Are dMMR and MSI-H both markers that will soon replace or work in conjunction with PD-L1 when determining immunotherapy for patients with metastatic NSCLC? Accurate testing and treatment selection is critical in identifying patients who will benefit from these therapies. Dr. Federico Cappuzzo, Dr. Solange Peters, and Professor Yi-Long Wu discuss emerging data from the recent WCLC, ESMO, and ASCO virtual conferences and offer their international and regional perspectives on the evolving use of immunotherapies in advanced NSCLC.
Welcome to CME on ReachMD. This activity, entitled “The Latest Clinical Considerations for Non-Small Cell Lung Cancer: A Global Approach.” is provided by AGILE and is supported by an independent educational grant from Merck.
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Here is Dr. Federico Cappuzzo
Welcome to our discussion on “The Latest Clinical Considerations for Non-Small Cell Lung Cancer: A Global Approach.” I’m Dr. Federico Cappuzzo, and I’m joined today by Dr. Solange Peters and Professor Yi-Long Wu. Welcome to the program.
Thank you, Federico. It’s a great pleasure for me, really, to be here with you and try to share some of the approaches we might use in Europe to treat non-small cell lung cancer patients with immunotherapy. It’s a pleasure to be here.
Thank you, Dr. Cappuzzo. I am very, very pleased to be here and to join in this discussion. Thank you.
Let’s get started with a topic we are frequently asked to address, because it’s an area of much confusion. I’m talking about predictive testing to determine treatment. Let’s talk about the current rationale for the selection of immunotherapy based on testing result. Professor Wu, why don’t you get us started?
So far we’re now almost 60% of patients with the driver gene, and also we know the non-small cell cancer could be by the squamous carcinoma and the adenocarcinoma. Based on this data, so very important, we need to select the patients for immunotherapy. For instance, the important biomarker is the PD-1. We could, based on PD-1, select the patient for the monotherapy or the combination. And also, the biomarker could predict the side effects. So this is why we need to test the biomarker, to select the patients.
I fully agree. We need biomarkers to be able to select patients for the benefit of what we do. In lung cancer, we probably have been the pioneers in trying to define the role of PD-L1 as being assessed and measured on tumor cells to predict the efficacy, the activity of the monotherapy, or the anti-PD-1 or anti-PD-L1. And we have been showing that there is still just 1 out of 4 patients who might still benefit from a simple monotherapy of anti-PD-1 or anti-PD-L1, provided the tumor cells – more than 50% of the tumor cells express PD-L1. So second biomarker – the usual suspect, right? – is the surrogate of the presence of neoantigens, that is tumor mutational burden, the TMB. TMB is supposed to speak about the visibility of the tumor by the immune system. Maybe TMB needs some more time to develop, and I’m quite convinced that we have now consistent data, not only in lung cancer, but across diseases, showing and signaling that TMB or neoantigen loads might be good biomarkers to predict immunotherapy efficacy. But remember, using one specific platform or foundation medicine, TMB is already a biomarker to be used in the US for the use of pembrolizumab because it is easiest. So we need more work, but it’s already something which is important, added in the US, and needs some more time in Europe.
I think that also we have some additional relevant biomarkers that could be useful for selecting patients that are a candidate for immunotherapy. And among these biomarkers, certainly the HRD or DNA mismatch repair deficiencies, including microsatellite instability, represent an important potential biomarker. We have evidence also from clinical trials showing that patients, particularly with microsatellite instability, are particularly sensitive to immunotherapy. And this is something that we are observing not only in lung cancer, but also in many other diseases. We have clear evidence that immunotherapy is still working, and also we know that at least the approval of some agents, for example, pembrolizumab specifically, for patients presenting this event.
I don’t know if, Yi-Long or Solange, you have some additional insight on this discussion. If you want to add some comment on that.
So I think there’s this kind of very important assessment of trying to find drivers, particularly in nonsquamous, to make sure that there’s no driver and no other options, and the second thing is PD-L1. We usually also have TMB here in my center because it’s a question of curiosity, but also it’s a question of defining the landscape of neoantigen for other experiments and approaches.
