Tag: brothers

Transcript

hello everyone I am Rahul Gosain and
I’m Rohit Gosain
and we are oncology Brothers a lot of data was presented at the World Conference on lung cancer in Singapore but today we’ll focus on four practice informing studies that should be on your
radar as a medical oncologist to start we’ll discuss Flora II then
looking at the second line treatment options for mutated egfr patients of course we’ll touch on Mars 2 for mesothelioma anti-close will focus onevoke 2 with potential new Frontline treatment options in non-small cell lung cancer to walk us through these critical studies we’re joined by none other than Dr Stephen Liu from Lombardi Cancer Center Stephen thank you so much for joining us today yeah thanks for having me Rohit Rahul a pleasure to talk about these and have a little bit of discussion on the perspectives Stephen welcome we have a lot of exciting studies to cover can we first start off with Flora too looking at the role of OC merch nib which we are already aware about how to utilize it is
an individual setting but now this is to combine chemotherapy with OC mercnib in metastatic non-small cell lung cancer patient with commonly GFR mutations if you don’t mind talking about this
study and going about the study design and followed by a study results please you’re happy to uh this is a randomized phase three trial for patients with egfr mutant lung cancer we’re talking about
the common sensitizing mutations it would be Exon 19 deletion Exon 21l858r and I think that thinking about this study you know we know that Osama nib are a third gen egfr kinase Inhibitors
our preferred standard of care in the front line setting has been for quite some time but despite the fact that this is an effective agent that it is well tolerated that is the best that we have
the outcomes leave a lot to be desired when we saw those first studies uh you know now five years ago media progression-free survival of almost 19 months was so much better than what we
had before but I think the three of us agree when we have a patient diagnosed with eg primary lung cancer and we expect a PFS of a year and a half that is not long enough and over the past
couple of years we’ve seen other Frontline tkis and other targets like Ross one like Rhett like ALK really Eclipse egfr has been a little static we need something new I mean something better what is there well you know several years ago we saw two large studies one nej009 a Japanese study one from Tata Memorial looking at the addition of cytotoxic chemotherapy Platinum penetrixon to Frontline egfr kinase Inhibitors now those were first generation Inhibitors specifically to Fitness and what they showed was when
you add chemotherapy to a tki you increase toxicity no surprise you increase response rate and progression free survival also no surprise when you’re adding active drugs what was surprising was that you significantly improved survival that was intriguing and the question is can you do the same thing with a third generation inhibitor now while this study was going on we saw a couple other things emerge that my color interpretation one the nej009
study the Japanese study that showed chemotherapy improved survival with your fit nib more follow-up that study actually lost significance for survival and two the again study done by The J Cog group also Japan looked at just a limited run of chemotherapy you know in their hypothesis here if we think about the science say well if there are clones at the beginning that are destined to
cause resistance to a submerg nib can we eliminate them now and reap the benefits later is everything Manifest Destiny are we already seeing the eventual resistant clones present can we target those with chemotherapy and then just let those Americans keep working for years on end and we saw that a limited course of
chemotherapy really did not impact overall Survival on the benefit of progression-free survival was transient really suggesting that’s not how it works and it really is constant suppression so with all that as Prelude we see Flora two floor two well-designed study large trial randomized phase three now they stratify patients by Race by egfr mutation not mutation type whether it was Central or local and by performance status not the ones I would have chosen but the cohorts did seem pretty balanced at the end and patients are randomized to a standard arm of Osmar and a balloon or an experimental arm of osironment plus chemotherapy that
chemotherapy Platinum Plus pematrexate induction followed by maintenance though you could stop the maintenance in the
event of toxicity or intolerability and continue the tki in the control arm of ocean emergency there was not a mandated crossover and so we’re not really comparing concurrent versus sequential
we’re comparing an upfront strategy of combined chemotherapy and targeted therapy versus upfront with targeted therapy the primary endpoint here is progression free survival and between us I don’t know that that’s the best end point here um what we saw was that when you add chemotherapy you’re adding active drugs
