® titled “Updates in Systemic Therapy for Nonmetastatic Lung Cancer.” I’m Dr Benjamin Levy from Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, primarily out of Sibley Memorial Hospital in Washington, DC. I’m thrilled to be joined by an expert panel of faculty. First, Dr Ticiana Leal, from the University of Wisconsin–Madison. We are also joined by Dr Jarushka Naidoo, who recently moved across the pond. Dr Naidoo is a consultant thoracic medical oncologist at Beaumont Hospital in Dublin, Ireland. Also joining us is Dr Ravi Salgia, from the City of Hope Comprehensive Cancer Center in California; and Dr Jun Zhang, from the University of Kansas in Kansas City.

Today we’re going to discuss a number of topics pertaining to stage I through stage III in non–small cell lung cancer, including adjuvant EGFR TKIs [tyrosine kinase inhibitors]; perioperative immunotherapy, with a focus on neoadjuvant immunotherapy; and consolidation immunotherapy in stage III non–small cell lung cancer. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions around treatment selection. Let’s get started on our first topic.

You can’t have a panel discussion or a committee meeting or a Zoom panel discussion without talking about ADAURA, which has recently been presented on and is now published. Although not FDA approved yet, this is clearly practice changing. But before we talk about ADAURA and the role of adjuvant osimertinib for resected 

-mutant lung cancer, perhaps we can go over general treatment approaches for patients with resected early stage lung cancer.

Dr Zhang, do you want to kind of walk us through what your approach is for patients with resected early stage lung cancer? What do you talk to them about? Walk us through your conversation with them when they come to your office.

 Sure. So the focus of the resected early stage non–small cell lung cancer at this moment is primarily on folks in the adjuvant setting. We offer adjuvant chemotherapy for stage II and stage III disease, as well as for those of selected high-risk stage IB disease, such as those with a tumor larger than 4 cm. There is also a consideration for radiation therapy for patients who have a positive surgical margin. Now, for N2 disease, however, this is debatable. At this moment, I would say it is generally recommended, but we know that the data are not solid. In fact, the recent data from ESMO [European Society for Medical Oncology Congress], the most recent data from LUNG ART may potentially change our practice.

In addition, based on the data from ADAURA, if a patient has an 

 mutation, we should seriously consider osimertinib for patients with stage IB, II/IIIA disease.

 That’s a great overview. Dr Leal, how do you talk to patients? What chemotherapy are you generally using for these patients? Is it carboplatin? Is it cisplatin? What’s your partner there for patients with resected non–small cell lung cancer?

 For patients with early stage resected non–small cell lung cancer with generally stage II or stage III disease, and select patients with stage IB disease with larger tumors greater than 4 cm, we’ll talk about the role of adjuvant chemotherapy with regard to risk reduction or recurrence as well as overall survival. In general, my preference, based on the results of randomized trials and the meta-analysis, is to use a cisplatin-based regimen. For patients with a good performance status, good renal function, with nonsquamous histology, who are motivated to go through 4 cycles of adjuvant chemotherapy, I discuss the roll of cisplatin in combination with pemetrexed.

For the squamous population, we use cisplatin. The partner would be either docetaxel or gemcitabine. We talk about risk reduction and the 5-year overall survival benefit that is modest—in the order of 5%. There is probably more of a benefit in the population with nodal positivity. We do have that discussion about toxicity and quality of life. It depends on the patient’s goals as well.

 Dr Naidoo, do you ever offer carboplatin as adjuvant therapy? What’s that patient look like? You know, cisplatin is not the easiest to get through. We’re trying to do 4 cycles of a platinum-based regimen. Usually, the data are with cisplatin. Are there data, or do we ever consider using carboplatin for patients?

 I certainly do. Of course, this is an extrapolation of the data in stage IV disease. Dr Joan Schiller’s paper in the 

 showed that all our platinum-based chemotherapies have overlapping survival curves in the stage IV setting, in terms of outcomes. I think it’s safe enough to extrapolate that in this setting. Carboplatin and Taxol is a very reasonable approach for patients who may have a borderline performance status. It is also a reasonable option if, for some reason, you feel that a cisplatin-based regimen may not be appropriate. For example, renal impairment.