Each country probably has a different way in which biomarkers are explored, simply because also the approval of the drug is different. In Italy, generally, we are not doing TMB. Very few centers are doing TMB. We, of course, screen all patients for PD-L1, and we also screen all our patients for DNA mismatch repair deficiencies. This is across all cancer types because we know the difficulties specifically of immunotherapy in this kind of patients.
I think because in the clinical practice, the IO positive, the chemotherapy is very, very popular and very, very common. So in China, most physicians don’t test the PD-1 for the patients. But in some special situations, such as for the elderly patients or the performance status is poor, in this state, I would test the PD-1 to select the monotherapy. So this is the clinical practice point.
So for our patients where immunotherapy is appropriate, how do we determine when to use monotherapy versus combination therapy? And more importantly, what are we learning about the sequencing of immunotherapy? And we start with Dr. Peters.
Excellent, Federico. As I said before, what is very reassuring is we have now consistent data telling that there is this opportunity for 1 patient out of 4 to only receive monotherapy. Would it be pembrolizumab, atezolizumab, and maybe in the future, cemiplimab? This is respectively related to 3 trials, the KEYNOTE-024, the IMpower110, and the EMPOWER-Lung 1. All of these trials demonstrate that in this case of high PD-L1 expression on tumor cells – more than 50% of the tumors are expressing PD-L1 – the monotherapy is first of all superior to chemo, but also has shown that with long-term follow-up for KEYNOTE-024 at the ESMO meetings this year, allowing for an amazing long-term benefit, with more than 30% of survival at 5 years with pembro monotherapy only. So really meaning that it’s an opportunity. It’s an opportunity for a long-term and durable benefit, allowing, you know, to keep the chemotherapies that we all fear, a little bit, the side effects from, and also that patients don’t like so much, for the subsequent final treatment. So just to conserve and protect the quality of life with the chemo-sparing regimen of monotherapy checkpoints and keep the chemotherapy for second line. So I think this is really a great option that, I guess in Europe, we all still try to use in most of the patients with high PD-L1 expression.
I think, Solange, I agree with your comment. But unfortunately, immunotherapy is not effective in all patients with cancer because we have a significant proportion of patients that are not sensitive to immunotherapy, at least when immunotherapy is used as a single agent. This is the reason why, in my practice, I generally give preference to the combination of immunotherapy and chemotherapy. Of course, it’s important to consider the general condition of the patient, and the age, and of course if chemotherapy is contraindicated or not. But if chemotherapy is not generally contraindicated, I generally give preference to the combination of immunotherapy and chemotherapy, which is the way in which we guarantee to the patient the most effective regimen, particularly in those situations in which there is a very high risk of progression.
I want to talk about the IO plus IO, the combination. I think that now, because most patients are afraid of chemotherapy because of the toxicity, the IO plus IO combination is the better alternative and very, very promising, especially with the CHECKMATE 227, the comprehensive clinical trial. So the PD-L1, more than 1% of patients can benefit from this, the IO plus IO. And at least the combination is also approved by the FDA in some countries. But for me, I think that I’m very interested in the PD-L1-negative patients; the IO plus IO also shows a better promise of results. But I also think the CTLA-4, the inhibitor, is not approved in most Asian countries, including China. So this means in this situation, we could not use an IO plus IO in our clinical practice.
Thank you, thank you. I think that you introduced also a very important point, and it is, of course, evaluation of toxicity. Of course, when we have to decide about mono-immunotherapy versus a combo with chemotherapy or IO plus IO treatment, we need to consider also the risk of adverse events that we have with the combination.
I’m a little conservative here. I think that in terms of facing a metastatic disease, I still think and guess that this opportunity of trying to give a simple treatment, with monotherapy, anti-PD-1 or anti-PD-L1 – I usually use monotherapy, anti-PD-1 – is a great opportunity. I also like the idea that I keep the chemo for a second-line option. However, there might be some patients, like you said before, who might be really in danger because of the disease, a threatening disease, because of its location or its burden in terms of tumor burden, right?
