Welcome to the ESLC webinar ESMO 2024 Highlights. I am Dr. Michele Aldea, a medical oncologist in Gustavusis, France, and together with Francesco Pasiglia, assistant professor at the University of Turin in Italy, we will be your presentation moderators today. We will start with some brief housekeeping items. After the presentation has concluded, you may ask any question by using the question and answer button that it's featuring in your video screen. We will be addressing questions after the three speaker presentations as the time will permit. Good afternoon to everyone and welcome to this webinar also from my side. I'm pleased to be here and to co-chair this ESLC webinar together with my co-chair Michele Aldea and now we have some technical information to provide to the audience. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education, ACCME. The International Association for the Study of Lung Cancer, IACLC, is accredited by the ACCME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates live formats for this educational activity for a maximum of 1.00 AMA PRA Category 1 credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. All the planners, speakers, and reviewers of this webinar today have disclosed a conflict of interest and this information is provided here in the next slide that I'm going to show you right now. Dr. Silvia Novello will be our first presenter today. She's a professor of medical oncology and the director of medical oncology at San Luigi Hospital in Orbasano, Italy. She will be presenting highlights of early stage non-small cell lung cancer. So thanks again for this kind invitation. I will focus on non-metastatic non-small cell lung cancer and this is my agenda. So I briefly touched the key results in the adjuvant and neoadjuvant setting as well as in the perioperative setting too and I will talk in the last slide about the LORA trial for the unresectable stage 3 disease. This is the treatment scenario in stage 3 unresectable disease and in early stage resectable. Historically we were used to talk about neoadjuvant and adjuvant setting. At the present time the vast majority of the trial and some results already available are talking about the perioperative approach and I will start about the adjuvant setting and more precisely I will spend a few words on BR31 trial. We are talking about stage 1b to 3a non-small cell lung cancer patients candidate to complete resection with a good performance status. EGFR and ALK rearranged patients were allowed to enter in this trial. The patient underwent a complete surgical resection and then received a platinum doublet chemotherapy and then randomized in a two-to-one fashion to receive durvalumab 20 milligram meter square every four weeks for one year versus placebo and we are talking about a large sample size more than 1000 patients. As you can see there is a hierarchical design so the primary endpoint is the DFS in patient with a PDL1 equal or higher to 25% and sequentially there was and there is the consideration of a key secondary endpoint. During this asthma we have seen the presentation about the subgroup of patient wild type or negative for EGFR and ALK. Even if the numbers and the figures are so small unfortunately we can't see a difference in terms of DFS looking at the overall population. So there is no improvement adding durvalumab in the adjuvant setting in the population of ALK and the EGFR negative patient with a PDL1 equal or higher to 25% as well as no differences in the other subgroup of patient. This is the context. I believe that we cannot compare one trial versus the other even if here are in the same slides because these are the measure of let's say the most important or those trial in which the follow up is longer together so the EMPOWER010 the keynote and the trial presented during the asthma meeting. But we are talking about different PD1 or PDL1 immunocheckpoint, different trial design in terms of statistical design, different design in terms of the use of platinum compounds and the use of chemotherapy or not, different percentage looking at the histotype and looking at the stage 3A and 2 disease. Having said that, it is true that these are the results of the trial. So we have overall two trials in the overall population showing a positive result. For instance, in my country the actual clinical practice is based on the results of the EMPOWER010 and we have the BR31 trial presented at the asthma that is a negative trial. To be honest, I do not have the answer to the question why this happened. I believe that we have to put together all the differences I have listed in the previous slide together with the fact that we are talking about trials conducted in different countries and where the surgery is extremely relevant and maybe the expertise and the surgical approach is important. While in the ALENA trial we are heading at least in my opinion another piece to the puzzle of precision medicine in early stages. Here we are talking about stage 1B to 3A, again good performance status with ALK rearrangement and we are talking about a sample size of around 200 patients randomised after a complete resection to receive alectinib versus platinum-based chemotherapy for cycle, alectinib for two years. And you can appreciate the difference in terms of DFS, the ASA ratio is 0.24 