Transcription
A sanction for very kind introduction and thank you committee member for giving me this opportunity to talk about check money filter for asparagus councils. Sorry, no treatment option for gastric cancer recently increasing with FTD TBI in Imola in Asian countries and policemen for PD impulsive Shapiro operation or MSI high tumors. And these treatment options are discussed in pan-Asian just moyes moguy trying and recommended if available.
And after that, not a few trial try out, try to eyeball later upfront checkpoint inhibitors in area lines of treatment. So Kyoto 61 could not show the improvement in your bio. His family's mob Imperium positive GPS map operation sub avakov clear closed mobile PDL and negative patient shorter shorter survival. We spam the regime Bismarck dam park with taxol. In contrast, patient with higher PD expression defined as GPS 1000 MSI tumor showed a greater treatment effect of people is mode. So query gastric cancer is not one disease in terms of respond to checkpoint blockade.
So today's my talk mainly focused on gastric cancer, but this Q not Wyatt one trial force what year cancer also suggested there predictive value or PDI expression where only period on CBS canceled Mets a primary endpoint. So until now, three randomized control trial of checkpoint inhibitor in fostering completed enrollment. Keynote 62, check matter six one, I hand attraction for trial. And today we have a result from keno 262.
So looking at the first comparison between families mom on syrupy and chemotherapy, it Mets appointment and a point to show no inferiority, no verse Bible. Upper limit of nineteen ninety point two percent confidence interval was one point Wyatt, which was lower than play define one point two. Looking at the 95% confidence interval, upper limit was one point one. So these hazard ratio suggested to know inferiority. Moreover, low instance of grocery or higher event may support no the reality of survival. However, it showed across the survival curve, initially publishing of did worse, very similar to that of Aquino 61. And after media, led survival benefit of embolism was suggested.
So in gastric cancer field, non fairy aura tea trials have changed the clinical practice to use all of our parameter like s 100 Jeremy Hawks approaching. So hazard ratio from this keynote 62 in language that of past people water no inferiority trial. However, cross survival curve is one of the concern to apply this into clinical practice. So looking at the cervical analysis, most of the subgroups shoulder hazard ratio rate on one, but still some difference was suggested according to region hand sight of a primary tumors. But this trend was completely different in cleaner to 61. Hazard ratio was better in G Junction tumor in no Asian countries. So this may be confounded by other factors. So maybe we need other Mars factorial analysis.
In contrast, both keynote of 62 and 61 suggested the greater treatment effect of embolism up in CPS Championship operation. Media over survival was improved by six months since in 62 trial. I think this must be the Rogers to difference in medium over survival in any phase 3 trial for gastric cancer field. MS a high result were not available now, but it was only six point five percent in CPS one operation. And Keynote 61, MS are hybrids only 12 percent in cheapest am patient operation. So most of the CPS tempation cooperation our microsatellite to stable.
So this keynote 62 confirmed the portland and inferiority over the bible, but it showed across the survival curve. And then maybe the some missing information faster on is a survival possible Gresham or a PFS to what happened after first progression and a second is additional by Americas. So we have a pH CPS 10th cheapest M must be the important factor, but still not perfect. So wonder interesting characteristic of this keynote of 62 is disco between PFS and over survival. Peeping sheepish tempation cooperation media DFS was three months is shorter with families mode on chemotherapy. In contrast, media over the Bible showed a six months improvement. And this kind of discordance between over survival and the PFS were also deported from other clinical trial with checkpoint inhibitors. Usually hazard ratio over the Bible are better than that of the previous and a correlation between PFS and over the Bible was not high, very low. So 62 results were not outlier.
Another discordance in 62 result were media and PFS and mean treatment aversion. This was very similar in chemotherapy arm, but more than three months is difference in families mobile. So this may be explained by the difference between media and me, but still suggested as some possibility that not a few patient may continue embolism up even after progressive disease at Central assessment. And the actually proportion patient with subsequent therapy are very similar between terms. So I think this is very difficult to explain the survival possible ration they are different. But how is the efficacy of a path to study chemotherapy? And actually, this kind of analysis was already reported from other trial such as the author is Messiah for non small cell lung cancer, where a media over survival was included by for Mance's, but no significant difference in provision for survival. So actually survival post progression were longer visit is reasonable arm compared with chemotherapy arm. And importantly, patient who continued to the rhythm of even after first progressive disease show the most favorable outcome compared with patient food country few receive the additional chemotherapy or no treatment. In pebble yzma trial, fostering PFS to was analyzed. PFS to was defined until the disease progression during the second ranking therapy. It should a nine months difference with families ma first followed by chemotherapy compared with chemotherapy followed by Purisima want opinion therapy. Is very very high rate of crossover treatment. So seekers might be matter, but this carbon alysus is better to be down in keynote of 62 to understand over the Bible result corrector II.
