Treatment in R/M-SCCHN in the Year 2025 - Standard and Considerations for am Individualized Treatment

00:00:00: You are listening to an ADIS journal podcast.

00:00:05: Thank you for joining us on this ADIS podcast today.

00:00:08: This session was funded by an educational grant from Merck Healthcare Germany and MSD.

00:00:14: In this session, the medical treatment options for recurrent and or metastatic squamous cell castenoma of the head and neck will be discussed.

00:00:20: I'm delighted, therefore, to be joined by experts Dr.

00:00:23: Conrad Klinghammer and Dr.

00:00:25: Philip Ivani, who will explore this topic together.

00:00:28: So... Shall we start today with a brief introduction to you both?

00:00:31: Well, thank you for the introduction.

00:00:34: I'm Konrad from the Charité in Berlin and I'm joined by Philipp here.

00:00:39: Hi Konrad, hi Legia.

00:00:40: So it's a pleasure being here.

00:00:42: And Konrad, you also should mention your last name, which is Klinghammer.

00:00:47: My last name is Ivani and I'm from the Hannover Medical High School.

00:00:51: And both of us, I think this is a common thing of us, Konrad.

00:00:56: We are medical oncologists and we have some passion for the patient's medical treatment of head and neck cancer.

00:01:02: You agree?

00:01:03: Absolutely.

00:01:05: I've been in this field for actually since the beginning of my career as a doctor and meanwhile leading the head and neck cancer study group in Germany and most of the patients I see on my daily life are had a neck cancer patients so I'm quite into that field and I'm still loving

00:01:26: it.

00:01:27: Right and you said since the beginning of your career so from your optical shape it's only five years but your series are very important and we're happy having you as the lead group of the medical working party.

00:01:39: we're also integrated and you're doing a great job.

00:01:41: but let's let's go to the topic.

00:01:43: the audience I guess is not so much interested in our vitae rather than what we have to tell Absolutely.

00:01:50: Let's start with some general aspects of head and neck cancer.

00:01:54: We're looking at quite a common disease.

00:01:58: It's something that occurs worldwide.

00:02:01: We don't have very good data from Africa about the incidents, but at least for Europe and the Middle East and Eastern Asia and North America, we do see that we have an incidence in between five to about twenty patients per one hundred thousand.

00:02:24: The main risk factor is apparently smoking and some patients are affected by HPV.

00:02:31: But concentrating on Germany, we see about sixteen to seventeen thousand people diagnosed with head and neck cancer.

00:02:39: And you have to keep in mind that about half of them are still dying and especially those that.

00:02:48: that come to the situation that the disease is recurrent, we talk about that later on.

00:02:53: We'll need medical treatment.

00:02:56: There's still more men than women that acquire the disease.

00:03:00: And especially when we talk about oral cancer and pharyngeal cancer, it's much more common than laryngeal cancer.

00:03:10: We predominantly see that in men.

00:03:13: And head and neck cancer, and you already heard it from what I that I talked about this is not only a disease of one anatomical situation or one anatomical area rather than this is a subset of what they all have in common.

00:03:33: that are squamous cell carcinomas.

00:03:35: starting from the oral cavity to the oral pharynx, the hypo-pharynx and the larynx.

00:03:42: And what you need to take out in the consideration of a general head and neck tumor is nasopharyngeal tumors.

00:03:49: Nasopharyngeal are also squamous carcinomas, but they are much more common in Asia and we don't see them so often in Germany.

00:03:58: And they're also from their etiology, quite a different thing.

00:04:02: And what's really... but we see some of them are salivary gland cancers.

00:04:07: We will not speak about salivary gland cancers, even though they are extremely interesting, especially in regard to molecular alterations, but we will keep them out of the scope today.

00:04:21: cannot absolutely read.

00:04:23: I think it's worse to mention that celebrate land cancer consists, I guess, about twenty seven different diverse histology subtypes.

00:04:31: So it's really a chapter for its own.

00:04:33: One brief question, by the way, you just mentioned the German data about the prevalence and the gender distribution.

00:04:39: Is the gender distribution due to the higher prevalence of HPV positive tumors in USA different than in Europe?

00:04:49: We see the predominance of the general disease of head and neck cancer is more often in men because of smoking and alcoholic habits that are more common in men than in women.

00:05:04: Even though we have to consider, unfortunately, the numbers in total are rising in women.

00:05:11: For HPV, it's about the same.

00:05:14: There is no gender difference in between those two groups.