as well as it is important to notice the delay in the appearance of brain metastasis, the CNS-DFS, the ASA ratio is 0.22. No surprises in terms of adverse events, what we are looking in this trial is more or less what we are used to see in the advanced disease and the adverse events are concentrated, let me say, in the first six months of treatment. And the benefit is there regardless of the type of variants, talking about ALK rearrangement, while there is a worse DFS in those patients with the baseline co-mutation with the p53. What about the perioperative disease? So this is the context and the list of trials, for sake of time I will not talk about the rational 315 conducted only in stage 3 and only in Asia, but mainly because the other two trials presented during ASIMO are telling us more or less the same message. So starting from the Checkmate 770, in this case, we are getting some information about additional biomarkers to better identify those patients who must benefit from the perioperative nivolumab and more precisely the neoadjuvant nivolumab plus chemotherapy showed a greater CT DNA clearance associated with a complete pathological response and sequentially to an EFS and event-free survival benefit. And by contrast, the lack of the early signal of CT DNA clearance may identify patients who are unlikely to reach a pathological complete response. More or less in the same direction is the AGEAN trial. We know already the results of these perioperative trials showing an advantage of the use of dorvalumab in the perioperative setting. And again, in this case, all patients with a pathological complete response and more or less the entire population also of those with a measured pathological response and a CT DNA clearance, while the lack of CT DNA clearance may identify and recognise those patients who are unlikely to reach and to develop a pathological complete response. And there is a strict correlation between the event-free survival and the CT DNA clearance more than the relationship between the complete pathological response and the event-free survival. So, this is an important signal that is not yet part of our clinical practice, but is for sure generating a hypothesis. Moving to the neoadjuvant setting here, the first question could be, do we really need the immunotherapy in stage one? So, first we are talking about high-risk stage one osmocellular cancer, pure solid or with a solid component between two and four centimetres, the endpoint in this case is the pathological complete response rate. We are moving to a small sample size because we are talking about 50 patients, in the vast majority they are male, half and half more or less adenocarcinoma and squamous carcinoma. I believe that to answer to the question, do we need neoadjuvant immunotherapy in stage one, we have to put this trial in the context of a clinical practice with the implementation of a programme looking at the evaluation of a solitary pulmonary nodule or in a clinical practice with the implementation of a secondary prevention. We know very well that the goal of the screening for lung cancer is the reduction in mortality, but in between we hope to be able to have this switch of stage with an increase of stage one and is in this context that we have to put such kind of trials. This study met the primary endpoint because the rate of pathological complete response reached is near to 23 percent and the predefined threshold was 10 percent. Together with this trial, we got already some results of long follow-up for chemo-free immunotherapy in resectable non-small cell lung cancer in the neoadjuvant setting, and there is a confirmation of the results with five-year event-free survival of 57 and 50 respectively and five-year overall survival rate 70 and 67 percent with NEVO and NEVO-EP again respectively. In this case, there was the research concentrated focusing on the identification of biomarker, again able to recognize those patients who most benefit from this approach, and as we already know, the level and the expression of PD-L1 is strictly correlated with immunotherapy, mainly if we are talking about immunotherapy without chemo, so also in this case there is a demonstration of the correlation between PD-L1 expression and longer benefit, while there are some molecular profiles, mainly KRAS, STK-11, and KIPP1 together with SMARCA4 positive patients with worse correlation, but only in the case of the trial with NEVO and not with the combination. Moving to the last part of my presentation and to the stage three unresectable disease, where our standard of care is actually based on the PACIFIC trial, here are the results of the LORA trial. We are talking about a patient with an unresectable stage three who underwent the standard of care and then randomized it in a two-to-one fashion to receive Osimertinib once daily versus placebo, and I believe that the results are pretty clear. Here you have the curves in terms of progression-free survival with different kind of staging and evaluation of the disease. The results are there well shown, as well as we have also the significant improvement again concerning the delay of brain mets with 83% of risk reduction with this approach. So, my conclusion in this slide, I believe that we have some controversial role of adjuvant immunotherapy in