thank you for the invitation and to open this session with a topical topic on EGFR Hatake resistance and novel treatment strategies some background is a permutation are observed in about 10% of metastatic lung adenocarcinomas some to frequent mutation are excellent in directions and at age 58 a mutation in X and 21 encoding the kindness of the EGF receptor in this situation first-generation TK eyes defeating nib a flirtini bond a fatty nib demonstrated the benefit as compared to platinum as doublet chemotherapy in the first line setting with median PFS hunging from 9 to 13 months in those tires so resistance inevitably occurs in this situation and I will focus on acquired resistance that is different than high memory resistance response height to EG fatty ki is about 80 percent so a small subset of patient 20% may do not respond to those drugs and it may be a related to compliance issues pharmacodynamic interaction and possibly polymorphism in apoptosis related genes I will focus on acquired resistance meaning resistance occurring after an initial response to the ki we have different clinical profile in this situation and we have to distinguish systemic possession meaning the growth of multiple lesions for existing of new lesions in the in the lung in the brain or other Hawkins we have to distinguish systemic progression from a legal provision or ago progression occurs at one of a limited number of sides again on a pre-existing or a new lesion a time of of perversion the management of illegal possession is different from that of systemic progression and it’s common sense that in the setting of illegal possession patient receive local treatment and we now have a body of evidence showing that it’s of interest to have a local treatment for the illegal pervasive disease together with a continuation of the tki which may lead to increase the PFS of four to seven months in this cohort of patient what are the criteria to define our operation this is highly discussed topic we can consider such a strategy in the setting of CNS possession without lab dominant girl disease and in the situation of up to four extra CNS sites available to local therapy which may consist of surgery stereotactic body radiation therapy slow progression is another clinical profile in the setting of acquired resistance and we now have some data also for slope evasion suggesting the interest of continuation of the tki beyond as his possession we have now data published of the aspiration tile aspiration was a trial conducted in EGF amitin lung cancer evolute in the first line and the prospective study that compared PFS according to resist pollution to PFS based on the clinician assessment and you can see that the PFS was increased by three months when continued ating a lot nib beyond resist possession in those patient you had some patient with oligopolistic disease who received local therapy but also patient with systemic pollution but a slow growing progression my recommendation when continued ating at EK i beyond pollution is to have a close follow-up of patient to avoid missing the time of rapidly growing happy possession requiring certain line treatment systemic pollution the standard treatment so far as been chemotherapy cisplatin bath the platen bath doublet chemotherapy as reported in the impressed Heil impressed really is a study that compared the continuation of Jeffrey nib to placebo in addition to platinum a therapy for patients ending with acquired resistance to japheth nib this trial was negative for its primary endpoint but what is of

interest with those data is that response rate and the PFS rates with platinum a metric said in the setting of a grade resistance were actually similar to what is observed in the first line setting so when switching from a TI to chemotherapy so accommodation is to use a platen bath doublet it’s obviously better to focus on the mechanism of resistance the molecular mechanism of resistance that may be observed at the time of acquired resistance and those mechanism are multiple and three major groups of molecular mechanism to acquire resistance of in her body so far the most frequent is the occurrence of an additional mutation in the same pathway meaning the development of a t79 TM clone within the tumor that continues to activate the EGFR signaling pathways but limit the efficacy of the third-generation adiabatic AI the second mechanism is bypass meaning that there is a switch in the tumor cells from the EGFR signalling pathway to another pathway LBB to persuade med pathway another mechanism is transdifferentiation pretty rare and it consists of the transformation of a Jeff Ament adeno carcinoma into small cell lung cancer it’s important to understand that those resistance mechanisms that constitute the bulk of the tumor at the time of pollution may be actually be observed at the in the initial tumor in a small subset of tumor cells meaning that if you use sufficiently sensitive techniques to identify all the sub clones that are present in the initial tomorrow you may identify the major clone which is the EGF a mutant clone but also in a small subset of tumor cells the clones are wearing the resistance mechanisms so at the time of acquired resistance to identify the mechanism alekhya ler mechanism of resistance V biopsy is mandatory is it feasible yes this is the results of a French collaborative study showing that he biopsy is feasible in about 80% of patients but when you do a biopsy you have to choose a target lesion so you will use the legend that is accessible or halation that is happily growing but you have to keep in mind that the resistance mechanism may be different in one lesion from one nation to another in this cohort of patient t7 entire mutation was far more frequent in torus equations as compared to CNS lesion so maybe instead of choosing one lesion – three biopsy it’s better to have a global view of the disease using new techniques liquid biopsies mostly consisting of the analysis of circulating free DNA when you do that instead of cutting one branch of the tree you just have to pick up the leaves and you will have a global view of the mechanisms of resistance that are present in the primary tumor but also in all the meta stress because you will will take all the DNA tumor DNA from those lesions what to do at the time of acquired resistance maybe one idea could be to switch from one tki to another if it you need to a lot nib a lot need to a fatty nib it doesn’t work it doesn’t work when you do that the results are far lower than that of chemotherapy so if this should not be done another strategy that has been investigated his dwelling abyssion of EDF air using a t ki alpha t nib and static Simha which targets extracellular part of the receptor we have some interesting and promising data from this phase two trial showing that dwell in evasion may be of interest in the setting of a crowd resistance but these results should be confirmed in clinical trial and the friendship intergroup is currently running a trial testing the combination of a patent even satiric see map in this situation may be of small of