00:05:20: You know, this is the reason why I agreed for this podcast, because I can get some questions appropriately answered by your comrades.

00:05:26: So thank you.

00:05:27: OK, so let's see now a little bit about the treatment landscape, because at least for the German medical oncologists and during the education period, sometimes it looks to me it's complicated, but in fact, it's not.

00:05:41: Most of the diseases are primarily diagnosed in a localized setting.

00:05:46: This is a domain of the colleagues who are doing the operation or the concomitant definite radio chemotherapy.

00:05:55: And this unfortunately does not cure the majority of the patient after approximately two years.

00:06:03: um, fifty percent of the patient recur and then either they have a recurrent or they have a metastatic stages or they have both of it recurrent and metastatic.

00:06:12: That's the reason why on the medical conferences, um, it's always short-cutted with R, um, slash M, um, S, C, H, and M. And, um, of course, this is also the domain of, um, local therapy, but, um, there the medical oncologist starts doing and dealing the disease.

00:06:28: Um, but ultimately, um, Over all, the five-year survival for the disease is eighty-three percent over all stages, but once it is recurrent metastatic, the long-term outcome is still considerably poor and we have a need for improvement.

00:06:48: If we end up now, as I mentioned in the recurrent or metastatic state, we are approximately twenty percent of the patient do have both recurrent as well as metastatic.

00:06:59: why forty percent are metastatic only and forty percent do have recurrent disease.

00:07:06: We have different options although the choice of appropriate therapy is sometimes challenging.

00:07:11: We have damage operation if it's from the anatomical side possible.

00:07:16: We have reradiation if it's also from the prior radiation aspect feasible.

00:07:24: Those both theoretical strategies do have a lack of evidence to some extent because we don't have randomized trials really in this setting.

00:07:31: We have over the year increasing quality of retrospective analysis, but it's from the evidence level quite shaky.

00:07:38: And of course, this is also the field of medical treatment where we have randomized and prospective trials.

00:07:47: What would be the patient you sent for irradiation again?

00:07:50: We have some general aspect.

00:07:52: We would say this is a patient irradiate again.

00:07:56: What would be the patient?

00:07:58: I mean, this is the first answer.

00:08:01: All those patients need to be discussed in a multidisciplinary tumor board, right?

00:08:04: And this is sometimes, I don't know how multidisciplinary tumor boards work abroad, but sometimes in Germany, it's also a question of political interpretation of the data.

00:08:15: At the rule of thumb, everyone who was radiated within two years in this recurrent, mostly the options for re-radiation is limited.

00:08:24: However, with improving technological approaches of radiotherapy, we are starting to do it also sometime in this field.

00:08:37: However, I think at the rule of thumb, everyone who's recurrent within two years, is not a good candidate.

00:08:44: And for the operation, I mean, this is always a question of mobility and technical capability of the surgeon.

00:08:50: And if both options are not feasible, or of course, patient preference, right?

00:08:56: I mean, radiotherapy is not always funny.

00:08:59: I'm causing a lot of toxicity.

00:09:00: And we often have patients who are refusing re-radiation as an approach, right?

00:09:05: And then we are ending up in medical treatment, summarizing, and the decision is always mandatory.

00:09:12: right so and of course we are discussing i guess about medical treatment because this is our profession and what i always like is about medical treatment or what i always consider is what is really the patient who is suffering from the disease does have for medical need and personal preferences and so i like this kind of analysis which has been done by Mr.

00:09:35: Patel from the Tata Memorial Hospital, which is an awesome hospital in India.

00:09:40: You know, ten thousand unit diagnosed had a neck cancer treated at one center.

00:09:45: It's incredible, right?

00:09:47: They make very often very smart analysis as this one, which I shortly would like to summarize.

00:09:53: They made a survey in patients who were suffering from had a neck cancer who already went through radiotherapy.

00:10:01: both adjuvant as well as definite treatment setting.

00:10:04: They ask them, what is your need?

00:10:06: What are you interested in if we would do now continue with chemotherapy?

00:10:12: And the answer is, for me at least, a little bit surprising, but also, if you ask me, reflects really the need.

00:10:19: Thirty-five percent of the patients said they would like to have a reduction of symptoms as well as an improvement of overall survival.

00:10:29: And this is surprising.

00:10:30: Forty-one said, overall survival is everything, and twenty-four percent said, I need to get my symptoms controlled.

00:10:40: And they also said, if I go really after radiotherapy into a chemotherapy, I expect at least one year of life improvement, right?

