the SWOG study looking at this.

VS: The new study that has been designed is the ALLIANCE 021806 study which is in the same population where they’re studying neoadjuvant chemotherapy versus no chemotherapy and pre-op surgery without the addition of radiation which is perhaps how it differs from the already resulted data with the PREOPANC. In this study we are not using gemcitabine nab-paclitaxel, it is FOLFIRINOX being used as the pre-operative therapy.

IC: So you mentioned a bit about radiotherapy, maybe if again I can just get your opinion about what do you think the role of radiation is either preoperatively or postoperatively in patients who have got localised pancreatic cancer.

MD: To my opinion no role at all.

IC: No role for radiotherapy?

MD: No more, no more. Stop radiotherapy.

IC: Stop radiotherapy?

MD: Stop radiotherapy. This is where we differ.

VS: This is where we differ.

IC: Okay, well why don’t you give us your view?

VS: Sure. I have two comments on this, one that currently we have no data that strongly points us, as Michel mentioned, about the use of radiation in neoadjuvant or adjuvant setting. However, if you look at the meta-analysis there is perhaps a role in R1 resected patients and N1 patients. There is a soft data, it is not a hard data to push for every patient to get this. I think it is a discussion that we should have with our patients. I will point out that the definitive data may be answered by the RTOG 0848 trial where they’re getting adjuvant gemcitabine followed by radiation versus not. That trial has finished accrual and we’re waiting the results.

IC: Excellent. Now, unfortunately for a lot of our pancreatic cancer patients they probably up front either don’t have localised disease, they already present with metastatic disease, or develop recurrent disease after all the surgery and then adjuvant therapy. So in this group of patients the prognosis is still very poor with our current treatment. Maybe, again, if I can just ask Michel if you could outline perhaps briefly what is your current lines of treatment that you would treat for patients that have got metastatic pancreatic cancer?

MD: Again I would say that as a Frenchman I use a lot of FOLFIRINOX because it has been proven that FOLFIRINOX in the metastatic setting was better in terms of overall survival, response rate, 30% response rate, was better than gemcitabine alone. Clearly this is an aggressive chemotherapy regimen and we cannot give this regimen to all the patients but maybe to 30% of the patients. So for the others it’s interesting, a small part could receive, at least in France, could receive a combination of gemcitabine and nab-paclitaxel and the others receive only gemcitabine and we see a lot of patients that are only able to receive gemcitabine alone because metastatic pancreatic cancer remains a very aggressive disease.

IC: Now, recently the NCCN guideline has now said that we have to test patients for BRCA in all patients with pancreatic cancer. Maybe if I can ask you first of all to outline what the NCCN guidelines actually are stating and what is your view about more tumour profiling in patients that have got pancreatic cancer?

VS: So the reason why some of these guidelines came out was our understanding that perhaps 80% of the patients who test positive for germline BRCA1 and 2 do not have a strong family history for us to test them in the first place. This was looked upon very strongly by several committees, including the NCCN and the ASCO guidelines. I’ll start with the ASCO guideline, that white paper came out last year and suggested that we consider germline testing in all patients with pancreatic cancer. That was in itself a bold statement for the ASCO guidelines and I think, knowing that the patients without family risk factors also test positive for germline mutations, the NCCN guidelines have come out stating that all patients are now recommended to undergo germline testing which, in my view, is a much stronger recommendation than the ASCO guidelines.

IC: So roughly what proportion of patients are actually BRCA mutation positive for pancreatic cancer?
VS: In the recent POLO phase III trial around 5 point some percent of patients were tested positive for BRCA1 and 2. If you look at some of the smaller literature studies they have shown that it could be anywhere from 5-10% are germline testing and then additional patients may have somatic mutations.

IC: Now you mentioned POLO just now, maybe if you can outline for us, this is obviously some very exciting data that was presented at a plenary session and I understand is now also published in The New England Journal of Medicine. So do you think you could outline that study and what are the results?