resected nosmal cell lung cancer, but I do not believe that in the future we will continue to talk about neoadjuvant and adjuvant. We have to look again at this definition in our future. Alektinib, at least for me after surgery, is the new standard of care in resectable early stage ALK-positive nosmal cell lung cancer, adding a piece in the precision medicine in early stages. ctDNA clearance should be considered a predictor of clinical benefit from neoadjuvant chemoimmunotherapy, and this generates for sure a hypothesis to design prospective trials. While we need biomarker-driven study to identify those subgroup of patients benefiting more from neoadjuvant chemo-free immunotherapy-based approach, again in resectable nosmal cell lung cancer, and we have a new standard of care for non-resectable stage 3 EGFR-mutated nosmal cell lung cancer patient. Thank you for your attention. Thanks, Professor Novello, for the excellent summary, and now we move to the next speaker of this webinar with Professor Benjamin Best, who is the Director of Clinical Research at the Gustave Rousty Institute and is Professor of Medical Oncology at Paris Sackler University in France, and Professor Best will cover the topic of metastatic nosmal cell lung cancer highlight. Thank you very much. Metastatic nosmal cell lung cancer, we have now a very clear paradigm. When you see a patient, in particular if it's an unsquamous, you have to screen for targets, and you will have access to drugs first line or second line, but this will be the standard of care if you find a target. If you don't have a target, PD-L1 will be the biomarker. In the PD-L1 negative, we all agree that we have to give chemo and immunotherapy. I mean, so in some part of the world, you can also give a quadriplet with two immunotherapies or two immunotherapies alone. And then when PD-L1 is higher than 1%, in some places you can choose between single agent IO or chemo IO. And when PD-L1 is higher than 50% in other places, it will be the only population where you can give a single agent IO. So in this field, what is new, and we will start with immunotherapy. So let's take the population of the PD-L1 1+. In this population, in particular in the US and China, in the 1+, pembrolizumab is approved as single agent. In Europe, it will be restricted to the patient with a staining of 50 plus, but in the U.S. and China, PAMBROLIZUMAB is approved in that setting. And in this population, so an untreated population with advanced non-swollen cancer, no EGFR mutation or ALKRE arrangement, PD-L1 1% or more, PAMBROLIZUMAB was compared to EVONECIMAB. EVONECIMAB is a dual antibody against PD-1 and VGFR. It was presented right before ESMO at Wollong, but the primary endpoint was PFS. And although the population is a bit different from the one you can see in global trials around the globe with a lot of squamous, for example, not so many female in the trial, but a very strong signal for PFS versus PAMBROLIZUMAB. And the performance of the PAMBROLIZUMAB arm is roughly what you expect. So I just put this study to say that this is a drug we are talking a lot lately, but we are clearly looking for something more than PD-1 blockers or PD-L1 blockers, even with CTLA-4 blockers. And it's been a while we're talking about LAC3. We know that these drugs are approved in melanoma, but what is the role in non-small cell cancer? Small study, about more than 300 patients randomized still, that compare chemo plus nevo in untreated patients, whatever the PD-L1 status, plus REDLATLIMAB, which is a LAC3 modulator. I will just focus on the specific population that is the PD-L1, 1 to 49%. Even if it's a small group and you can see only roughly 30% per arm, 30 patients per arm, sorry. But this is where maybe there is the strongest signal. There are obviously some questions about the power of this type of sub-analysis, but phase three could be done in this specific population. Maybe this is the intermediate PD-L1 is the good population for the LAC3, let's see. TGIT is also a checkpoint inhibitor we are talking a lot about for now years, and we don't see so much positive trial around. So this is a new trial dedicated to the population with high PD-L1, more than 50%. And in this population, DORSTALIMAB, an anti-PD-L1 anti-blocker, was compared to a combination of DORSTALIMAB and an antibody against TGIT. In terms of response rate, there is, you can see small cohorts of roughly 30 patients, but there is a tendency to have a higher response when the anti-TGIT antibody is higher. And it's interesting also to see that in terms of toxicity, the higher the TGIT is, the higher the treatment-related adverse events are. So maybe there is a signal here, and again, that could be a trial in a high PD-L1 to explore this new TGIT antibody. Now I will move to the antibody-drug conjugates. We have seen the results of two drugs against TROP2, datomotapab derixtican, sasituzumab govitican, and in both phase 3, results were either negative or lightly positive, I would say, and datopotamab derixtican was positive, but only in the subpopulation, the non-squamous. We could say that we were waiting a lot from these drugs, and these two trials probably have mitigated our expectation around these drugs. The PARMAN03 study was presented at World Lang, and this is the first randomized study in a