that we know work well in this cancer subtype you increase response rate a little bit not a surprise you also significantly improve progression free survival that was the primary endpoint of this study now if we go by blinded independent review versus
investigative the numbers are a little bit different the primary endpoint was actually investigator assessed and they’re the median progression free survival was a little over 16 months a little under what we saw in Florida so a control arm underperformed a little bit
but even with the blind independent review the hazard ratios were the same really what we saw was about an eight to
nine month Improvement in progression free survival Hazard ratio around 0.6 that’s the same for both arms so that is
a pretty significant Improvement in progression free survive the trade-off is toxicity there’s not a lot of it and really a lot of grade three toxicities they’re the toxicities that we expect Milo depression nausea vomiting overall survival is very immature at this point but as of right now there’s not a clear survival benefit those curves overlap too early to tell right fortunately too early to tell but it leaves us with the question when we add chemotherapy we significantly improve progression-free survival the cancer stays under control for longer but at what cost not so much
talking about financial cost though it is a consideration talking about the cost of toxicity and importantly on quality of life for some people it will absolutely be worth it for others it
won’t I think that we’ll be able to have those more meaningful discussions when we know what the impact on Survival is
and maybe when I can better tell who gets most of the benefit based on biomarkers commutations ctd analysis my sense is that we’re just scratching the surface I think this is an option this
is a strategy and there are certain this is where it makes sense but I do not think this is right for everybody you brought up some critical points not right for everybody but we did see that
again just PFS patients with CNS or maybe heavy tumor burden as a surrogate might benefit but again having that conversation with the patient is so important you’re right the subset of patients
that had Baseline brain metastases that has a ratio of progression free survival seem to be a little bit better now is that because Platinum penetrexate has some CNS efficacy quite possibly but
does that impact long-term outcomes does it just mean that a patient received stereotypic radio surgery one dose and
does that really impact uh the whole perspective everything we don’t know it’s all the details that matter so that
subset did seem to do a little bit better with the addition of chemotherapy but we don’t know if that translates
into improved long-term outcomes yet absolutely Stephen thank you for covering that and before we move on again it is so critical to recognize the importance of NGS testing so that we can
have these discussions with our patients and this is not only important in metastatic disease but now also in early stage where we’re seeing a bigger and bigger role for adjuvant or periopian
you know chemotherapy based on neural approvals and even at this uh conference there was a subgroup analysis from Aegean trial where patients who had egfr mutation got exposed to periop uh chemo immunotherapy and they did not have any benefit so again testing and looking for these actionable mutation in early and
metastatic setting is very important you’re absolutely right that that’s a huge important message these really are different diseases and we are handicapping ourselves if we don’t have
that information without the right biomarker information we cannot make the right decisions none of us can’t we’re
just guessing and we have to do better than that so you know our jobs are already hard enough we’re going to make
it easy you gotta have that biomarker information it’s a different disease totally different approach so moving right on second line treatment options here with patients with egfr mutation is very limited and once you’ve progressed on osomertoneva or maybe some Selected Few with also Merton and chemo we don’t have much Dr Lou your thoughts on Chris’s house too so Christmas 2 is a study looking at the egfr Met by specific antibody amavantimab now we’re pretty familiar with this agent it’s approved for egfr
Exxon 20 insertion lung cancer it’s being said in a couple different
settings and here we see it in the common and atypical egfr mutations through the crystal study different cohorts now when we combine it with lazertanib I get a lot of questions about lizard Luzerne is another third generation agfr inhibitor currently
approved in Korea pretty similar I think in terms of efficacy not studied head-to-head but sort of the same types of metrics as other third gen egfr Inhibitors a little bit different in terms of sine effects though a little bit less diarrhea a little more paresthesias but I think that I would consider it similar to a third generation for inhibitor like o submerged not the same but similar here
you’re combining in advance map with laser nib and with chemotherapy so really a four-pronged approach this is a