So one that important caviar is that treatment duration is not same with effective treatment period. This very interesting paper published ingestion inside from Japanese group investigated binding amount ipdois memory t-cells. It was detectable even after five months since last administration amount opinion therapies. It was also detectable even after subsequent therapy. And care 67 positivity in t-cell predicted outcome after discontinuation or efficacy of subsequent therapy. And this may partially explains a carrier by effect or enhancement of subsequent treatment. And actually, not a few report suggested better activity of cytotoxic agent america tiring agent after checkpoint Brocket. Left side is a gastric cancer data from Japan, which showed a very high response rate of usual cytotoxic chemotherapy after checkpoint blockade. So this kind of analysis is also better to be down in keynote of 62.
So next is by america's first families may be investigating users initiated the trial suggested a high response rate EBV positive case or high TM v case by whole exome sequencing. Policing to Chinese trial suggested show the one partial response among four e BB case. So not all and less was rate was still higher in can be high patient according to the whole exome sequencing. So we already have a approximately 130 patient with an Ebola be no institution after Japanese approval. We identified 15% of response and notification showed microsatellite instability. And two out of six EBV positive case showed the objective response. So again, not all and TM be by name GST not clearly correlated with the outcome. And the tmb by m GS are also still controversial in other studies such as attraction to and MA impact. So I think it might be better to analyze tmb by whole exome sequence and EBV status in a larger study such as the keynote 262.
And one the important point is that not a biomarker for responder, but also a biomarker for non-responder might be also very important. So this kind of beloved the progression or hypo progressive disease may partially explains a cross the survival curve even in CPS Championship operation after proper Oh bunny Bonham. We experienced the approximately twenty patient piece of this kind of rapid progression. And this patient has some characteristics such as gene amplification Reba mitosis and Raja tumor size. And this patient had buried two Opelousas less than two ounces and very few chance to receive subsequent therapies. Very interesting recent report in clinical cancer research suggests that the son PG important make approach may induce this kind of a hyper progression. And this may explain by the fact that a proportion of anti PD one may activate macrophages and dendritic cells. It was with reproduced in preclinical studies. We also evaluated about C material from patient fusion rapid progression in gastric cancer. And the shear we observe the high infiltration k67 positive regulatory t-cell in local tumor after treatment.
So we're going back to the preclinical study and we confirmed that exposure to anti PD one query activated pd-1 positive regulatory t-cell represented by a very high clear 67 positivity after at a pyramid therapy. And this cheery Excel clearly inhibitor she races. So using the theory again, it's the mouse model anti PD one enlarge the tumors compared with the control. So this is a very similar phenomenon or wizard hyper progression in clinic. So actually PD one positive killer cells are more enriched in non-responder with checkpoint blocking. And very interesting read this PDL positive cell more enriched in gastric cancer compared with NOS mostraron cancers. In contrast, the PD one post we see racers are more English in their spotters as you can see this PFS curve. And this may be this is explained by the fact that the strongest stimulation signals through TCO result in very high PD one expression on Shirra ASSEL. So PD one on cd8 reflect the antigenicity. So neeraja india's more higher expression on silly APD one on shield SS compared with OSHA Advantium. So if we combine these two factor P apostrophe s's and a pity one positive T really sells it more collectively predicted outcome after checkpoint blockade. So this result should be further confirmed in additional studies. And listen to single-cell RNA sequencing clarify the exact a phenotype to be activated by PD one Balkan such as TC f 7m r XL some kind of effector memory t-cells in a silly sorry 9p teleportation ASL. I think this exact found that camel collector II predict outcome after checkpoint blockade because checkpoint block and not work for cancer cell, but work slew immune system.
So at this time, it' tree remains unclear that familism up for serious vamp operation become one. So treatment option or not, but it should be discussed with regulatory authority and within several gathering committee in each country's. But if available, all track to use for forming case such as GPS a higher please there without any clinical significant symptoms and a high chance to receive subsequent therapy in Japanese patient population notification met this criteria.
Let's move to the chemo combination. There are several rationale to combine Kim's European a checkpoint blocker, but I think the most important wise to reduce the tumor burden. This nature paper published two years before suggest a ratio between October Eric a sixteen seven seven positive PDO and posterior cell and the tumor Boram is very important to predict the outcome. So to reduce the tumor body my chemotherapy may improve outcome. But once amis concept is that chemotherapy may induce teaming in new Antley. This may not true, but with a many chemotherapy, this was very disgusting annals of oncology got Roskam syrup you may boost immunotherapies through moderation be immunophenotype.