Absolutely. I agree with this comment, and it is important also for the audience to understand when it’s better to be more aggressive, and when, probably, we can give a less aggressive therapy. Thank you for all of your comments.
So for those just joining us, this is CME on ReachMD. I’m Dr. Federico Cappuzzo, and I’m here today with Dr. Solange Peters and Professor Yi-Long Wu, and we are discussing emerging data on the use of immunotherapy in metastatic non-small cell lung cancer.
Let’s turn our attention to all of the exciting new data that were recently presented. We just had the World Lung Cancer Conference in January, and last year we had 2 exciting meetings – the ESMO meeting and also the ASCO meeting. So Professor Wu, what impressed you on these meetings?
So in this World Lung Cancer meeting, there is some exciting results about immunotherapy, the results of the IO plus IO in the phase 3 clinical trials. Here, I would mention the KEYNOTE-598. This is a design of pembro plus ipilimumab versus the pembro plus a placebo in the first-line treatment for the metastatic non-small cell lung cancer with PD-L1 expressed in more than 50%. So this combination, IO plus IO, was successful in the CHECKMATE 227, but for the KEYNOTE-598, this is the failure KEYNOTE trial with the overall survival 21.4 months, versus the 21.9 months. Note the not significant difference between these two groups.
Thank you very much, Dr. Wu. I think that also we had some very important data coming from the ESMO meeting. The first are the data of the EMPOWER-Lung 1 trial, and it is a trial with a new anti-PD-1 inhibitor, that is cemiplimab. It is a drug, and cemiplimab is already approved in cutaneous squamous cell carcinoma. And the EMPOWER-Lung 1 trial was a trial comparing cemiplimab versus standard platinum-based chemotherapy in patients with non-small cell lung cancer. This trial was clearly positive by showing a significant improvement in both progression-free survival and, most importantly, in terms of overall survival. Particularly, the benefit was very strong in the group of patients with high levels of PD-L1 expressions. So we have another agent confirming the superiority of immunotherapy versus platinum-based chemotherapy.
Among the new immunotherapeutic agents, the anti-TIGIT agents represent a very important class of agent. These agents are generally very well tolerated, and therefore it is very easy also to combine with other agents. And during the ASCO and the ESMO meetings, we were presented the data on the new anti-TIGIT, particularly tiragolumab is one of the most exciting agents. And data on the combination of tiragolumab and atezolizumab showed that this combination, specifically in a group of patients with high levels of PD-L1 expression, is particularly promising. Dr. Peters, what about the ASCO 2020?
Thank you, Federico. I think the ASCO 2020 had the opportunity to give us some insights about additional or stronger immunotherapy components. So I think CheckMate 227 is paving the way of CTLA-4 in non-small cell lung cancer, but the trial is probably too complex to just take it as it is, right, for prescribing, at least globally. So the sister of this trial is a very clean and well-conducted trial called CheckMate 9LA, which was also presented at ASCO and now published, which is using ipi/nivo and a short duration of chemo – 2 cycles of platinum-based chemo. It is compared to chemo and has shown a benefit in overall survival, has shown this early signal for plateauing, and has shown a new opportunity to potentially be very good for our patients, very short course of chemo, and using potentially immunogenic cell deaths, followed by ipi/nivo maintenance for a maximum of 2 years or until progression. So this is really something which is of interest, this long-term follow-up to try to understand if this might impact the 5-year story, what’s happening long term for these patients in line with what we have observed in melanoma.
Thank you, Solange. I think that we covered the majority of the topics, so the relevant topics that we’re presented at the latest meetings. I think, as a general comment, that today we have more options that we can offer in the frontline setting, but unfortunately, we have few options in patients who are failing treatment. So the second-line therapy remains, unfortunately, an important, relevant problem for our patients. Solange, what is your idea of that? I mean, if we don’t have a clinical trial, in daily clinical practice, what can we offer to the patients?