relatively modest cohort here we’re seeing about a response rate of 50 clear activity but there is toxicity as well
aim event tab is a little bit of a tougher schedule we know that we give that medicine weekly for a month and then every two weeks when the chemotherapy brings its own toxicities but this is a what’s appealing about this it’s an empiric strategy that sort
of covers a lot of different possible mechanisms of resistance we think of how we battle tki resistance a lot of us will advocate for biopsy we’ll use that biopsy to profile this new evolved tumor
and if we see a hidden vulnerability we’ll attack it whether it’s met
amplification a red fusion a new bra mutation will adapt along with the cancer the reality is that’s kind of hard to do and while a lot of us especially in Academia will say we biopsy everybody use that to inform things that’s not true right if we look at the Elio study which our colleague Dr zosha petrovska presented at esmo last
year this was a study that was only designed to do biopsies so you have patients receiving customer dip and they agree to have a biopsy at progression for profiling so you have a patient that
is motivated and agrees doing being you have a site that’s familiar with biopsies an investigator that is invested in doing these biopsies and it’s paid for by the study and even under those perfect completely non-real-world conditions the rate of
successful paired biopsy was 39 so that’s the best that we can do so if we say we biology 100 of patients get a bridge I can tell you right now it’s just not readable so we do the best that we can but what we want is really an empiric strategy something’s going to
work for everybody there’s some appeal to having Simplicity and that’s why chemotherapy is a good approach whether we should continue tki or not we don’t know that’ll be the compel study
antibody drug conjugates like trope2 like her three adcs those are appealing and this strategy where you have am Advanced to have the covers met which we know is common mediating resistance you have lizardium so you retain that CNS activity and chemotherapy is sort of four-pronged approach to really attack
resistant cancers is sort of naturally appealing we’re going to have more options the hard part over the next year or two will be kind of a rank and file as to when to use what option M event map as you mentioned that it is approved for excellent each year for 20 mutation now we are eagerly waiting first line data for this drug to get a little more comfortable in managing toxicity with this drug you’re already aware about the infusion reaction some particular
clinical pearls without me of antimatter for Community oncologists yeah you know I can tell you my approach I’ve had a pretty good success with it the infusion reaction is common north of 70 of people will have an infusion reaction but here’s my Approach if we’re using am Advanced and we’re going to go forward to this I tell people that we are going to see an infusion reaction if we don’t
that’s okay but I say usually we will but that’s okay that’s expected and it’s not an allergic reaction it doesn’t mean we can’t continue this treatment the way we give it is weekly for the first four
weeks and then every two weeks and that first dose we split in the day one day two and that first day that’s when you see the infusion reaction so my nurses know that we’re going to see an infusion reaction here they’re standing at the ready they’re ready to act patient is expecting it when it occurs we treat sort of standard with hypersensitivity reactions but I don’t reach Alex we
don’t slow the rate down and keep going we don’t waste time with it have the infusion reaction we watch make sure you’re okay once you’re okay we throw the bag away go home come back tomorrow
we’ll finish off this first week it’ll never happen again so as long as we expect it going forward that to me is not the barrier we expect it as soon as you get it go home we’re done we’re going to pick it up tomorrow it’ll never happen again to me the main adverse
event that I manage with inventive is rash right so we do see a lot of rash which is an On Target off tumor effect egfr expressed on the skin we’re hitting that in really rash and that’s true with
all these edisons it’s better to be proactive than reactive so when we think of different creams emollients protection from sun it’s huge all these things can help minimize that rash can’t avoid it but we can try to minimize it wow there’s a lot happening in this
space and you’ve also briefly mentioned another ADC for her Thief based on her CNET trial there’s exciting data to come all right now let’s focus on mesothelioma and one of the most talk studies from the conference Mars 2. Stephen your take care yeah no this is
this is a tough one none of us are surgeons and you know be careful what we say start off by saying we’re not surgeons but this was an important study this looked at patients with resectable
mesothelioma that means disease on one side of the tumor the surgeon felt they could resect good performance status all the patients start off receiving chemotherapy and then they’re still