biomarker-selected population. So here, and it's in contrast of the TROP2 ADC that are tested in all comers here, the drug is tested in the patients in which you can find an expression of CEQM5 in their non-squamous non-small cell encounter, and it's roughly 20% of the patients that will be tested as high CEQM5. Only those patients were randomized between Tuzorab, an ADC against CEQM5, and or versus docetaxel. And unfortunately, even with a biomarker-selected population, both PFS and OS were negative and disappointing. Of that, CEQM5 appeared to be a prognostic factor, which was quite unexpected, in fact. So just to say that the field of the TROP2 ADC at the moment in non-small cell encounter is still a moving field. We are not sure this drug will really make it. And there was one presentation interesting because it's a new MET ADC. We know that telizov is a drug that is currently in phase three, but this is a drug that still have the same antibody, the telizopart, which is an antibody against MET. But there, the payload is a top-of-one inhibitor. And I think that the response rate and median PFS in the all-comer population is interesting. And when, although it's a very small number, but it seems that when a population is then rich in MET positive non-small cell encounter, the response rate seems to be higher and maybe interesting. So early data, but just to say that in this moving field of ADC, maybe the MET ADCs are the ones that we should keep an eye on. Let's move to the target therapies. In EGFR-mutated non-small cell encounter, the Mariposa 2 study was recently published and it showed that in patients exposed to ozimertinib, and that has progressive disease after ozimertinib, chemotherapy or chemotherapy with amivantamab, a dual EGFR-MET antibody, showed a benefit for the combination of chemotherapy and amivantamab. It's a regimen that is approved or sometime can be prescribed within the expanded access program. And this is, I think, one of the new standards of care after ozimertinib exposure. The Mariposa 2 study was updated. The overall survival has a clear trend in favouring the combination of amivantamab plus chemotherapy. We see that they are still in both arms, quite a number of subsequent treatment. And now the real question we have with amivantamab is, will amivantamab be a preferred first-line regimen with lasartanib? This is the Mariposa 1, the Mariposa trial first-line or ozimertinib first-line and then escalate to a combination of chemo plus amivantamab. I think it's one of the main questions we have today. What shows this data is that it's a potent option after ozimertinib. Interestingly, some additional data were presented at ESMO looking at the resistance mechanism to amivantamab plus lasartanib, and it shows that amivantamab is really a drug that is working through both EGFR inhibition and MET inhibition. So clearly an interesting drug in the field. Amivantamab is also a standard of care in the small population that has an exon 20 EGFR mutation, roughly 1% of non-swollen cancer. And in this population, chemotherapy plus amivantamab has been shown in the papillon trial to be a standard of care. So one of the questions we have is when such patients receive first-line chemo amivantamab, will TKI be an option? Zipalazertib is a TKI against the specific exon 20 EGFR mutation. And interestingly, the activity is still clearly seen after exposure of amivantamab when the patients receive only amivantamab, the response rate in 18 patients was 50% with overall median PFS of almost 10 months. So yes, after chemo amivantamab, probably EGFR TKI will be an interesting option. Do we have something new here after ozimertinib today? When you don't have access to amivantamab, you prescribe a chemotherapy, a platinum-based chemotherapy. And this BNT327 compound is again a bispecific like evanesimab. It's a bispecific antibody against PD-L1 and VGF. So again, dual modulator of an immune checkpoint inhibitor and of the angiogenesis pathway. And here with chemotherapy, it seems that there is an interesting signal in 64 patients. It's very early data. You see the typical toxicity of the VGFR antibody, meaning proteinuria, hypertension, and some bleeding. Would it be better? We know that in China, evanesimab is approved with chemotherapy past EGFR TKI. A study is ongoing in the global population. Let's move to ALK. ALK positive is 3-5% of the non squamous, non small cell cancer. We know that we have today many options, including second generation inhibitors, such as alektinib and brigatinib, and the third generation lorlatinib. Lorlatinib was recently, the crown study for lorlatinib was recently updated with an impressive PFS with a 5-year follow-up. Although we have 5-year follow-up, we still don't see the overall survival curves, which is a bit frustrating, but still three decent options. Some might think that lorlatinib is a better option because the AZA ratio is stronger against crisotinib in first time, but again, without evidence of improvement of overall survival. So here, do we have newcomers? Yes. Interesting drug, NVL-655. It's an ALK inhibitor that was tested in the phase 1-2, the ALKOV study. And in this study, patients were all pre-treated with at least one TKI. You can look at the middle in the patient that received at least two ALK TKI, including