So until now, many clinical trials have been conducted so far to combine chemotherapy and a checkpoint blockade for several kind of tumors. And the muscle trial showed a significant improvement in PFS in the overall survival. So why not redo same trial for gas Council? And actually, clean up 62 is the first trial to access this clinical question. But disappointingly, no implementing over Sababa was observed in Bolshevik swine to appears temperatures in cooperation. And the most surprising result from this 62 is a better outcome with families moments or appear in cheapest tempation cooperation compared with kim Sara people's pain balm is not in terms of long-term survival. So at this time, the exact reason of this negative result remains unclear, but we should discuss from several aspect. So one of them is a backbone of chemotherapy process Prussia and car approaches showed a significant improvement over the Bible in lung cancer trial. So at least Express may not diminish the activity of checkpoint inhibitors. And the other trial also applied the Platinum a gentle backbone chemotherapy. In contrast, exert regime may be a better partner or with a checkpoint inhibitor because it induced more in neurological cancer cell death comparability strategy. One of them was published in each of the four years before.
So other is a5 a few he had done a castle trial with a very similar stream design like 1802 62. We can indirectly compare embolism or therapy and Families Marissa file review on the since protein. And here we did not observe the any significant difference in terms of one-year PFS and two-year PFS between families mom our therapy and the team combination over our survival also showed a no significant difference, but it did not show the deterrent effect. So long the very important the difference between head and in cancer and gastric cancer is a maintenance 5 review. In head and neck cancer, we usually stop the five review with the platinum agent, but in gastric as are not a few doctors or not a few patient received their five a few as a mandarin therapy after discontinuation progeny agent. And actually, in several preclinical studies suggested repeated administration of five a few have a negative impact of immune system depression nucleotide lead to the inhibition be effective function as well as the interference with differentials from naive cell into memory self. And the other in vivo study also suggests that the inhibition of a festa function as well as reduced to mine filtering reinforcer after five a few repeated five of you. By the way, we should stay tuned for attraction for and a segment system on I trial. So maybe we should know more detail about the chemotherapy or molecular tagging in therapy from analytical point of view.
This very interesting recent Nature Medicine paper evaluated the chemo in induction after and following subsequent report review narrative breast cancer. And hear induction is dr. revision dispatching improve the response rate reserved for wings of seeking therapy, but it was not observe with cyclophosphamide and in radiation. So maybe type of chemotherapy and the duration must be important. So previously we investigated biopsy material from gastric cancer patient received a five review a nuclear protein. Here we did not observe any change of immunophenotype at two months of treatment. In contrast, Ram sharam ablation therapy showed a trend of reduced regulatory t-cell local tumor. And we confounded Perceval to a very highly expressed in regulatory t-cells level of live as well. The other Mouse kinase inhibitor show the same efficacy to reduce a tear in clinic. And it also reduced a tumor cells in America for the solution. So far inhibition and this effect words per interesting. We observed more with a low adult higher dose is not better. So we have conducted a phase one trial of regulation abandoned OMA and the preliminary result were presented in previous ASCO and will be updated in this as modulus updated biomarkers. And here we observe the response rate of forty four percent in gastric cancer. And all patient were microsatellite to stable. And a certain patient were previously received the checkpoint inhibitor and experienced the progression. Past three of them achieved a partial response. And these are actual patient who achieved a good response with this combination with Reba matrices. As you know, Reba is very helpless to achieve the response with the PDM volcano mouth era. Media PFS is along six months is for gas chances. And this patient shoulder disease progression Alton evolve mammography, but showing the last month with a graph in a van Bommel. An especially increased infiltration of regulatory t-cell after treatment. And after nibble mammography, but it showed a reduction after combination therapy. And actually, this response was maintained approximately whiner. And right side is a right side suggest that the patient if we show the partial response also show the trend over regular activity. So this might be the mode of action. So we laughing a limb. But here is also another example of much kindness in shifter, which showed a similar effect in preclinical study.
So we have conducted a phase 2 trial, but imaginable in the primer is Mapo gastric cancer. We already finished enrollment. We will report the result in your futures. But I do not think that the target immunosuppressed will sell maybe not enough for Moscow. And on all patients for gastric cancer, not a few case may require in no injection for that purpose. Discernible carotid virotherapy might be wrong. For example, these three machines on karateka Dino virus, which we precariat only in thermal as positive cell and result in cancer cell death. At that time, it activates a PCR cbsl. So we have conducted a combination trial for gastric and expression cancer. And the preliminary result were presented in previous area. It showed a primary tumor reduction in most cases. And some patient also the reduction in distant metastases. And after an karateka therapy, some patients show that infiltration PT bat the hypogeum posterior. So in local tumors. So we have started the infusion for Reba metastasis and the final cut is therapy will be coming for sorry to tumor cell.
In last I asked ordinary point to specific cuts directly for gastric and pancreas castle. A very promising activity response rate was our 3%. So this is my summary. Sorry, I might be option for treatment for anti PD 134. We can denote 60 to show they're crossed over survivable, but it still opens a door for checkpoint inhibitor area lines of treatment. Crossed over sabado curve and Kim combination not work. So these results suggest that we need a better biomarker and a better combination. Thank you for great attentions.