Obviously, the data that all our adjuvant approaches are based on pertain to cisplatin and vinorelbine. I know of some sticklers who still give cisplatin and vinorelbine. So there are a lot of options, in terms of chemotherapy, in the adjuvant setting. A histology-based approach such as what Dr Leal outlined is very reasonable. The classic cisplatin-vinorelbine regimen is also an option, as well as carboplatin-paclitaxel.

 Dr Salgia, what is your general approach in the adjuvant setting? What do you select as chemotherapy? How do you discuss this with patients? Is there anything you want to add?

 You know, it’s a multidisciplinary effort, right? We talk about every patient, and it becomes much more personalized. If they qualify for a clinical trial, that’s what we tend to consider first, in that sense. But you really have to think about that patient population. You think about managing an older population. You think about how to manage the poor performance status population. You consider the achievement of having an overall survival. Really, it’s individualized. It’s stage based, performance status based, molecular analysis based—all those are factors to consider.

 Yeah, all your points are well received and nicely summarized. One thing I would add is that I tell patients, “We’re going to try to give 4 cycles of adjuvant cisplatin-based chemotherapy.” Patients are under the assumption, “If I get 4 cycles and I’m in the clear, there’s no chance of recurrence.”

We have to have to have this balanced discussion that the benefit is there. It’s modest in some patients. It’s worth it for many of our patients. But I try to go over that benefit. You have anywhere from a 5% to 15%, maybe 20% improvement, and a 5-year survival with the use of adjuvant chemotherapy. Unfortunately, there is the chance of recurrence. This will lead in nicely to our discussion on the ADAURA data.

Treatment of Early-Stage NSCLC: Current Standard of Care

 We’ll talk about neoadjuvant immunotherapy in the next segment, but how about neoadjuvant chemotherapy? Is that an option for patients? I mean, 4 cycles before surgery vs 4 cycles after surgery. Does it make a difference, Dr Naidoo?

 I trained at a very pro-neoadjuvant chemotherapy institution, so I feel I’ve been well schooled on these data. But my understanding is there are believers and nonbelievers when it comes to neoadjuvant approaches or neoadjuvant chemotherapy in the context of lung cancer.

The believers would say there are good data to suggest that for patients who get neoadjuvant chemotherapy, there is a 40% increased rate of completion of their chemotherapy based on the phase 3 NATCH study. This is opposed to those who receive chemotherapy in the adjuvant setting. Obviously, it’s an in vivo test of the response rate of the chemotherapy. It may potentially downstage patients to allow them to have a less morbid surgery. Of course, there’s the potential benefit of eradicating micrometastatic disease.

Those are the points by those who are in favor of a neoadjuvant approach. As an adjuvant approach, we recognize that surgery is a definitive part of this definitive paradigm. Neoadjuvant chemotherapy is delaying the time to the definitive part of things, potentially introducing toxicity early and potentially complicating the achievement of an uncomplicated surgery.

Then, of course, there are complications of interpreting a pathologic staging—ypT staging as opposed to a simple pT staging—if we use a neoadjuvant approach. There are pros and cons. As Dr Salgia mentioned, discussing both options with the patient is reasonable because there are pros and cons. It’s a tailored approach.

 Dr Zhang, do you guys consider neoadjuvant chemotherapy at your institution?

Again, this is a multidisciplinary discussion. If the tumor is very small, we prefer to go for surgery and adjuvant chemotherapy. But let’s say the patient has a relatively larger tumor. In that instance we prefer neoadjuvant chemotherapy in order to try to shrink the tumor, then we go to surgery.

 Dr Leal, what is the University of Wisconsin experience with neoadjuvant vs adjuvant therapy outside a clinical trial?

Outside a clinical trial, we are preferentially an adjuvant chemotherapy institution.

 OK. Dr Salgia, what is City of Hope’s experience with this?