lorlatinib, the response rate is 35%. So interesting because this is an TKI, an ALK TKI that has activity post-lorlatinib. It is potent against the G1202R resistance mutation. So it's by definition a third generation ALK inhibitor. Is it a fourth generation ALK inhibitor? I don't know, but activity post-lorlatinib, I think this is very good news, plus a good safety profile and intracranial activity. And I will end with the ROS1-positive non-small cell cancer. Here, we know that crisotinib and taletrectinib are the ones that are approved. New second generation inhibitors are coming. An update that will be done with taletrectinib. Taletrectinib is a second generation ROS1 inhibitor. It's the G2032R resistance mutation. This is why we call it a second generation inhibitor. I think the interesting part here is that the TKI naive cohort was presented and updated. 160 patients treated with taletrectinib, response rate 88%, and a PFS, median PFS of 45 months. Quite impressive. My last slide will be around zidazantinib, which is formerly known as NVL520. It's a ROS1 inhibitor. And again, it's the resistance mutation G2032R. So it's a second generation ROS1 inhibitor. Good safety profile. It doesn't need to track, so it avoids all the toxicity related to track. And overall, in all the populations that receive at least one TKI, response rate 44%, 38% in patients that receive the second generation repatriactinib. So again, very good drug. We should keep an eye on this one. And with that, I thank you for your attention. Thank you, Dr. Best, for your comprehensive presentation. Now, our final presenter will be Dr. Ross Soh, who is a medical oncologist at the National University Cancer Institute in Singapore. And he will speak about small cell lung cancer and TMIC tumors. Okay, thank you very much, everyone. And I'd like to thank ISLC for inviting me to present the ESMO highlights. And I'll be presenting on three abstracts. And since this is the non-small cell diseases that I'll be presenting, the first one I'll be talking about will be the Adriatic subset analysis in small cell lung cancer. And then similar theme in small cell lung cancer is a new compound of BMS6012 with chemotherapy in extensive disease, small cell lung cancer, and finally on the TMIC epithelial tumors using a combination of lambdatinib and embolizumab. Okay, so there's my overview again. So let's go to the first study. The first one is actually presented by Suresh Senan at ESMO. Basically, he's looked at the subset analysis. The Adriatic study was originally presented by David Spiegel at ESCO this year. And in the Adriatic study, just to remind everyone, this study for patients with limited stage small cell lung cancer, in other words, from stage one to three, had a good ECOG performance status and must have had received standard of care concurrent platinum-based chemoradiation treatment. And these patients randomized to either duvalumab consolidation or duvalumab plus tremolumab, which is CTLA-4 inhibitor, or to the control arm, which is placebo. So the data that was presented at ESCO was on the data from duvalumab and placebo. The data for duvalumab and tremolumab is still ongoing. The primary endpoints of this Adriatic study was overall survival as well as progression pre-survival. Treatment with the consolidation therapy was for a maximum of 24 months. Right. So here you can see here that some of the factors that the PCI was permitted before randomization. Chemotherapy was four cycles of platinum metoposite and radiation, either BD dose or once a day dose over six weeks. Right. So this is the results that was presented at ESCO. The overall survival was met, and you can see here the overall survival was around about 56 months with the addition of consolidation duvalumab following concurrent chemoradiation, limited stage small cell lung cancer. And in contrast, patients receiving a placebo, the overall survival was 33 months. PFS was also positive with a median of 16.6 months PFS with the addition of duvalumab and consolidation and about nine months in the control arm. Right. So in that ESVO, Suresh Sanan actually looked at a subset analysis asking about the outcomes according to number one, whether PCI was given, radiation schedule of either daily radiation or twice a day radiation. And finally, the third subset analysis was the type of platinum agent used. So for these three variables, they analyze the outcomes, including overall survival, progression pre-survival and safety in the patients with duvalumab versus placebo. Okay. So this is the patient, the outcomes of the three variables. In terms of PCI received in the, between the two treatment arms is pretty well balanced between the duvalumab and placebo arm, about 55% in each treatment group. In terms of platinum type, again, one third, two thirds of patients in both treatment arms received carboxysplatin respectively. And finally, in terms of the type of radiation given, a BD dose was given around about a quarter of patients with duvalumab, whereas a little bit more patients, 30% of patients received twice daily fluorescent radiation in the placebo arm. Right. So this is the baseline demographics. The bottom line was that patients who had treated with PCI tend to have more favorable features, such as a younger age. So around about a third