00:10:49: So this should be always reflected.

00:10:51: And if you go to the items they address on this survey, Of course, one of the highest mentioned items were cure and survival, but as the third most item in this evaluation, the patient already said, we would like to have pain relief.

00:11:08: And then symptomatic aspects were mentioned.

00:11:11: And this keeps me a little bit always concerning the needs of the patient that symptom control is really a very important parameter, which we should reflect once we are considering medical treatment.

00:11:24: Yeah, absolutely.

00:11:25: I think symptom control, especially in a palliative setting, is goal number one because it's so much connected to quality of life.

00:11:32: And this is what I also always discuss with my patients.

00:11:37: And I think there might be a cultural difference, but in regard to the expectation of cure in the palliative setting, I would say at least for the population I'm treating, the expectation is not so high.

00:11:53: We discussed this very openly.

00:11:56: But you already touched slightly the necessity of symptom control.

00:12:03: And I think when patients present to us, we always make up what is the most important decision factor for which treatment we go for.

00:12:17: And on the one hand, we have those patient factors that mean, like, how old are they?

00:12:23: How is their performance status?

00:12:26: What is their social environment?

00:12:28: Are they coming by their own?

00:12:30: Are they living in socially isolated and without a network?

00:12:37: Are they probably alcoholics?

00:12:40: And also, are they coming from a very rural area where they have to travel long distance to the treatment center, which makes it sometimes not feasible to come every week rather than every three weeks.

00:12:55: So treatment schedule might be an issue.

00:12:57: And on the other hand, we have two more factors.

00:13:01: And that means, is this a symptomatic tumor?

00:13:04: Is that causing pain?

00:13:06: Is it bleeding?

00:13:07: Is it a big tumor?

00:13:09: that is where we have the fear of airway obstruction, and also biological factors like PD-I-I expression, a very important factor.

00:13:22: I think we will discuss that later on for the employment of immunotherapy.

00:13:29: There I need to point out, right?

00:13:32: highlighted the importance of a multidisciplinary tumor border.

00:13:36: But you very nicely worked out now and mentioned all individual aspects.

00:13:40: And this is also a recommendation for every multidisciplinary tumor ward.

00:13:46: There must be one physician who knows the clinics and all those parameters of each patient.

00:13:53: Yeah, absolutely.

00:13:54: I think what we always tend to do in the boards is that we make treatment recommendation based on the data and on the guidelines.

00:14:05: And sometimes the guidelines just don't fit the patient.

00:14:09: And this is then the situation where after counseling the patient and discussing the recommendation, we need to go back to the board and say, well, this is simply not feasible.

00:14:24: adjust the recommendation.

00:14:26: However, what we did in the community of the ERTC with a couple years back, we asked all those people that apply medical treatment, what is the most important factor for you to make what you base your treatment decision on?

00:14:46: And no matter whether it's chemotherapy, immunotherapy, or immunokemotherapy, it's always the same.

00:14:54: It's that ecoc is the most important factor.

00:14:57: So the patient's performance status that it is, is very decisive.

00:15:03: So the patient that is fit.

00:15:06: would rather also qualify for chemotherapy or a combination, whilst a patient that is unfit might not get a chemotherapeutic treatment and might only be treated by immunotherapy.

00:15:23: We go into the data later on, but I think to keep in mind, ECOG is the most important factor.

00:15:30: And it's also the most important prognostic factor.

00:15:34: No matter what treatment you give.

00:15:37: The better the performance status of the patient is, the better the outcome is.

00:15:43: And I think this is also a reason why we see only very fit patients on clinical trials, which we always discuss, is that so good?

00:15:54: Is that really representative of our population?

00:15:58: But at least for the pharma-driven trials, we only see very fit patients on those trials.

00:16:05: And it's worse to mention Conrad, the work you mentioned, which is showing actually this predicting response of IO, right?

00:16:14: I like those kind of analysis a lot because we are wasting so much money for precision oncology and molecular diagnostic and sometimes the old easygoing marker, estimated by experienced physician, is more predictive than those markers.

00:16:29: So first things first is always my idea, right?

00:16:32: Absolutely.

00:16:33: We are in a time where we always try to fit something into something we can measure.

00:16:38: But yeah, this is something we cannot measure very well so far.

00:16:44: We are on the way, though.

00:16:46: Yeah, but let's go now to do more and more medical treatment.

00:16:51: What kind of agents we are using?

00:16:53: I think there's not even so too many agents.