respectable they then go to surgery now they are an extended plurectomy decortication or they discontinue chemotherapy if they go to surgery after surgery they complete chemotherapy really ask them a question is this a surgical disease the surgical resection
improve outcomes and I think all of us were taught that that’s the standard if it’s resectable you resect what we realize though as we get older is that’s not based on a lot of Science in fact a
lot of what we do is not based on science it’s based on Dogma it’s based on logic intuition bias but for years we thought that if we could resect it we should resect it the Mars 2 study it’s
complicated to run a large surgeon trial is a UK study led by Dr Eric Lim I’m from the Brompton and what they showed
was that the arm that got surgery not only did they not do better than chemotherapy alone it did worse now it wasn’t statistically
detrimental but the hatch register here was 1.28 that’s the wrong side of one and the curve split right away some challenges here the staging not necessarily this type of station that everyone would do pet scan invasive media style staging wasn’t required for everybody curves do cross over time there was some comment on sort of a unacceptably High 90-day mortality you know I don’t know that those hold up and other studies show similar numbers while we look at subsequent care while it’s true that the con the control on the surgery arm had a lower likelihood of getting immunotherapy later which we know can improve survival maybe that sways the survival they weren’t precluded from getting immunotherapy something they weren’t allowed to get immunotherapy it’s simply that when you undergo a surgery like this it takes a lot out of you a lot happens afterwards and unfortunately I suspect that many just weren’t well enough to receive immunotherapy uh I think that the conclusions here that this surgery which we had for years considered routine
should not be routine and that now we question the role of surgery in this disease at all it doesn’t mean that there’s not a role I think there’s still some room for more questions in the confines of a study but I think the burden of proof really is to show that
there is benefit on surgery are there certain cases where surgery can be beneficial I think that we can’t assume that that’s the case we need to show it because um you know this study really suggests patients who had surgery and have done worse than those without it and perhaps we should just move on to something like immunotherapy which gives patients a better chance of long-term survival so this was shocking a few lessons here one first I think this was an extremely well thought out well-designed trial
there’s no perfect study I thought it was extremely well presented in fact I think it’s one of the best presentations I’ve ever I’ve ever heard and I encourage others to listen to when they can but to me an important us and not being a surgeon an important lesson for
me is that we have to challenge Dogma we have to challenge things that we’ve been told or the right way to do it that don’t have any evidence that aren’t based in science and we need to kind of go back say hey this thing that we’ve been doing forever should we actually be doing it I think our patients deserve
that absolutely thanks so much for covering that and I think you can’t stress the importance of how important this study was and you definitely covered it well because Dr Lim did such a phenomenal job at stating what is very important here now we as Community oncologists especially practicing in rural setting
we’re always struggling to who to partner up with these patient population this has to be the right volume Setter but now we are we won’t have to dive in with these questions the data is going
to put systemic treatment up at the Forefront and give our patients chance to stay at home and not go for surgery under these circumstances now back to the general variant of non-smalls of lung cancer where we are relying on pdl1 score to dictate our
treatment based on Dr Gad Yale’s presentation it is reassuring that chemo with immunotherapy is in fact the right approach for low PDL inpatient population on the other Spectrum where High pdl1 where we have been relying on single agent pembralizumab this study evoked to questions whether substitution map in addition to pembrolizumab potentially will have better outcome Dr Liu can you please share your perspective on this data yeah you know I
think that you might actually have more experience with this drug than me I’ve always used it and try to find some studies this is a drug that is approved for breast cancer proof of bladder cancer
extremely fun drug to say is an antidepressant but it’s a conjugate so we’ve got a trope2 antibody with a Linker to an sn38 payload which is sort of the active component of a rinati can it’s a very active drug my colleagues in the breast division here at Georgetown really speak favorably this agent so now we’re looking at it lung cancer now the evoke 2 studies of phase
two study and it’s got four arms but it’s not randomized
um it’s really looking at a couple different strategies one is adding
