This video features Martin J. Edelman, MD, presenting on adjuvant chemo/IO/targeted therapies. This presentation was given at our October 20th Management of Early Stage Non-Small Cell Lung Cancer event in 2022.
Hi, good evening. My name is martin Adelman. Um I'm going to uh discuss adjuvant therapy for respected non small cell lung cancer. The state of the art in 2022. My apologies for not being able to be there this evening. This is an overview of the talk. I'll discuss the roll and endpoints and adjuvant therapies and the evidence basis for platinum doublet chemotherapy as an adjuvant. Uh and then go on to the more modern developments in immunotherapy and targeted therapy, Probably unnecessary for this audience. But for all of these situations, the uh studies involved patients who had localized disease at least four centimeters um with uh perry bronchial or Hyler lymph nodes and one lymph nodes or in two nodes that were completely resected within an atomic resection. Um So what's the purpose for a german therapy? Well, the goal is to increase the rate of cure uh overall survival. Um We frequently will use disease free survival as a surrogate for this. It is not always appropriate and may not always be the appropriate surrogate, but it takes a long time to get to overall survival and this is a reasonable intermediate uh doctor treat will discuss issues of pathologic cr with neo adjuvant approach. I think it's important that with all adjuvant and neo adjuvant approaches is to understand that uh there's a substantial risk of harm. Uh So if one takes a typical situation, lung cancer where After a section 60% will recur and 40% are cured uh perhaps with current therapy with current uh chemotherapy. Uh typically you'd say an absolute 10% increase in curate. Um and those patients clearly benefited and it was the gain was definitely worth the pain. However, for uh Those patients were already cured uh there was certainly no advantage and substantial risk and for those who recur uh they've had all the hazards of uh chemotherapy and received none of the benefits, but once again, to emphasize you have to treat 100 patients in order for those additional tend to be cured. So, adjuvant chemotherapy was debated for a long time and thoracic oncology world. Um This was the typical study design for the trials that have evaluated this resected Stage one B uh Stage two A two B and stage 38 patients randomized to either observation or platinum doublet chemotherapy. The first truly positive trial was done in europe and showed a small but very real advantage and absolute of about approximately 5%. Um important to understand that many of these patients never got chemotherapy or did not receive really adequate chemotherapy or what we would consider modern regimens so fairly impressive. I believe only about 50 55% to prescribed doses were actually administered. Uh Two more uh uh to somewhat better trials. One from Canada one from the italian group gave a more consistent regimen of Cis platinum vernarelli B Uh and demonstrated an absolute improvement of approximately 10% uh with the greatest degree of improvement for those with respected and to disease and this is pretty much the uh the the these are the sort of initial definitive trials that established the role of adjuvant chemotherapy and cancer attempts to go beyond that were not successful until recently. The largest most prominent of which was the addition of Susan uh anti VHF antibody to uh standard chemotherapy. These are the results from the E cock 15 05 trial uh doesn't get any uh clearer than that, that there was no advantage uh to the addition of uh There was a hint that perhaps uh cis platinum matrix, it was a superior regimen for the non squamous carcinomas. All the other regiments were about the same. Uh This has this led to a japanese study comparing generality and cis platinum versus methotrexate, uh Cis platinum and non squamous, non small cell lung cancer. Uh This was presented just this year at S. Mo and showed absolutely no advantage. So histology specific chemotherapy regimens are appropriate non uh favored. There have been attempts to optimize chemotherapy based upon molecular markers. Uh The issue is the studies that have been done to date have used, really understanding and markers that were developed in the late nineties early two thousand's, most particularly er C C one as a marker of platinum resistance uh and is is a marker of uh methotrexate resistance as you can see this compared a number of regimens which were the were really the strategy with selection based upon these markers kind of an interesting result that showed that there was uh a hint of an overall survival advantage but did not achieve uh the goal um uh the actual uh intended significance but uh you know less than 0.78 hazard ratio over there. Uh There was somewhat less toxicity in the tailored arms. Uh So perhaps uh uh an indication that there may be a way to better select things but certainly not definitive but perhaps were the operation. So in summary for adjuvant chemotherapy, it is effective and established, it is curative. This is based upon overall survival results, the absolute benefits. Approximately 10% goes up, the greater the risk of the patient. And now typically four courses of cis platinum based doublet. I do not share the data, but Carbon Planet is certainly a reasonable alternative and absolutely justified for those who are unable or intolerant so immunotherapy. Well, this is the new kid on the block. Um Numerous studies demonstrate the benefits of anti PD one and PD L one therapies in 1st and 2nd line treatment of advanced non small cell lung cancer, pacific, demonstrated the benefit of immunotherapy after definitive chemo radiotherapy in stage three disease. And it's very typical to take any agent that shows even modest advantages and later stages of disease into the actual in setting. And this is the typical design. R zero resection platinum based chemotherapy for four courses and then a randomization between the anti Pd one L. One therapy for a year and a control which would either be observation. So the key trial here is the I. M 010 trial. Um and this was a randomized phase three study and respected non small cell over 1000 patients randomized between and best supportive care and shows this clear a disease free survival advantage. However, to date