VS: So phase III POLO multi-centre study was conducted across several countries and it was tested in a population with metastatic patients who had received at least sixteen weeks of platinum based therapy without progression. The study had two arms with three to two randomisation to either olaparib or placebo. When they followed patients on both arms they noted with the primary endpoint of progression free survival that it was 7.4 months versus 3.8 months in favour of the olaparib containing arm. The overall survival for this trial has also been reported, it’s a premature reporting of 46% of time events that have happened. As of now that has not shown any significant difference in overall survival.

IC: So Michel, how would these results… what does that mean to you, the POLO results? Do you think it’s something that when olaparib becomes available do you think this should be our new standard of care for patients who have got a BRCA mutation?

MD: Yes, clearly yes. I think it’s a first step of personalised medicine and the demonstration of a role of targeted therapy in pancreatic cancer, this is very interesting for our patients. As it has been said, even if median overall survival was not different it’s a little bit too early for that and when we have seen the results in terms of duration of response or duration of stabilisation there are even 18% of responses in the group of patients receiving olaparib. So this is something that is clearly, to my opinion, very, very interesting for our patients. After that the problem is the testing and in Europe, especially in European countries, it’s huge work. 

IC: So in the US it’s standard now but in Europe…

MD: Yes, it’s not the standard at all for pancreatic cancer. It is for breast cancer obviously but it is not for pancreatic cancer. So it means that for a genetician it will represent a huge amount of work and we have to organise our hospitals to do that.

IC: So you think there needs to be a change in our infrastructure in terms of obtaining this kind of genetic testing?

MD: Absolutely.

IC: And also genetic counselling for patients obviously with a family because this is going way beyond the actual patients but the family as well.

MD: Yes, we don’t know but if we find a man or a woman with a germline mutation we have to look at the family of this person. So maybe there is nothing in the family but we have to test, we cannot stay like that. So this is something, this is a huge work for our oncogeneticians.

IC: Yes. Now, perhaps in the last moments of this session there are also some data presented at ASCO this year where they also look at other genomic abnormalities. Some of them are in the same pathway to BRCA so they look at the DNA repair pathways but all the other pathways and they’re trying to match, after comprehensively characterising the abnormalities, trying to match therapy. They do find in a small proportion of patients that actually they are able to match therapy to these so-called actionable mutations. They enjoy better survival but it’s still a very small number of patients. Do you think, maybe I’ll come back to Vaihab, do you think this is a strategy that we should really pursue intensively or do you think that actually really it is not going to make a huge impact?

VS: Yes, this is a very important point that the POLO data is only valid for germline BRCA1 and 2 and that to pathogenic mutations. I think we should make a clear statement that this is not valid for, for example, variants of unknown significance. It’s important to make a distinction between them; it is not easy even for sometimes an oncogenetician to tell us the difference between the two. Using HGVS nomenclature or C nomenclature is important for this perspective.  The use of somatic mutations and other DNA damage repair mutations such as PALB2, ATM, RAD51 is of utmost importance and I think that should still be considered a research question and should be appropriately designed into research trials, both as maintenance and perhaps second line trials.

MD: And you have to know that attempts on personalised medicine in pancreatic cancers are a lot of data at this moment with a lot of negative results because pancreatic cancer is rarely… for BRCA mutations clearly this is the best way that is very important in the carcinogenesis but for other types of pancreatic cancer there are a lot of pathways that probably are mutated and dysregulated. At the end to find the specific target to fight is something that remains very, very difficult. So I am not so confident in personalised medicine in pancreatic cancer when I look at all the negative results that have been published at this moment.

IC: Great. So it sounds like from this year’s ASCO on the management of pancreatic cancer we may have a third option in adjuvant treatment in terms of gemcitabine nab-paclitaxel. We’re still going to wait for the overall survival data to mature. For patients now we should really reorganise our health service infrastructure so that we can test patients for germline BRCA and for those who actually have a BRCA mutation after treatment with a platinum based chemotherapy we should consider the use of olaparib as a maintenance therapy. So on this note I really would like to thank Vaihab and Michel for joining me for this session and I would like to thank the audience for listening to us. Thank you.