of patients in the PC, patients who received PCI had either in development of placebo or age over 65, as well as the, in terms of radiation delivery about just a one third of patients also received twice daily radiation therapy. All right. So what are the results? So in the patients who had PCI given, when we compared duvalumab and placebo, there was a improvement in progression, an overall survival of megapart, with a hazard ratio of 0.75 in those shown here. And this is similar in those who were not receiving PCI. The three years survival rate was 62%, versus 56%. And in those without PCI, the difference was more marked. You can see here, the three year survival rate was 50%, versus 37% in those who did not receive PCI. This is the progression free survival. There was actually no benefit with development, seeing the, regardless of the PCI status in terms of the median progression free survival. Even though numerically there was a difference, this could be put down to the smaller sample size. And the three-year progression, free survival, as mentioned before, the numerically it was higher, the three-year PFS rate was 55% in patients who received PCI and 38% in those who were on placebo. And in the patients who did not have a PCI, the benefit was much lower, 37% versus 29% three-year progression, free survival rate. In terms of the platinum status, there was a greater benefit seen in patients, surprisingly, who received cardboard patent compared to patients who received cis-patent-based chemotherapy. You can see here, the size of the benefit was greater in terms of three-year survival rate, 65 versus 47%. And there was actually no difference when you looked at the patients who received cis-patent. So this is the radiation type, it was BD or once daily. You can see here, the three-year survival rate was 66%, with twice daily versus placebo, 57%. In those patients receiving once daily radiation, there was a benefit, 53%, 10% higher than 43% with placebo. So in conclusion, with the Adriatic subset analysis, the magnitude of benefit with DERVA versus placebo was consistent within both the PCI and the radiation subgroups. There was, interestingly, a greater benefit seen in the cardboard patent group than the cis-patent. And just to emphasize that consolidation development is the new standard of care in the patients who are treated with chemo, radiation, in limited stage small cell lung cancer. So moving on to another abstract, still focusing on small cell lung cancer. This is the extensive stage disease. BMS6012 is an anti-picosco-monosylo-so-ganglioside inhibitor in combination with platinum etoposide and volumet. This is in the first line treatment. So picosco-monosylo-ganglioside 1 is overexpressed in small cell lung cancer, seen around about 60 to 80% of small cell lung cancers. And in addition to this antigen, enhances ADCC as well as CDC and ADCP. And there's some synergism when you combine it with an injected inhibitor. So this is a randomized phase 2 study looking at the accommodation of BMS6012 plus chemonevo compared to just chemonevo alone in a so-called control arm. And patients had maintenance BMS6012 plus nevo versus nevo alone. The primary end points of safety and progression-free survival. So what do we see here is actually there's no difference in the progression-free survival with the addition of 6012. Likewise, there was no difference in overall survival with the addition of BMS6012 in addition to chemonevo versus chemonevo. The response rate was also similar as well. The toxicity-wise, there were higher rates of pruritus and some other low-grade skin toxicities such as skin rash as shown in the tornado plot on your left. So the conclusion was that there was actually no different outcomes with the addition of BMS6012 to a combination of platinum etoposide and nivolumab in extensive stage muscle lung cancer. No biomarker so far has been shown to be of use and we really need more predictive biomarkers. The investigators said to be planning a phase 3 study. Not sure how this will pan out of this compound versus standard care. Right. So finally, the last abstract is that of lanvetinib plus pamperlizumab. And this is for patients who have pre-treated thiamoma and thiamine carcinoma. Right. So following first-line therapy, there's actually no standard of care in patients in the pre-treated thiamine epithelial tumors in following platinum-based chemotherapy. Many agents have been used in the past, including immunotropin inhibitors and anti-angiogenic therapies. And these agents have been tried as monotherapy as single agents. And there's some evidence of activity. So the PICARTI study is a single phase 2 study taking in patients with a B3 thiamoma or thiamine carcinoma. They might have seen at least one line of platinum-based chemotherapy, must have measurable disease, and no prior anti-angiogenic agents. So patients had a combination of lanvetinib, 20 milligrams daily, plus pamperlizumab, 200 mg every three weeks, for up to two years. Primary endpoint of the study was the five-month progression-free survival rate by investigator assessment. And there's secondary endpoints of the response rate, survival, and safety. Right. So here you can see here that the five-month progression-free survival rate, it was actually met. It was a positive study. It