sustus to pembralizmet and they’re looking at it in pdl1 high or pdl1 less than 50 which includes by the way low and negative that a 50 50 split or a triplet combination of test two’s map plus Platinum and that would be in squamous with pembralism now at this date of young Cho Dr Cho from Yonce University in Korea presented cohort and cohort B so really just looking at the
test use map plus pembralism and in the pdl1 high so pretty high response rate 69 that’s encouraging and in the PDL one
less than 50 which was low or negative we saw a response for about 44 um where do those fit in terms of our historic standards now it’s a little difficult to do across study comparisons this is relatively small study with about 30 patients in each arm in
addition what do you compare it to are you comparing it to Pembroke alone which I would argue you’re probably looking at
like a keynote 042 and that’s the case then in 042 you know the response rate for pl1 high was lower than that but um you know 39 and so this seems better than that but test2’s map is kind of like a chemotherapy agent and so if you’re comparing it instead to Keynote 189 but for keynote 189 the response was 61 which is pretty similar to 69 so is this is the comparative Pembroke alone or is it Pembroke plus chemotherapy I think it’s actually more Pembroke plus chemotherapy so that 69 response rate kind of on par with the 61 response rate now where it gets harder is the PDL won less than 50 because they always saw the response rate was 44 with sas2’s map uh government take n plus pembralism now in
keynote 042 that response rate was 29 um for pdl1 low uh but you know 189 was more like 48 so it depends on whether
you’re comparing it to chemo IO or IO alone but to me that’s still not the right question when we look at the addition of an antibody drug conjugate to immunotherapy which we’re seeing with this study which we’re also seeing with the trip high and lung studies with data podomap the appeal here is not response written response rate is kind of an early signal of activity and we take it but you know pushing the response rate up even to 100 that’s not what we’re after here what we’re after here is more durable
survival and if adcs antibi drug conjugates are going to make an impact in our patients lives and in our practice in this setting it’s going to be survival it’s going to be durable survival if there is a Synergy between adcs and checkpoint Inhibitors if it is whether it’s ADCC whether it’s antigen release changing the spatial Dynamics through the bystander effect whatever it’s doing if the adcs are
having some Synergy with immunotherapy that can provoke more immune-mediated responses that could hopefully translate
to better landmark and long-term survival that’s the difference you can make if we give 20 cytotoxics with Pembroke we can increase response rate that’s our goal here our goal is tomanage that balance it with toxicity and improve long-term survival this study
won’t show us that it shows us that it’s feasible to do it was pretty well tolerated and there’s activity at least additive activity but what we really need are randomized studies to show is this getting us where we need to go in terms of survival because
improving the response rate you know it’s just kind of joking a stats not so interested in that we want people to live longer and for that we need randomized studies and longer follow-up
and I think I cannot agree more survival and quality of life those should be the primary endpoints and again uh phase three data with randomized study would definitely dictate that and we’ll
have to see where that takes us while we are certainly used to this drug statistics of map as you stress with bladder and breast cancer so as a generalist I think one come about it’ll be easier to adapt when it comes to practice a lot here and we cannot thank you
enough for discussing these studies as always stay tuned for a recap from this discussion we have covered four studies with Dr Liu post-world conference on lung cancer when it comes to non-small cell lung cancer looking for actionable mutation is very critical for patients with common egfr mutation also Martinez with
chemotherapy might be the right option for a very small subset maybe with intracranial disease or heavy tumor burden whereas single agent also murder for now Remains the standard of care
unless we see a overall survival benefit with this combination approach treatment options in second line after we’ll see mercknip are in fact limited there is more to come but MF antimab does look like a promising option which is already in fact approved for Exxon 20 egfr mutation and new agents targeting R3 should be on your radar as well then with absolute we also discussed March 2 study and systemic chemotherapy up front seems to be the right approach even for resectable mesothelioma patients based on this data and then chemo plus IO Remains the standard of care for low pdl1 whereas for high pdl1 we are seeing promising activity with
saskatoon’s map in combination with immunotherapy join us back for more practice changing coverage the oncology Brothers.