iron dressed to target exactly the mechanism of resistance and i will spend some time on t 790 mmm t 790 m is a most frequent mechanism of resistance to EGF first generation t ki it’s observed in 60 to 70 percent of patient at a time of acquired resistance and we now have specific t ki third-generation TK eyes that primarily target t 790 m one of those the guy is a DD 92-91 was immersed in eben and you can see that the profile of this drug is completely different than that of taffeta nib primarily the drug targets the 790 m and e GF amitin mutations and the drug does not target while type III affair meaning that the side-effects far lower than what is observed with first-generation DKI we have data from this first this first higher phase one trial published in 2015 you can see that the response heights 61% the PFF median PFS nearly ten months is pretty similar to what we have in the first line setting with first-generation TK eyes on the contrary the drug is completely ineffective in t 790 m negative patients so it means that if you want to use as ad 92-91 in the setting of a greater resistance you need to identify the 790 m and then a biopsy or do a liquid biopsy to identify this mutation ultimately nib is now approved by the EMEA in the setting of T 790 m positive lung cancer another tki third generation t ki targeting t 790 m is hostility neighbor hostility NEMA as a similar profiles and Ozzy martini again a phase one trial showing promising response rate and PFS fights in the situation of acquired resistance related to t 790 m hostility knee may also have some effect in t 790 am negative patient with a response rate of thirty five percent and this may be related to off target effects as a drug also targets igf-1 r which has been reported previously as a mechanism of resistance to achieve a first-generation TK eyes one question is whether also so generation TK eyes should be administered as in the first line setting similar to what we do with antibiotics we try to use antibiotics that cover all the resistance mechanism but in this situation then you have to demonstrate that the third generation t ki as a first-line treatment will do better than the sequential approach with the third generation TI and then as a third generation t ki and clinical trials are actually ongoing in the situation we have some preliminary data showing that third generation tki are half interest in the first line setting but we are still awaiting for the results of those studies both with ultimate nib and hostility neba actually the next issue when using sir generation TK I will be the resistance because those third generation TK I will have will be effective for a specific period of time but at some point resistance will cure and we already have some data regarding the mechanisms of resistance to third generation TK I especially with Ozzy martini and one frequent mechanism of resistance to Ozzy martini is the emergence of a sub clone of boring another EGF a mutation which is c7 97’s see 797 as mutation occurs at the time of resistance to Ozzy martini but there is here another level of complexity which is the locations exact location on the DNA of the mutation see 797 F in head may be observed on a different allele than the t7 NTM in blue o on the same allele and to know that you need to use highly sensitive sequencing techniques but there is something irrelevant there because preclinically if you look at cell lines you can see that if the caesar 797 s mutation is located on a

different allele you will have some effectiveness of a challenge with defeat nib so maybe in the setting of patient treated with fer generation t ki z nose imatinib imagines us of 7c 797 s you may have challenged a patient with defeat in it so you can develop sequential approaches using the t ki that are availa but the algorithm is becoming more and more complex with necessity to identify whether services transmutation on the same allele or different allele on the DNA so it increases the level of complexity of the management of patient interestingly with hostility nib the mechanisms of resistance seems to be a little bit different than that reported with awesomer nib and the most frequent molecular event at the time of resistance to hostility nib is related to the loss of the t7 90m mutation meaning the loss of the cloner behind 3790 a mutation so maybe some difference is related to the drug by itself but it also may be related to the sequence and again if we look at some very clinical data we can see that in cell lines the resistance mechanisms are different depending on the delivery of the third-generation tki upfront after the administration of a third-generation tki but what does that mean it means that if you use a certain aeration tki with imatinib oscillating EEB in the first line setting maybe the molecular events in the tumor will be very different than the molecular event that you may observe if you do first generation tki and then a third generation DKI so we have to understand what is the best sequence also based on the resistance mechanism which are different depending on the treatment sequence so this was 47 90m we have other mechanisms of resistance consisting of bypass the most frequent bypass is actually the amplification of met so it’s observed in 3 to 10 percent of tumors at the time of acquired resistance to first generation tki we have some data showing that 330 nib is effective in this situation it’s more effective if the amplification of met is uh-oh so again a need for quantification of the amplification of the meat Jen transdifferentiation is very rare less than five percent of patient transformation into small cell lung cancer and this mechanism is very important to keep in mind because it can be identified only if you do a biopsy if you do liquid biopsy you will not identify small cell lung cancer chemotherapy bazan Platina top aside is effective in this situation interestingly the transformation into small cell lung cancer is related to a single molecular event which is a loss of everyone and loss of everyone is well known in a small cell lung cancer of a hull so this is a mechanism molecular mechanism that leads to a specific morphological appearance of the polymerization so targeting resistance is becoming more and more complex because of t7 90m because of the global strategy and the sequence of treatment but you we are also have to keep in mind that we need to consider the micro environment in this situation we have some data about Angelina disinhibition in EGF a maternal cancer results of this Japanese phase 2 study showing that if you combine a low T nib with bevacizumab and TVG a antibody you will increase the PFS of a patient by 7 months as compared to a Latina balloon in this study the PFS with a Latina bevacizumab combination was 16 months and the results have been somehow confirmed by this perspective European phase 2 study so single arm study combining a lot nib plus bevacizumab and again 16 months PFS was reported interestingly specifically in patient presenting with t7 NTM de novo mutation meaning a small subset of the above in t 790 a mutation we also have data about immunotherapy in EGFR

maternal cancer the interest is to combine high response highs to the key t ki to the prolonged duration of response provided by immunotherapy and this is preliminary data we clearly need to look at clinical trials in this situation so we need to consider the strategy overhaul and this is very important for the patient because the survival of EGFR mutant lung cancer patient treated with diet therapy is about four years so you need to deliver all the therapeutic option in a good sequence to avoid missing a chance for the patient targeting resistance is a modern way to do the treatment of acquired resistance targeting t7n TM with specific TI but we need to know whether continuation beyond possession is of interest and that with time of the strategy and again chemotherapy still as a whole in this situation together with the targeting of the microenvironment i thank you for your attention