00:16:56: There's only a handful of agents.

00:16:58: We have, looking back into the times where we only had chemotherapy, there's those platinum compounds, which are also standard for radio chemotherapy.

00:17:09: Then we have the FIFE-FU as a compound that is working.

00:17:14: Taxanes are very good efficacy.

00:17:17: We have EGFR receptor antibody sataximab, but only sataximab.

00:17:21: This has been shown really efficacy, not others.

00:17:26: MTX, methotrexate, that is something we have seen.

00:17:30: There is an efficacy, not high, but a bit.

00:17:34: And the last... ones that joined that club on the PD-I inhibitors in the volumab and pamprolizumab.

00:17:42: But if we look at the development and especially in comparison to other diseases like breast or lung cancer, where we can celebrate a new compound almost every year, the development in head and neck cancer has been really, really difficult.

00:17:58: And there is a high medical need to introduce new compounds into that field.

00:18:04: There is many trials, but many trials have already failed within the last ten years to introduce new compounds, so it's not easy to treat.

00:18:13: Yeah,

00:18:14: I absolutely agree.

00:18:16: Okay, so yeah, actually that's quite frustrating, right?

00:18:21: But to be honest, so many trials compared to lung cancer and other diseases of gynecological oncology.

00:18:27: We don't have so much tries running around.

00:18:30: Currently, we see a wave.

00:18:31: We cannot see what comes out of it, but it's a risky investment to try to develop a drug in the setting.

00:18:36: But let's go to one of the landmarks and what we have learned from it.

00:18:43: I think after we saw the first trial very long ago, which showed.

00:18:49: Improvement of all also by combinator chemotherapy the first land my try was done from the very well known colleague.

00:18:57: for more than a Dutch guy he was a P.I.

00:19:00: of the extreme try which and for approximately ten years dominated more or less the treatment landscape mainly in Europe because the taximab as he was mentioned.

00:19:11: was not improved in USA and they have had some license problems, so it was not so common in USA for a long time.

00:19:18: However, what was described, this was a combination of platinum and five FU combined with Cetaximab, the anti-EGFR antibody, six cycles, and then followed as long as the patient were not progressing by a Cetaximab maintenance concept.

00:19:35: And this was compared one to one towards platinum.

00:19:39: five FU, the old a historical standard.

00:19:42: that primary endpoint was a wall survivor.

00:19:44: This try reached its end point and showed an improvement in overall survival, although it's not an earth-shaking effect, but it improved it from seven point four months to ten point one months, have a ratio of point eight.

00:20:00: So from the statistical side, clearly significant.

00:20:03: And the secondary endpoint showed also an improvement in PFS.

00:20:07: And what is interesting, actually, in this time, I think We both have been young physicians trying to interpret and read papers and trying to understand what they're writing.

00:20:17: We also saw the first data about the quality of lives in early, let's say, times of the development of the methodology itself.

00:20:28: And it also showed that the improvement with overall survival in PFS as a result of anti-EGFR treatment showed also in some items improvement of quality of life.

00:20:39: And so for me, my take home of this treatment, although it's quite toxic, is once you're reaching an objective response, it looks like also that the quality of life gets better.

00:20:53: Yeah, absolutely.

00:20:55: Fully agree and we've seen that with many patients that do actually respond to the treatment, newer data show that it's up to almost sixty percent of patients that respond and this is highly effective and therefore also reducing symptom burden.

00:21:15: What I would like to add is that over those trials where we have employed extreme skin we saw that not all patients make it that they get six cycles and the majority of patients had four to five cycles and efficacy doesn't seem to be affected by whether you get all the six cycles or lower number four to five.

00:21:44: That may not change in a clinical setting where we adopted to sparing some toxicity by giving a lower number of cycles to four, but we can discuss that later on.

00:21:58: I already said that many patients did not make it through the entire course of the planned schedule.

00:22:06: It's a different trial which we should discuss as a landmark trial where we learn from.

00:22:11: I guess so Conrad, please.

00:22:12: Oh yeah, it's not that old.

00:22:15: You talked about the Xtreme trial.

00:22:17: that came around two thousand eight and about ten years later Keynote forty eight was presented and naturally it had a control arm and that was the Xtreme trial you just mentioned and that was our current standard to that time.

00:22:35: And one comparator was Pembro.

00:22:39: PD-I inhibitor, Pembrolizumab as a monotherapy.

00:22:43: And the other comparator to the extreme was Pembrol with a chemo-therapeutic backbone of platinum in five a few.

