Fred Hirsch, MD, PhD, compares the effectiveness of mono-immunotherapy versus chemotherapy versus immunotherapy + chemotherapy for Non-Small Cell Lung Cancer patients with PD-L1 expression.Referring a patient is easy. Just click the "Refer a Patient Online" button.
Hello everyone. My name is dr fred Hersch. I'm the executive director for the Center for Jurassic oncology at Mount Sinai in new york. I'm also professor in medicine and pathology at Icahn School of Medicine at Mount Sinai. So I will talk about PDL- one expression and practical implications for lung cancer. Here is my disclosures. So let me start with single agents immunotherapy in first line setting and we have data for patients with high PD L. One expression. Keynote 42 comparing Pembroke Lucy McCabe became a therapy in first line setting was a landmark study and of course came out positive as we can see. However looking into the role of PD L. One expression We can see here that this is data from patients with more than 50% and and below that we can see data for patients with a lower expression and there seems to be a difference. So when we're talking monotherapy uh immuno immuno therapy in patients with lung cancer we believe we have strong data indicating that high Tps For PDL one expression indicate a better outcome. There are other drugs out the other studies out there, Keynote 24 empower. 110 and empower with semi pro mob. They all more or less demonstrated clearly that in patients with high PD L one expression there was clearly superiority for single agents immuno therapy compared with chemotherapy And that of course led to n. c. c. n. guidelines. Also in patients expressing more than 50%. That pembroke lucy mab either either as monotherapy or combined with chemotherapy is all superiority. Superior superior to chemotherapy alone. Um why should we give combination of chemotherapy and immunotherapy when we can use immunotherapy alone in this setting. And that is a discussion I will come back to now chemotherapy immunotherapy combinations here we can see some studies. Keynote 189 in proverbs 830 improper 250 keynote four or seven. They all led to FDA approval of the combination of chemotherapy and immunotherapy for patients with advanced non small cell lung cancer. Take one example here, Keynote 1 89 that is the first line study comparing pembroke lucy mum's with chemotherapy for non squamous advanced non small cell lung cancer. To the left. We can see the overall result. But what we can see here To the right, when we are talking different subgroups of PDF one expression is that there do not seem to be emerging of a difference in the different subgroups. When we are talking immunotherapy and chemotherapy. In combination here is keynote 1 89. This is four year follow up and we can see here the patients with high tps and patients with low tps and there there is some difference but not much of a difference according to PD L. One status. So Keynote 407 in squamous lung cancer showed practically the same thing That when we are talking a combination of immunotherapy and chemotherapy PDF. one subgroup status does not seem to have a significant clinical impact. The same has been demonstrated in retrospective analysis combining um immunotherapy monotherapy with immunotherapy in combination with chemotherapy and we can see her for high PD L. One expression. There was no difference which goes back to my discussion why adding chemotherapy To the treatment regiment when you can achieve the same results with immunotherapy alone. And we again we are talking PDF one status more than 50%. Now, what about the subgroup 1 to 49%? Well, FDA presented last year at esco very interesting pulled data analysis from their studies listed to the right and they compared chemo immunotherapy versus immunotherapy alone. And here we can see that in this particular PD L one uh space, there was practically no difference between the combination treatment. Um Now excuse me in this particular group, there was a difference to the benefit of a combination of io chemotherapy. In contrast to the subgroup with high pD L. One expression here are P. F. S. Data and overall survival data. And it was clearly in this retrospective pool analysis that in this particular PD L. One space the combination do better than monotherapy. One caveat here could be, it looks like only positive studies are included. What that means for interpretation in real life is probably not entirely clear. But I personally believe that the data from the pool analysis point in the right direction and. The N. C. C. N guideline for that particular PD L. One expression space 1% to 49%. Clearly also recommend combination of immunotherapy with chemotherapy both for adenocarcinoma and for squamous lung cancer. Now the prospective evidence will probably come through the ongoing in signal study which is a cooperative group study in the United States. And they compared it will compare immunotherapy monotherapy with combination in all different PDL- one subgroups. So that is a prospective study. And we will see what this study will tell us. What about the patients with low Pd L. One or no PD L one expression. I will say less than 1% is what I will call pd L. One negative. And here we have uh data from a combination of pembroke Lucimar chemotherapy versus chemotherapy alone. And we can clearly