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Interview with Florian Lordick Critical Trials in Gastric Cancer at ASCO 2017: A Review
Dr. Caudle: Welcome to PracticeUpdate. I’m your host, Dr. Jennifer Caudle, and joining me today is Dr. Florian Lordick. Dr. Lordick is a Professor of Oncology and the Director of the University Cancer Center in Leipzig, Germany. Dr. Lordick, thank you so much for joining us today.
Dr. Lordick: My pleasure.
Dr. Caudle: Well, we’re happy to have you here, so let’s begin. Could you review the key findings of the Keynote-059 trial of pembrolizumab monotherapy for previously treated gastric cancer, and just as a follow-up given that pembro was used third or fourth line, do you think it should be used earlier in disease?
Dr. Lordick: Yeah, thank you for all those questions. Keynote-059 is an interesting trial and for the first time, it shows in a relatively large cohort of Western patients, patients who in the majority were recruited in the United States of America or in Europe, that pembrolizumab, which is a PD-1 antibody, is active and effective in patients with metastatic gastric and ED junction cancer. And this is an important finding because earlier this year at the ASCO GI meeting, we have seen a randomized trial of nivolumab compared to placebo in the same setting, third-line setting, and we saw that nivolumab is effective in this line of treatment but all the patients were recruited from East Asia, and so the information was incomplete if this compound or this class of drugs is also effective in the Western population and now we know it is.
And the key findings were that around 11% of patients in third and fourth line who have received previous lines of treatment respond to pembrolizumab in terms of a complete response or a partial response, and if you take the subgroup of patients whose tumors are tested positive for PD-L1 expression, then you even have a bigger response rate, which goes up to 24%, and so this is a good message because for this group of patients previously, we did not have active treatment anymore. There was just no treatment and now we have an active compound. And of course, now, research is going on who is the group of patients, the cohort of patients who is benefitting most. We know already that if there is PD-L1 expression there is a higher probability of response.
Charles Fuchs, who presented to the abstract ulcer, reported about a small subgroup of patients who present with microsatellite instable tumors, which we call MSI gastric cancers, and they have a very high response rate going up to 60%, but this is only a small subgroup. And there is also research going on in gene expression profiling and there seems to be a group with activated T-cell and inflammatory response who are also more probable to benefit from this, but this is ongoing research. And coming back to your question if this may be an interesting compound for combining with first line chemotherapy, we don’t know yet but there was a poster that showed the first 25 patients where pembrolizumab was combined to cisplatin 5-FU chemotherapy and this showed a very interesting response rate and a median overall survival duration of 20 months. So, if this is confirmed in ongoing studies this could even be an option in early alliance of treatment.
Dr. Caudle: Right. Right. Okay. Well, thank you, for that. It’s very interesting. Moving along a little bit, lets talk about the CheckMate study. The CheckMate 032 study compared nivolumab with or without ipilimumab in chemotherapy refractory gastric or esophageal cancers. Can you discuss maybe what the key findings of this study were and how does this compare to the results with pembrolizumab?
Dr. Lordick: Yeah. The study cohort is quite comparable to the pembrolizumab Keynote study and the new thing in CheckMate 032 is that the PD-1 inhibitor was combined with a CTLA-4 inhibitor, so two checkpoint inhibitors were combined in the checkmate study and the most interesting arm of this randomized phase 2 study was the arm that combined nivolumab 1 mg/kg with ipilimumab 3 mg/kg given every 2 weeks until progression, and so combination chemotherapy may also play a role. Combination immune checkpoint therapy may also play a role in the future because what we see and what we get as information from CheckMate was that the response rate was higher than with a PD-1 inhibitor alone. The response rate was 20% and if you focus on the patient cohort with a positive PD-L1 expression in their tumor, it goes up to 40%, so 40% response rate in a patient cohort that could not be treated previously with the combination of nivolumab and ipilimumab. This sounds quite interesting. So, this combination is also brought forward to first line in an ongoing trial and we have to await this data to see if this will come into practice, but it’s very interesting data also.
Dr. Caudle: Right. Absolutely. And you know we certainly do need further studies but it is very interesting. You know, I guess we were talking a little bit about CheckMate 032, you know, how would any of this potentially impact your practice decisions, especially in that setting? You know, how would it change things?
Dr. Lordick: Well first of all, it’s very interesting to have the data. Now we need to see the responses from the authorities which drugs will be approved. We have an interesting statement and decision from the FDA this week that approved pembrolizumab for all MSI tumors, so for gastric cancers that are microsatellite instable, and it’s approximately 4% of the overall cohort in stage IV, doctors in the US will be allowed to use the pembrolizumab from now on. The situation is different in other countries so European countries have not yet taken a decision on that. So this may have a direct impact on our clinical practice. For the rest of practice changing things, we definitely have to wait for definitive data from randomized controlled data studies and we need to await the reactions from the authorities.
Dr. Caudle: Right. Right. No. Understood. And finally, in an earlier stage of the disease there was also a trial comparing two chemotherapy regimens, FLOT and epirubicin, cisplatin and either 5-FU or capecitabine in early-stage gastric cancer. So what did this trial find and how might this impact our medical practice?
Dr. Lordick: Yeah. Actually, we have a standard of care for localized and locally advanced gastric cancer in Europe and also many centers in the US use that and this is perioperative chemotherapy, and the reason why we use that is the MAGIC Trial that was done in UK and published 10 years ago that combined surgery to perioperative chemotherapy based on epirubicin, cisplatin, and 5-FU or capecitabine, a regimen that we call ECF/ECX. So this standard existed now for 10 years, and now the German group compared the old regimen to a newer regimen, which we called FLOT, which is 5-FU, leucovorin, oxaliplatin, and docetaxel. And interestingly, preliminary data of this study have already been published this year in Lancet Oncology and they showed that with FLOT we achieve more tumor responses than with ECF. Now at this ASCO meeting, my colleague Salah Al-Batran presented the data from this German study and interestingly and amazingly, FLOT also achieves better survival rates and we are talking about a median survival of 35 months with ECF and 50 months with FLOT, and we are also talking about a 3-year overall survival rate of 47% with ECF compared to 58% with FLOT, so this makes a 9% difference between ECF and FLOT after 3 years.
So, this is important data and I spoke to many of my colleagues at this conference, and many said, yes, this has the potential to be adopted as a new standard of care for the treatment of localized gastric cancer.
Dr. Caudle: That’s very interesting and kind of exciting as well. Absolutely. Well, Dr. Lordick, thank you, so much for joining us today and sharing your insights.
Dr. Lordick: It was my pleasure. Thank you very much.
Dr. Caudle: And thank you for tuning in to PracticeUpdate. I’m your host, Dr. Jennifer Caudle.