00:22:52: And to be honest, when I first saw this trial scheme, I was very skeptical whether immunomonotherapy could be better than... a chemo combination with sataxiomab in this difficult to treat patient population.

00:23:15: Now what we saw is that We need some PDL-I expression in those patients and going through all those tumors that evaluating them for PDL-I expression, we learned that about seventy-five to eighty percent of patients with had a neck cancer have some amount of PDL-I expression.

00:23:39: Some have only very little, about five to ten, but there are also some patients that show very high expression and we speak about a high expression when it comes to values from a CPS score higher than twenty.

00:23:56: And what we saw from the trial is comparing the chemo-sytoxyl map with the chemo-immunotherapy.

00:24:06: that chemo-immunotherapy was clearly better in the total population of the trial, also in the population that was with the PDL-I expression score, the CPS higher than one, but especially for those that have a high expression of PDL-I.

00:24:26: And that is reflected in overall survival benefit throughout.

00:24:33: really appreciate that there is a plateau after doing the chemotherapy that no matter if the if the immunotherapy is given alone or in the beginning with the chemotherapy that there is a plateau of patients that have seemed to have a long-term benefit.

00:24:51: I think we will discuss this later on again about this long-term benefit.

00:24:57: And looking at those patients that only get immunotherapy compared with chemotherapy, we also saw the benefit especially given for those patients with a high PDL-one expression of higher than twenty.

00:25:12: And just to exemplify with a number that At forty months we have overall survival rate of twenty one patients that means twenty one twenty percent.

00:25:24: one fifth of patients that enter the trial are still alive after two years.

00:25:30: Whereas.

00:25:31: if they've had the chemotherapy with the satuximab backbone, the numbers were only eight percent and those PDL-I high expressors.

00:25:40: I think this is always about the same.

00:25:43: The number is below ten percent of those that survived the second year.

00:25:51: What is a general aspect of immunotherapy is that if the patient are responding to the immunotherapy as on the immunomonotherapy they respond for long-term in general.

00:26:08: May I shortly ask a provocative question.

00:26:12: Is your strategy in general irrespective of all the parameters you considered five minutes ago for individual treatment?

00:26:21: If you have a CPS higher than twenty patient, is this always one size fits all PD-one monotherapy?

00:26:28: Not at all.

00:26:29: Okay.

00:26:31: To be honest, CPS, I use as a marker whether I'm allowed to give immunotherapy or not based on the license, but I'm much more guided by patient symptoms rather than PDL-I expression.

00:26:49: Okay.

00:26:51: And I think the numbers, or if we look at those subgroup analysis that were done after the trial was out, when they looked at those patients at the particular low expressors, looking only at those that have a CPS expression in between one and nineteen, we see that the immunomonotherapy is not better than, or not worse, it's the way you look at it, than the chemotherapy.

00:27:25: So, not being guided by a period of one expression here is, I think, the key message.

00:27:32: Better to look at the patient factors.

00:27:36: But don't need teratheory sensors.

00:27:39: if we would have a biomarker which takes the decision of all, right?

00:27:45: Okay, so let's go a little bit back.

00:27:48: We saw now two of the landmark trials, right?

00:27:53: And I think on what is important and what we did not mention, both of the landmark trials only considered and included patients who have not been progressing within six months of radio chemotherapy, which is a relevant proportion of patients.

00:28:12: And this needs to be kept in mind that both phase three trial didn't include those patients.

00:28:17: So you not necessarily can conduct from those trials that once you have a patient who is progressing early on after radiotherapy that the data affects also this kind of patient.

00:28:30: There we have actually an evidence lack.

00:28:33: We both mentioned landmark trials.

00:28:35: Conrad summarized very nice individual.

00:28:39: parameters and I'm now going to depict your different interpretation of the data because what is missing?

00:28:46: like in many fields of oncology we don't

00:28:49: have

00:28:50: head-to-head data of some of the really very important parameters and for me kind of the nicest trial I would like to see despite combination of new agents.

00:29:04: Once the keynote O-Forty-A trial was presented on ASCO, I think, and I'm not sure it was, in the same session at ASCO, the European group presented the TIP-Extreme trial, which has been a phase two trial, but large number in patient.

00:29:23: And they have actually a very good idea where we have had a good ratio, exchanging the toxic five-view with Tuxane.

00:29:32: I'm comparing it with a platinum and using Zetaximab.

00:29:36: And this is also a very important trial.

00:29:39: I would like to have it actually a try.