see the difference to the benefit of combination therapy. We have also seen this in updated form. What actually is strikingly in some of the studies which have included naval mob. And the problem with old chemotherapy in this particular space. And we can see here this study here is clearly showing that for pd L. One less than 1% the combination of IO IO do very well. This was not pursued by the company and is not in the F. D. A. Approval. Checkmate nine L. A. also include a nivel mab papilloma plus chemotherapy and we can see that combination do very well in the group less than 1%. So this is the treatment scenario we have today based on pD L. One expression. Let me start with patients with high PD L. One expression more than 50%. We have approval for single agent immunotherapy. We have a combination with chemotherapy and we have combination with another immunotherapy without chemotherapy. And in my opinion most places will probably in this space give single agent immunotherapy by exposed the patient to chemotherapy when you can achieve the same with monotherapy. There are exceptions to that. In my opinion though a young patients with a large tumor burden and where you need to see a quick response you will probably add chemotherapy to the immunotherapy in the lower PD L. One spaces to the left. The standard of care today will be a chemotherapy plus immunotherapy or immunotherapy with meaning and PDF. one blockage and the C. T. L. A. Four blockades. I think most most places will probably pursue chemotherapy plus immunotherapy in the whole space From 49% and down does histology matter? This is a retrospective full data analysis for patients with single agent immunotherapy and we can see here clearly that the differences particularly in non squamous while in squamous histology there doesn't seem to be much difference whether pD PD L. One is high or low as defined by 50%. Cut off values. Most recently we have seen data from immunotherapy as a juvenile therapy in early stage disease. Empower. Oh 10 studied adamant chemotherapy plus immunotherapy versus a standard of care which will be adamant chemotherapy. And this study clearly showed the impact superiority impact Of adding immunotherapy too adamant in the adjuvant setting. However, it is for me very clear that the high PDF one expression was driving the effect. The hesitates you. For patients with TPS more than 50% was 0.43. Um And it was clearly a difference between high PD L. One expressing tumors versus low PD L. One expressing tumors. Talking a little bit about biology and hydrogen itty. There is hydrogen itty and it is I have been puzzled quite a bit. Why should a PD L one negative tumor benefit from immunotherapy? And one reason could be as we can see here two areas from the same tomo are one is highly expressed. Finally one highly expressing PDF. one 1 1 side clearly negative X or no expression. Of course if you take an biopsy in this small area where there is no expression And let's say for the case of discussion, 80% of the tumor has expression this tumor should biologically respond to immunotherapy. Another thing we were dealing with was all the different assays and antibodies out there in clinical trials pursued by the different companies that led to the PD L. One. I see blueprint project where we compared the different antibodies and essays and we found that three of the essays deco 28 8 22 C three and ventanas 263 performed similarly. In contrast to SP 1 42 pursued by Genentech Rose for socialism map. So the conclusion from this study was that at least three of the assets could be used interchangeably. Another thing is why do we have cut offs of 50%, 1% PDF one expression is a dynamic process. And we have there has been demonstrated in knowing publication That as higher PDF one expression occurs as better outcome for immunotherapy in this case monotherapy. So here we see data from 50- 89 and from 9200. So this clearly in my opinion indicates that we need to look more granular early Into the PDF one expression PDF one expression is not made for defined cutoffs. So, my conclusion is PDF one has shown predictive capability. High expression of PDF one drives the effect, particularly when we are talking immunotherapy. As monotherapy For patients with high PDL- one expression. Monotherapy seems to be sufficient combination of chemotherapy might be needed in some selected cases which I have mentioned. There is a prospective study insignia will tell us hopefully the truth In the lower PDF one space immunotherapy in combination with chemotherapy seem to be superior to immunotherapy alone. So uh and for PD L one negative. I will think that It could be considered also immunotherapy in combination PDF one blockage with KTLA for blockage. This combination is approved in the other PDF one spaces as well. But in my opinion, The most intriguing data occurs with this particular chemo free combination in the PDL one negative tumors. So we need still to learn more about PD L one expression heterogeneity and the combination with other biomarkers. TMB I don't really know what to say about that, but I do believe that combination of markets and essays will be the solution in the future regarding predictive biomarkers for immunotherapy. So thank you very much for your attention.
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