was 88.4%. And the overall PFS was actually around about 15 months. The response rate was 23%. And the duration response was 8.2 months. So the investigators also looked at the dose intensity of lanvetinib. And basically, you can see here on the PFS curve, in patients who did not have a dose reduction of lanvetinib, they tended to have a longer progression-free survival, as shown in the survival curves here. The median PFS was 24 months in patients who did not have a dose reduction of lanvetinib. And whereas those who had to reduce the dose within the first eight weeks, the PFS was much lower with a PFS of 8.4 months. Safety-wise, you can see here that there was some immune-related toxicities, especially in the context of patients with pharmaceutical epithelial malignancies. About 14% of patients developed immune-related toxicity. Permanent discontinuation due to toxicities was seen in about a quarter of patients that was attributed to lanvetinib. And around about 18% of patients had to permanently discontinue the drug and was attributed to pembrolizumab. In terms of the severe toxicities, such as toxicities included pneumonitis and myocarditis and keflavitis was attributed to pembrolizumab. And in terms of lanvetinib, there's some skin toxicity, cardiac dysfunction, pulmonary abscess, and colitis. So in conclusion, the combination of pembrolizumab and lanvetinib yielded a five-month progression-free survival rate of 88%. Immune PFS of 15 months in patients with pre-treated pharmaceutical malignancies. It may provide additional treatment options, but we really should do randomized trials. This is an interesting signal, but randomized studies in the pre-treated setting should be conducted. Thank you very much. Thank you so much, Dr. So. Now we have some time for questions, around 10 minutes. Please do not hesitate to send us your questions. And we already have one. So the first question can be for Dr. Novello, but also for the other panelists. In case of resectable non-small cell lung cancer with rare driver alterations other than EGFR and ALK, what would be your preferred choice for the systemic treatment? Yes, thank you for this question. Obviously, all of us, we are interested to see more data in the precision medicine field in the early diseases, because these are those cases that we can cure in the real, I mean, of this world. But unfortunately, at the present time, the only data we have are for EGFR and ALK. I believe that in the next future, we will get the results for the RET fusion. But at the present time, my answer is that in the clinical practice, we are used to see at the PD-L1 expression. And our decision in the adjuvant setting is based on the PD-L1 expression. Together with this, it is true that today with you, we are talking about science, but then we have to deal with the regulatory agency. And in any case, in my country, I'm not allowed to administer TKIs in the adjuvant setting if these are not EGFR mutation or ALK rearrangement. Thank you so much. What about you, Dr. Bess and Dr. Souk? I fully agree. The main issue is the rarity of the molecular alteration BRAV600E is 1% of our lung cancer. It will be almost impossible to have an adjuvant trial with this drug. So, do we need to think of either something with a synthetic arm or a global study with any kind of alteration? This is not something we have done so much, but at one point, maybe we will have to pull this molecular alteration. Right. So, that's a very interesting question. And I echo what Dr. Bella has stated. In terms of the science, we go on PD-L1 expression and if they were EGFR-L negative. So, we just go on the trial data. So, if someone had a, for example, because we do NGS in the adjuvant setting, if they had a KRS-G12C, obviously there's no adjuvant data. Technically, we can offer our adjuvant immune-checked inhibitor. The PD-L1 is more than 50%. We can give latisalizumab. It doesn't preclude me from giving that even though the KRS-G12C was present because that's not an exclusion in the adjuvant trials. So, I would offer that depending on the type of oncogene. So, we know that some oncogenes that may be more sensitive to immune-checked inhibitors, such as BRAF and KRS mutations. However, the fusion genes are less likely to offer immune-checked inhibitors, although technically, you know, only ELK rearrangements were excluded in the adjuvant trials, right? But I think, you know, most of the fusion genes tend to be resistant in a way to immune-checked inhibitors. So, it'll be a discussion type thing with the patient when it comes into the type of oncogene that is detected. Thank you. We have another question from the audience regarding the all the faculty. If you plan to conduct a randomized study to investigate the efficacy, the activity and efficacy of four-generation Alp-PKI, which should be the best standard control arm according to your experience, according to your idea? We can start from Professor Betts and then also the other speakers. If I have a very simple view, I will say lorlatinib because this is where you see the strongest as a ratio against chrysotinib. But it's still intriguing that in the crown study, we have five years follow-up and not enough event for an OS analysis. It means that even the control arm, there is not enough death event to analyze the overall