00:29:41: comparing chemotherapy with PD-one and five review towards on the platinum and taxon try, but we don't have it.

00:29:49: And if you go and make some kind of trust trial interpretation, comparing keynote of forty eight and the tip extreme try, which.

00:29:57: did not reach this endpoint, but which showed nicely, if you ask me, what you can reach from the result nowadays with a sort of taximab-based chemo combination, including taxane.

00:30:11: And first of all, you correctly interpreted and explained us the data from Keynote O-Forty-Eight.

00:30:19: But in my opinion, you didn't mention the weakness of this regimen.

00:30:25: And this is the first six months.

00:30:27: Indirectly, you mentioned it because you said we have to check it very carefully.

00:30:31: If you look carefully to the curves in particular from keynote o-forty-eight of the PD-one monotherapy, you see within the six months that the overall survival is running below in the Kaplan-Meier curve from PD-one compared to the extreme.

00:30:48: This means we are losing patience early.

00:30:51: if we are using PD-one.

00:30:52: If you look then to the curve of the ITT population where PD-one is combined with chemotherapy, then you don't see this effect.

00:31:02: And this is strong evidence for me that we have a substantial proportion of patients who really demand chemotherapy in the beginning because then otherwise they are early on lost.

00:31:12: This weakness is not seen in the TPEX regimen, of course.

00:31:17: And there's a second aspect you set natural wise or as as a law that we see already a long lasting effect in the interpretation of the keynote trial.

00:31:27: If you look to the event number, it's still low and we have a lot of sensitive events.

00:31:33: So I think there is some uncertainty about it.

00:31:36: in general, although the curve looks good for the PD-one based therapies, right?

00:31:42: If you look to the TPEX trial, no question it's a phase two trial.

00:31:46: If you look to the tail of the curve, we have a higher number with longer follow-up, at least reported.

00:31:51: It's also not completely worse.

00:31:54: And to be honest, if you think about the data, sometimes I'm questionizing myself why they extreme on in the keynote, O-Forty-I and O-Forty-Eight.

00:32:04: try and reach ten point seven months, which is actually the same efficacy which Fremont showed ten, fifteen years ago, right?

00:32:13: And I would expect usually that a standard of care arm should improve over time compared to the old primary trial, right?

00:32:22: Which you can see in the TAPEX trial because they ended up with the EGFR chemotherapy irrespective of which component they needed.

00:32:31: both higher than thirteen months right so always keeps the tail of the curves a little bit in interpretation.

00:32:39: I'm absolutely with you but let's stress this point again that in the very beginning.

00:32:45: If you make a wrong choice you might lose your patient and you.

00:32:51: so what you actually need to think about is if you give.

00:32:55: immunotherapy as a monotherapy to your patients, the thought which needs to run through your mind is, do I run into trouble if this treatment is not working within the first three months?

00:33:10: And if this question is in doubt, you should consider to add chemotherapy.

00:33:15: You said something about long-lasting things.

00:33:19: the plateau effect, right?

00:33:20: And if you go to the data, I think currently it's not convincing if you look to keynote o-forty-eight that we have a plateau effect.

00:33:28: The PFS is still, we see events at the tail of the curve, which suggests that there is no PFS, a long lasting effect like we see in melanoma.

00:33:39: But on the other hand, maybe the cohort is too thick for having this kind of effect.

00:33:45: And let's go a little bit again to different points.

00:33:48: for individual treatment decision, if we make, again, this kind of cross-trial thoughts, which I just said, and you go to the keynote of forty-one, a forty-eighth trial, you see in this supplement of the publication, and I think there is potentially definitely also a different biology as well as a different medical need.

00:34:09: If you see the efficacy of either chemo with Pembro or Pembro-Mono, Independence of metastatic only or recurrent only you see that the recurrent only.

00:34:21: we don't know whether or not there is a different and it looks like that this cohort does not clearly profit from PD one base the therapies at least not like the other ones.

00:34:33: So it's again a question remission.

00:34:36: is key and recurrent only ones might have medical needs.

00:34:40: Keep in mind if you go through all the objective response data of the extreme regimen of typical regimen and PD-one based regimen, first of all, the take-home is, I guess, chemotherapy induces higher responses irrespective of which antibody you use.

00:34:55: And sometimes it looks, even though this is a cross-trial comparison, that EGFR-based regimen achieves high ORs with low PD.

00:35:05: primary progressive disease, right?

00:35:09: And again, I'm focusing again to a topic you mentioned.