 We have 31 sites, and we have a large academic site in Duarte, California. We also have many clinical networks. We have become very standardized. In the appropriate setting, a neoadjuvant approach makes sense so your surgical resection is much more feasible and palatable. Otherwise, we consider adjuvant therapy.

 This was nicely highlighted by all of us. There are pros and cons associated with each of these approaches. The meta-analysis with neoadjuvant chemotherapy has a hazard ratio identical to the meta-analysis of adjuvant chemotherapy. Both seem like reasonable options for patients, and both have their pros and cons.

Neoadjuvant Chemotherapy in Early-Stage NSCLC

Let’s move on to radiation. As Dr Zhang has discussed, there may or may not be a role for postoperative radiation therapy for patients with resected lung cancer. We have some interesting data that have come out of ESMO [European Society for Medical Oncology Congress] 2020 suggesting that maybe we should pump the brakes on radiation postresection. Dr Leal, can you walk us through these data that are just coming out of ESMO—the LUNG ART study?

 The role of postoperative radiation has been controversial. We have typically thought about using postoperative radiation in patients with positive margins in complete resection, and for patients who had, for whatever reason, incomplete nodal dissection. Then patients with N2 disease. At our institution, if patients had single-station N2 disease, a lot of times we would actually not proceed with postoperative radiation. So the study, in my opinion, is practice changing.

The LUNG ART study was presented at ESMO 2020. This is a phase 3 trial that looked at mediastinal PORT [postoperative radiotherapy] vs no PORT, 54 Gy and 27 to 30 fractions, for patients with complete resection with nodal exploration and N2 positivity. In this study, prior neoadjuvant chemotherapy was not allowed. The main end point of this trial was disease-free survival. The trial enrolled 500 patients with completely resected non–small cell lung cancer with N2 histology.

These patients were randomized 1:1. Results showed there was no improvement in disease-free survival, which was a primary end point for patients who received PORT vs no PORT. The difference here was 22 months for the patients who received no PORT vs 40.5 months for patients who received PORT. And the hazard ratio was 0.85.

Importantly, there was no difference in overall survival. There was a slight decrease in number in terms of mediastinal relapse in the patients who received PORT vs no PORT. But importantly, there was also increased toxicity, including grade 5 events. More cardiopulmonary mortality was seen in the patients who received PORT.

In my mind, this was a very well-designed study. It really answered the question that we have for worried about for years, and will help me decide not to use PORT in patients with completely resected N2-positive non–small cell lung cancer in the adjuvant setting.

Yeah, it was certainly a surprise on the heels of some retrospective data that would suggest that postoperative radiation therapy can lead to improved survival, specifically with resected N2 disease. Now we have a nicely designed phase 3 trial showing that’s not necessarily the case.

Dr Salgia, does this change your practice? Does it change your enthusiasm or likelihood for referral to radiation oncology with incidental N2 disease, or even N2 disease found at the time of resection?

 Absolutely, Dr Levy, and beautifully summarized, Dr Leal. As soon as that data came out, our whole group got an email from our radiation oncologist. “Look at this study on PORT.” We all chimed in as well, and so did our surgical colleagues. This is clearly practice changing, and we have to take this into account. N2 disease is still pretty tough to treat, but now we will not be referring for radiation based on this study. Very nicely done.

Dr Naidoo, what are your thoughts on this?

 I totally agree. Postoperative radiation to the chest, to the mediastinum, does not come with a “get out of jail free” card. These are patients who have already undergone surgery, have already undergone adjuvant chemotherapy. So this would be welcomed news for patients—to hear that their treatment journey had to come to a close and they didn’t need further thoracic radiation.

Yes. I would echo the sentiments that have just been relayed. N2 is such a challenging disease. There is a high rate of recurrence. We think that modalities that are instituted will lead to outcomes that are improved, and we’re learning that 1 of our main modalities that we’ve generally deployed in this setting is actually a negative study.