survival. It means that these patients that receive chrysotinib first line receive other drugs, second, third line, and they are still alive. And we have examples with GLX, for example, where chrysotinib versus allectinib, but with all the patients, well, 80% that crossover to allectinib in the control arm had the same overall survival. I guess the standard arm will be a second or third generation. If it's a second generation, all the patients should have access to a third generation, meaning that this kind of trial should embed a crossover to a third or a fourth generation allectinib. May I? Yeah. What about the investigator choice? I mean, we are all the time, as Professor Bass said, we are looking at the results of this trial comparing a new drug, what this is not yet the standard of care. So what about a comparator arm generally as the investigator choice? Step by step, we are reaching great results for the ALCA rearranged patients. So maybe we do not have the best comparator. And the best is what is the best in that specific moment for each investigator? Maybe to have an updated trial, this could be a solution. So the investigator choice. I do not believe that chemotherapy, even if platinum-based plus pemetrexate is a good choice for ALCA rearranged, maybe not for other addiction, but for ALCA rearranged, this is a good solution. But I do not believe that in the future and with a fourth generation alkinibitor, the chemotherapy pemetrexate based should be a good solution. So I agree with what Benjamin said, but my further proposal is why not a design with the investigator choice as a comparator arm? Okay, I guess I am the lucky last. So in terms of the standard of care would be what would be approved in the major regulatory authorities, which is either EMA or FDA. So it would be agents that can be suitable control arms would be included with gatinib, lectinib or low lectinib. These are acceptable control arms in a study where you need to compare with a fourth gen alkinibitor. So if you want to design a study where I had to have a balance between what's acceptable to the investigator, as well as you try to get a result that won't take too long. So I'll probably use a second generation alkinibitor such as Brigatinib, which may or may not be used widely globally or something more acceptable, which is something like a lectinib. So hopefully that answers your question. Thank you. I think that we have time for another question, maybe a small cell lung cancer. Oh, I have a question, actually, if you don't mind me asking it. So answering your question. I have a question to Professor Best. So for camel lung 03, right? It's a negative result. We saw that. Is it a problem with, is it the target or is it the drug? That's a very, very good point. The payload of Tuzarav is a drug that inhibits microtubule. So it's not that far from the c-tac cell. It's true that I think with most of the ADCs today, we are rediscovering topo-1 inhibitor. Those ones are easy to use because they don't have chronic toxicity, cumulative toxicity. They have the mucositis, but no neurotoxicity or toxicity like that. I think there are many explanation why a drug works, an ADC works. It's because of the target expression. I'm a strong believer that the payload efficacy is something that is meaningful in the results we have. Maybe we still need to we see good results with topo-1 ADCs in EGFR mutated non-swollen cancer. Maybe there is a specific biology there where we are the rediscovering that topo-1 inhibitor are good drugs in EGFR mutated non-swollen cancer where we have to, I think, really think broad. Thank you. I think we are at the end of the meeting. We have time for probably for the last question, just fast response from Dr. So, which is how should we treat patients who relapse after the adiabatic regimen? Very fast answer. Okay. So it's a tough question. It's a similar question. How do you treat patients who relapse after Laurel or after Pacific, right? So it depends on the nature of progression. Is it single site disease or multiple site? Also depends on the treatment-free interval. Is it within 12 months or nine months or many years after the end of the consolidation therapy? So that would be my, so there are many variables involved and therefore taking account all these things, it could be re-challenged or just go on to the next line of therapy or give local therapy. Thank you. Thank you. Thank you to all the speakers for their contribution to discuss and to, and we now are at the end of the meeting and we close the meeting as we start with the technical communication. So to claim credit for this webinar, you can complete and submit evaluation form link from the TNQ email you will receive after the webinar, or you can scan the QR code on the slide to complete and submit the evaluation immediately. And to discover more educational activities being offered by ISLC, please visit the website at the islc.org. And finally on behalf of my co-chair Dr. Aldea, on behalf of all the education committee, we thank all of you for joining us today. Thank you. Thank you so much. Thank you very much. Bye.

ESMO 2024 Highlights

lung cancer treatment

NSCLC

small cell lung cancer

biomarker-driven studies

EGFR mutations

antibody-drug conjugates

pembrolizumab lenvatinib

rare driver mutations