00:35:12: You mentioned the post hoc analysis from the keynote of forty eight addressing the cohort of one to nineteen CPS one to nineteen.

00:35:21: And actually, this is just hypotenuse generating that they are the PD one based therapies are superior.

00:35:28: And we did an analysis where we included with graphical and mathematical methods from all-relevant EGFR-based therapies, including TIPEX or including Xtreme, the data based on an optical extraction method, which health authorities usually do, and those reflecting and estimating the area under the curve rather than the first fifty percent, which is the more important thing for Kaplan-Meier-Bürn curves.

00:36:00: And we compare this in an indirect manner to the keynote o-forty-eight.

00:36:04: And what you there can see in this hypothesis generating analysis that CPS one to nineteen potentially is a cohort which really demands an individual treatment.

00:36:16: And Conrad, I don't know whether or not you see the point different, but surprised me when I saw the keynote data.

00:36:23: First of all, I was hoping that PD-one.

00:36:27: is way more un-toxic once we are combining this with Cisplatin V review.

00:36:33: and we saw the data and we learned no Cisplatin V review is really toxic irrespective of the antibody you include.

00:36:42: And then again I'm referring to the impressive session at ASCO in the old times once we have been young and full of energy.

00:36:50: You mentioned the question of how many cycles of platinum combination we need.

00:36:54: The typical regimen included only four cycles and used also seventy five milligram per square meters instead of one hundred and we saw there really a very nice decreased level of toxicity compared to extreme.

00:37:07: so that's why I think also for some patients this is really a good regimen right and in terms of quality of life in the first line setting I think it would be fair to say we don't have any superior regimen really.

00:37:19: if we go to the Published or at least in the report posted data would you would you agree on this?

00:37:26: and now absolutely.

00:37:27: but what we see is more agents we combine the two more toxic it becomes and this might also impair quality of life.

00:37:36: and naturally our patient population are elderly and frail and we.

00:37:42: Always need also to think about what are the alternatives to those that are evaluated in the clinical trials we just discussed.

00:37:54: What we have seen that patients that are elderly and frail, we asked the question, is metotrexate?

00:38:05: better than Pembro-Lizumab, or is Pembro-Lizumab better than Mr.

00:38:10: Drexved.

00:38:10: And we did a German trial.

00:38:12: Unfortunately, we were not able to recruit them fully.

00:38:15: We saw that they are equally effective, and that's actually something which is surprising.

00:38:21: We would attribute that Pembro is much better, but in the end, it's not.

00:38:27: And we come back to a point we made very early, ECOC.

00:38:31: is the most important factor no matter whether we look at chemotherapy or immunotherapy.

00:38:41: And so, immunotherapy might be just as good as immunotherapy.

00:38:50: And what we saw is that patients with that are evaluated in a French group.

00:38:56: It was called the Elan.

00:38:58: The Elan is a French study group that evaluated elderly people and had different trials running there.

00:39:07: What we saw there?

00:39:08: that monotherapeutic treatment is a good option for very frail, but if the elderly are fit.

00:39:17: We might as well give them a combination of treatment as we apply to the younger ones, since it's equally effective.

00:39:25: I said we need to step down in regard to treatment combination.

00:39:32: We might not give platinum, taxane and satuximab.

00:39:35: What we have learned from retrospective data, and there's really good retrospective data for that, that The combination of citroxymum with a platinum or carboplatin, for example, or pachytaxin is very effective in this group of patients with overall survival data.

00:39:55: They are just almost alike those that we know from keynote.

00:40:01: forty eight or typical trial.

00:40:02: So this is very convincing that if we.

00:40:07: If we think the patient might not bear the toxicity of three compounds, step down, take one out and go for treatment.

00:40:16: Right.

00:40:17: And to a short point, you mentioned the unfit.

00:40:20: I mean, some of the data are disastrous, in particular one for ECOP is really poor.

00:40:25: Sometimes there are patients where you honestly have to say best support of care is appropriate, right?

00:40:29: Absolutely.

00:40:31: The decision should always be guided by what is bringing quality of life to our patients.

00:40:39: We focused a lot on the first one.

00:40:41: Let's have a very brief look to the second line.

00:40:44: You also put your energy into a German guideline by the hematology, oncology society.

00:40:50: You made a nice graphical scheme.

00:40:52: It's basically very easy.

00:40:55: Once you choose for a first line, basically you switch the mode of action in terms of the antibody or the chemo therapy backbone.