this has not yet produced an overall survival advantage subgroup analysis not surprisingly showed that PD L. One the higher the expression uh the better you did with essentially no advantage for those with PD L. One that was not measurable, you know, less than 1%. Uh And this indicates that it may be a good idea not to administer this drug in those patients. Um And here's the primary analysis set for those who are over 1%. A very similar study, keynote 091 evaluated Pemberley MEB. Top line results, improved disease free survival interestingly. Uh It did not seem to do so for those with the higher Pd L one uh surprising and probably due to an over performance of the control arm, as you can see the control arm over here which never received anything other than standard chemotherapy seems to outperform the control arms and the other Uh two aspects. Um so for date this is likely to ultimately lead to approval but results being analyzed. So for adjuvant immunotherapy to date. Single sequential single agent immunotherapy at Tesla's mm now is approved. Um There are other agents out there. We participate in this new volume um Anvil trial through E. Cog. This is our current trial which is now evaluating uh sequential versus uh therapy versus concurrent concurrent rather versus sequential therapy. Um And this is open at all institute, all of Fox Chase Temple institutions. Um And just but just remember approved based on disease free survival, not yet. Overall survival. I believe the overall survival will be positive based upon the clear improvements in pacific as well as the fact that small numbers now of uh patients even with advanced disease appear to be cured with anti pd. So what about targeted treatments? Uh So the logical one to test over here were E G F. R mutated uh disease with the G F R T tyrosine kinase inhibitors. Uh This is the most mature of the targeted treatments. Um The basic design uh is that uh those with activating mutations either received chemotherapy followed by T. K. I. Or placebo or received the T. K. I. In place of standard chemotherapy. Keep these two different designs in mind. Um So this is the first trial to be reported that from the West Japan oncology group. And what it demonstrated was that there was an early progression free survival or rather disease free survival advantage in the first three years that then went away once the drug was with. And in a very similarly designed trial from the chinese group uh same basic randomization, Jeff, it versus general means this platinum two years of And you'll notice that once 24 months, very wide separation of the arms, but a year or so after cessation of the drug, this disappears. Excuse me. And the from overall survival survival advantage, these come together uh showing no overall advantage. So then we come to Adora which has gotten much more press than the other two. So same basic idea, evaluating an agreement uh, T. K. I this one, a third generation um inhibitor. Quite logical to do. So it's really the first time that I G F R T K. I demonstrated a true survival advantage. And this was over the standard E G F R T K I small but real over there very widely separated curves. Again, this is for disease free survival led to the FDA to approve this as a gym in therapy. Quality of life studies showed no difference between these two arms. Uh though I'm sure there was looking at these studies where uh for the Adora trial, it was platinum followed by martin where the other two trials it was really in comparison to. And uh at least one analysis of the adora data indicates that the chemotherapy treated patients did no better than those who went straight onto a submerged neb. So uh kind of an interesting result there. But what about concurrent chemotherapy in E G F R T K I. There's substantial evidence to randomized trials. One from India, one from japan. This is the japanese trial that show a clear DFS or PFS advantage. Uh This is with the use of chemotherapy and the E G F R T. K. I adore a two is a trial that asked this an advanced disease and we would probably need to consider that in the oven setting. If this is a patterns of recurrence also tend to be different with uh far more uh cns recurrent with a tendency towards a greater degree of extra cranial metastases. As the first sight of recurrence uh uh in the patients who receive uh general being uh platinum uh versus uh those who received just to fit. So what about other adoption trials? The canopy trial was presented earlier this year. Uh Not a great deal of publicity for that because it was exceedingly negative. This was based upon an observation that I'll one beta inhibition uh uh was studied to prevent coronary events and those with atherosclerosis. And by coincidence demonstrated uh a sharp reduction in the incidence of lung cancer led to this randomized trial comparing with observation with placebo in patients with resected disease. Um and as you can see so many other targets and targeted therapies that one can raise the question about adjuvant therapy. Um there's been a concentrated effort on this for at least a decade through the alchemist trial um noticed that spends a lot of time looking at screening here because the trial was designed before uh next generation sequencing or even molecular testing was easily available. This is the original design of the AL portion of that now, just a single arm. Um The problem is, most of these are exceedingly rare. Probably the only one that will really get tested is with care as we shall see. So in conclusion, patients with resected disease should receive four cycles of adjuvant platinum based chemotherapy. Recent studies show that the addition of immunotherapy sequentially uh is superior to chemotherapy alone. Uh Certainly in terms of disease free survival, overall survival has yet to be proved. There are current trials. Excuse me, that Explorer concurrent versus sequential immunotherapy. Oh Somerton, it has been approved for e g F R. Activating mutations in resected uh sector disease. Again, os data available. Um it's interesting that other trials have not shown the disadvantage. Um but we shall see uh about the finances of this and importantly no good data for adjuvant use of other targeted agents and non small cell lung cancer even with driver mutations. And I would strongly advise against that. Thank you very much for your attention