It’s a very good question. If you are not at an academic center and you have gone through this combination, like you said, Federico, it’s still a majority of patients with chemo/IO frontline. And you have to do that, right? Because IO has to be given to every single metastatic patient, so you have to give it frontline. But once you have done it, chemo/IO, what does remain for second line? So outside of a clinical trial center, well, it’s docetaxel, right? Docetaxel plus ramucirumab plus nintedanib if you can, but at least it’s docetaxel. So a little frustrating for, I would say, a precision oncology perspective. Of course, there are many clinical trials ongoing, but still, you will probably agree with me, no very strong signal to be found in terms of redefining a standard second line after chemo/IO. These trials are mainly envisaging the combination of a checkpoint plus anti-angiogenic – nintedanib, cabozantinib, ramucirumab, bevacizumab, lenvatinib. So all of these are ongoing as second line, IO plus anti-angiogenic. That’s what happening. There are also some more refined strategies, right? IO plus multi-target TKIs, like sitravatinib, which looks very promising.
Okay. Let’s shift our attention to international and regional guidelines, where we have seen that there are many differences in how we approach the use of immunotherapy. What are some of these regional differences, and how do we address that? Dr. Peters, can you tell us about the European perspective?
So Europe is a very specific environment in which you can see the European Medicine Agency, the EMA, will define the broad picture, right? What can you consider at every country level? But remember that beside or beyond EMA, every country level will have its own regulatory body – the payer, right – which is called the HTA, which is still country by country, despite our attempts to have one unique structure. But still, it’s country by country, meaning that the landscape of accessibility is in the reality still very different from one country to the other ones. So I guess what is very important is to have guidelines which allow every physician to find his way, despite some missing opportunities or missing the option in the country. So trial would really encourage. In Europe, what we do is we write these ESMO guidelines. Now in lung cancer it’s living guidelines, very adaptable over time, which consider, of course, every option with what we call a level of evidence; the quality of the trial; a degree of recommendation; how much it changes the fate of the patient; as well as what we call the MCBS – the magnitude of clinical benefit scale – which is based on EMA approval or after EMA approval, which will prioritize what you can do according to what you have.
So, Professor Wu, what is your perspective and what is the situation in Asia?
If we are based on the international standard, such as in China, we only approved pembro in the first-line setting, including the monotherapy or the combination with chemotherapy. In the second line, we are only nivo as the only one, the second-line drug. And also, the very, very exciting thing is, if the one drug is approved for an indication in the global setting – FDA or the EMA or the Japanese – but this indication is not approved in China, this drug now runs in the China market.
So unfortunately, that’s all the time that we have today. I want to thank our audience for listening in and thank my colleagues, Dr. Solange Peters and Professor Yi-Long Wu, for sharing their valuable insights. It was great speaking with both of you today. Thank you.
Thanks a lot, Federico. Wonderful discussion, thank you.
Yeah, thank you so much. I enjoyed this discussion. Thank you.
You have been listening to CME on ReachMD. This activity is provided by AGILE and is supported by an independent educational grant from Merck.
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In accordance with the ACCME Standards for Commercial Support, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. GLC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Director Medical Oncology
NCI Regina Elena
Consulting Fees: Merck Sharp and Dohme
Professor Solange Peters
Chair Medical Oncology
Oncology Department – CHUV
Consulting Fees: Merck Sharp and Dohme
Speakers Bureau: Merck Sharp and Dohme
Contracted Research: Merck Sharp and Dohme
Professor Yi-Long Wu
Guangdong Lung Cancer Institute
Guangdong Provincial People’s Hospital
Speakers Bureau: Merck Sharp and Dohme
- Jorge Bacigalupo has nothing to disclose.
- Ann Early has nothing to disclose.
- William A. Mencia, MD, FACEHP, CHCP has nothing to disclose.
- Brian P. McDonough MD, FAAFP has nothing to disclose.
- Tricia O’Leary has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Evaluate the most recent evidence from clinical trials on the effectiveness and safety of immunotherapies for metastatic NSCLC
- Distinguish how clinical practice guidelines used in Europe and China differ from the latest data for immunotherapies for metastatic NSCLC
- Describe best practices for biomarker testing to guide treatment decisions for patients with metastatic NSCLC
This activity is designed to meet the educational needs of medical oncologists, pathologists, and pulmonologists.
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This activity is supported by an independent educational grant from Merck
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