Dr Zhang, does that change how you would monitor these patients? Let’s say you have a patient with an N2-resected lung cancer and you’re giving 4 cycles of chemotherapy, but you can’t give radiation. They’re at high risk of relapse. Would you decrease the interval of the scans for these patients? What would your monitoring strategy be after chemotherapy?

 That is a tough question. At this moment, with no clear data, especially regarding survival benefits and additive toxicities, I would say this study is a very beautiful answer for a question that has haunted us for almost 20 years.

Without clear evidence of the benefit, I would just monitor the same way as what we’re doing. But of course if a patient shows worrisome symptoms, we can always scan earlier.

Role of Postoperative Radiotherapy in Early Stage NSCLC

 Let’s move on to a strategy that has worked recently, at least from a disease-free survival [DFS] end point, and that is adjuvant osimertinib. There clearly were very thought-provoking and potentially practice-changing data presented at ASCO [American Society of Clinical Oncology Annual Meeting], and we’ve had updates at ESMO [European Society for Medical Oncology Congress] that are also clinically important.

Dr Naidoo, can you talk to us a little about ADAURA’s study design and outcomes and then highlight some of the updates we found out about at ESMO this year?

 Sure. So ADAURA is causing a stir on every possible airwave. This was a phase 3, double-blind, randomized study. Theoretically, this was a simple study design of adjuvant osimertinib vs placebo in patients with stage IB, II/IIIA 

-mutant non–small cell lung cancer. This was a simple study where just over 600 patients were randomized in equal parts to placebo vs osimertinib. 

The study was stopped early because of efficacy seen on the investigational arm by an independent data-monitoring committee. This was based on the outcome for the disease-free survival end point for patients with stage II to IIIA disease who had been enrolled. It showed a hazard ratio of 0.17, which was highly statistically significant. And then in the overall population, there was a DFS hazard ratio of nearly 0.21. Again, highly significant. 

This equated to an 89% 2-year disease-free survival rate, compared with 53% on placebo. We saw the full publication about this in the 

Controversially, the overall survival outcome was immature—only 4% maturity. Of course, this is because the study was stopped early, which obviously complicates our ability to interpret some of these things and has created quite a war between the believers and nonbelievers regarding the DFS vs OS [overall survival] end points.

Moving on to the second part of your question about ESMO, what is really interesting is Dr [Masahiro] Tsuboi and colleagues presented an abstract at ESMO looking at the sites of recurrence in patients treated as part of ADAURA. This was an exploratory end point within the study.

All patients enrolled in the study were mandated to have some form of brain imaging, but only in the absence of symptoms, and this could have included MRI or CT scans of the brain—whichever was available at that particular institution. Very interestingly, 45 patients had CNS [central nervous system] events. Only 6 CNS events were noted in the osimertinib arm compared with 39 CNS events in the placebo arm. 

The median CNS DFS was not reached. It was 48.2 months for the placebo arm, and a very impressive Kaplan-Meier curve of the CNS DFS presented showed that the osimertinib arm nearly looked parallel, with a hazard ratio of 0.18.

Obviously, as we know, brain metastases is a very common outcome in patients with oncogene-addicted lung cancers—

-mutant lung cancers, and others. Patients can be very symptomatic. This can be a very difficult complication of this disease. It is difficult to manage. The idea that 1 could actually prevent CNS disease from occurring with adjuvant osimertinib is clinically important.

Obviously, there are some issues here in terms of the interpretation of these data. Not every patient was necessarily required to have baseline imaging, and that baseline imaging may have been different. As we know, CTs of the brain may miss about 10% of brain metastases compared with MRIs of the brain.

This may complicate our ability to interpret these results and may sort of say that these results may actually be telling us that osimertinib was treating subclinical disease in some cases. But regardless, a very impressive CNS DFS, and different and interesting data.

 That was a very nice summary, highlighting the pros and cons of both the original presentation and now the ESMO update with this potential theoretical protection of the CNS that we’re seeing but without mandated MRIs.