00:41:06: But we also made a nice German work here from Reward because we are talking about a lot of sequencing.

00:41:14: But we saw to the Reward data that only a minority of patients is ending up basically in second line.

00:41:23: we included one hundred seventy nine patient in the first line in this register and only forty five patient has been came in to receive a second line therapy.

00:41:34: so we can speculate a lot about this topic.

00:41:36: but keep in mind the first line is where we have to do the major punch right.

00:41:41: um and so what are we doing in second line?

00:41:46: Well, as you already said, keep it simple.

00:41:49: If you give a PD-one inhibitor in first line, choose satuximab-based regimen for second line.

00:41:55: And if satuximab-based regimen was first line, you go for immunotherapy in second.

00:42:01: So far, it's that simple.

00:42:04: We had some retrospective data, but meanwhile we have really good prospective data.

00:42:08: How good SITUXIMAP package is in second line setting.

00:42:14: There was this trial, it was the PACE ACE trial, run by Torsten Führer from Austria.

00:42:21: that showed us that patients that are treated with apacytoxymer combination after immunotherapy failure, they reach a disease control rate of almost seventy percent and that is spectacular.

00:42:37: The overall response was nearly to fifty percent in this patient population in second line.

00:42:42: And I think that is really something we need to consider when we go for second line treatment.

00:42:48: We talked so much about the palliative setting for our listeners.

00:42:53: Philipp, let's make a spark to the future.

00:42:56: What do you think is coming around?

00:42:59: We're going to, this is not the future, this is already the present situation, right?

00:43:04: We saw recently the data from Kino six, eight, nine.

00:43:08: This is neo-adjuvant treatment with PD-one, right?

00:43:11: And tremendous result.

00:43:12: We have an improvement and arrived FDA-approved PD-one with pambrylism of neo-adjuvant two times and followed by surgery and for high and low risk patient and then followed by radiokemoimmune therapy.

00:43:27: adjuvant setting and I'm absolutely sure although the FDA approved it with four CPS positive patient for a good reason to some extent that this will very rapidly also affect those patients who end up in recurrent metastatic, because then we have to address the question, oh, they receive already PD-I in the upfront perioperative setting, then the metastas- metastasized or recurrent setting is not the same.

00:43:52: But anyway, this is the biggest change it derived.

00:43:55: And we also have data from the NIVOS stop, which is from the French group phase III try also with a positive result, introducing also PD-One with new volume up in the adjuvant radio chemo immune therapy setting, although correct me, they also only included high-risk patients, right?

00:44:18: Absolutely, yeah.

00:44:19: And I also think that I get the impression if the immunotherapy learns that the tumor is still in place and the immune system once learns how the tumor looks like, the efficacy is long term.

00:44:38: I'm not so much convinced or I'm much more skeptical about the pure adjuvant setting because we had this negative trial with a tesolizumab, which was a randomized phase three trial in the exact same setting, but for those patients that are in a high-risk setting and they have not received new actual treatment, I think it's an appropriate choice that we have now with Nevo.

00:45:07: Let's see whether they go to get a license for that.

00:45:11: So far, we don't have that.

00:45:12: I do expect that for the perioperative treatment with Pembro, we will have a license very soon.

00:45:21: And you ask what we will see in the future.

00:45:23: I think this is now would be a different story because there's really a plethora of really exciting things going around.

00:45:30: So what is your final conclusion about what we discussed?

00:45:34: Well, I think the most important thing when you consider your patient for medical treatment is ECOC.

00:45:42: And you must consider PD-I expression if you want to choose immunotherapy, but go and look at symptoms and symptom control and be guided by a goal of quality of life improvement.

00:45:57: And I think this is something if we consider that you are on a very good track.

00:46:03: Yeah, I agree.

00:46:04: And so basically it's not that complicated.

00:46:07: We, as you mentioned, we have only a small plethora of agents, choose wisely in first line, switch the mode of action in second line.

00:46:16: And I think this keeps us happy.

00:46:18: And potentially we are invited again.

00:46:21: We will see in the near future really a change of the landscape.

00:46:24: And so that's my point.

00:46:26: Conrad, like always, it was a pleasure having the discussion with you.

00:46:30: I enjoyed it a lot.

00:46:31: I

00:46:32: can only give that back.

00:46:33: It's always nice to discuss with you and someone who knows the data.

00:46:38: Thank you.

00:46:39: Thank you

00:46:41: very much.

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00:47:03: The link to the article page can be found in the podcast description.