Dr Leal, what is your take on this? Is DFS enough? Do we need OS? We’ll probably never have it. The study was stopped prematurely. We’ve talked about how challenging and unforgiving lung cancer can be, even with resected lung cancer, and high rates of relapse. How do you put this all together, and what are you doing in your clinic?

 The results presented are very impressive, and there’s room for a lot of optimism. Obviously, we’d love to have OS results. That’s the gold standard. If we’re not going to get that data, I’ll take DFS. For patients who have this disease and for whom we worry about their outcomes, these results are meaningful. They are meaningful enough that if we don’t get OS data I would definitely still take action on it, with approval on DFS end point.

That being said, I have not yet changed my practice. I’ve been waiting to see the data evolve. I’m waiting to see an FDA approval. We have the ALCHEMIST trial at our institution. We are still enrolling patients to ALCHEMIST. There is an EGFR targeted therapy arm. But I think it will come soon, and I am having the discussion with patients. I’m explaining to patients, “These are the results. This is what’s coming.” It’s just a matter of time before I really incorporate it into my clinical practice.

 Dr Zhang, what are your thoughts on this? Does this change things for you?

 Yes. When you look at the initial design of study and their defined hazard ratio, they still ended up with 0.17. This is of dramatic significance. And I agree with Dr Leal. Even if there’s no OS data, I definitely will still prescribe osimertinib once it’s FDA approved for those patients based on these significant, unprecedented results of DFS.

 Dr Salgia, what are your thoughts on ADAURA?

Because we have a large patient population with 

 mutations, patients have been very well informed through social media, through the various articles, and their families. If you don’t bring it up, in terms of thinking about osimertinib in the adjuvant setting, patients will.

For early stage disease, we’ve been doing a molecular analysis. If they potentially have a L858R exon 19 deletion, we do consider that if they don’t qualify for a clinical trial. But the more important issue is getting payer approval. We have to make sure this is paid for because the cost-effectiveness analysis does not give us the opportunity to give osimertinib to everyone. It’s almost $18,000 a month. So we have to make sure that it’s affordable.

 Nicely done. This is a balanced discussion. I’ll play naysayer, and I’d love to get people’s reactions. How can we justify the routine use of the drug given the cost of $20,000 a month in the absence of OS data and with a poorly designed trial? You know, we’re not looking at early vs delayed. 

How many patients with metastatic disease who met it out in the control arm actually get osimertinib? And why give the drug now when you can give it when patients relapse? Is there an answer to this? These are the common questions that we continually get on this—cost, no OS, poorly designed. Also, a high percentage of patients didn’t get adjuvant chemotherapy and weren’t properly treated. So can we routinely justify this in the absence of OS data given the challenges posed?

 I’m normally on that side of the fence, but just to play the other side, it would be very difficult, very challenging to do a study where we actually compared, head-to-head, the outcomes for a patient who got adjuvant treatment vs if they got it in a metastatic setting. That would be a very challenging study to do. 

Also, the feeling or the basis on which we believe or we advocated for adjuvant therapy in the past is that once patients develop metastatic disease, treatment is not given with the intent of cure. But we know that in the adjuvant setting this is the goal. Let’s face it, that is the most meaningful, the most powerful goal we can every achieve as cancer specialists.

If we have a shot at cure, therein lies the reasons why many would be open to the use of adjuvant osimertinib, even with an end point that isn’t necessarily considered the gold standard.

Phase 3 ADAURA Study: EGFR-Mutated NSCLC

 Who gets this, and for how long? Dr Leal, you’re not considering doing it yet, but let’s say you’ve decided that you’re going to give it routinely. Whom would you give it to, and for how long would you give the drug to them?

 One of the things I want to add, in terms of adjuvant vs early metastatic, is that there are challenges with NGS [next-generation sequencing] testing. We’ll discuss this later on, but this is also something to look at. We know that the rates of NGS testing, even nowadays, across practices vary quite a bit. So yes, we could potentially use this at progression with metastatic disease. Are we treating patients who would never recur? Those are important considerations, and that’s why I’m cautious about giving it a bit more time. I want to see if we are going to see a bigger signal for which we’ll feel more comfortable exposing patients early to prolong therapy with potential adverse effects. Ultimately, they’re very well tolerated. But we do see a lot of adverse effects. I was actually quite impressed to see the data from a trial that was done with 

 patients from a patient perspective. We can look at toxicity grading on clinical trials and look at higher-grade toxicity as how we report toxicities. But with patients who are young and are otherwise going back to work and trying to live their lives as normal as possible, you have to think about long-term toxicity, chronic low-grade toxicity, and how that affects their quality of life. So I do want to see some of that as well.

Whom would I give it to? I definitely think it is appropriate for the stage II/IIIA population. This is the population of higher risk of recurrence, in which we saw the most meaningful benefit. Regarding the duration of therapy, I would try to mirror what the study is doing.

 Dr Zhang, what are your thoughts on this? Would you give it to a similar patient population? Are there people you wouldn’t give it to?

 Based on the study, stage II and III patients benefit the most. But the number also suggests, at least from the hazard ratio, that even stage IB patients get benefit as well. So these are patients for whom I also might consider this treatment if there’s another contraindication or if the patient is able to tolerate therapy.

Back to your question regarding whether we should start now or wait for the time when the patient develops metastatic disease, I would like to add that although there are probably not much clinical data, from a cancer biology perspective, if you let cancer continue to grow there will be clonal evolution. And yes, those patients develop metastatic cancer. They are more likely to respond to osimertinib. But at the same time, they may have some other concurrent mutations that might potentially affect the response from osimertinib. That is the reason why I would like to start to mirror the study.

 How do we put this all together in terms of testing? We’re taught that we need to find these driver mutations in advanced-stage disease. If they have a particular genetic alteration, we want them to go on genotype-directed therapy. Now we have these data in the early stage setting that would suggest that mutations matter in terms of treatment decisions, adjuvantly. How do we put this together, in terms of testing? Should everyone be tested? All early stage patients? If so, how? Is it just 

, or is it all mutations? Dr Salgia, what are you guys thinking about doing, or what are you doing at City of Hope Comprehensive Cancer Center? What’s your take on this?

 That’s an absolutely great question, and I have enjoyed the discussion. I strongly believe that we should test everyone. This is really important if it can help us make a clinical decision, if we can make a potential predictive value. As Dr Zhang said, are there any concomitant mutations? If you have 

 and RB, is that a negative predictor for osimertinib, as compared with 

 mutations without any concomitant mutations? The second thing is, are there nongenetic mechanisms involved as well, such as EMT [epithelial-mesenchymal transitions]?

All those are important, from the perspective of having this predictive value. I’ve been in practice for over 30 years. I’m so excited that we’re seeing long-term survivors. We even have contemplated and are doing survivorship clinics for our patients. How great is that, right? So why not take advantage of all the information we can get and make the best clinical decision. Also, we have research behind the scenes and in front of the scenes too. Learn more so that we can add to the equation. I’m actually very excited about the DFS [disease-free survival] data, no question about it. But I do think we should do NGS testing on everyone.

 Dr Leal, what are your thoughts on this?

 I agree. I would echo those statements, and I really don’t have much to add. You said it very well, Dr Salgia. I definitely agree with testing everyone with NGS testing.

 Dr Naidoo, give us your early experience in Ireland, in Europe. What’s being done there?

 Great question. I think doing NGS testing is the ideal approach. It provides information that you can save in your back pocket and can hopefully act on if needed in the future. In countries where we have a national health service and all this is not necessarily reimbursable by an individual payer, the discussion is a little different.

Certainly here, and in different places in Europe, there are standard panels that are done. The panel is usually completed, but the results are reported only for actionable alterations that are reimbursable therapeutic targets. Usually the data are there, but it’s going to be mined only if there’s something we can do about it.

I might disagree in some way, but I understand the thinking behind that. It doesn’t allow for the bit of the oncologic cookbook that can occur occasionally, where we see an alteration and might have a hunch or phase 1 or phase 2 data. It limits a bit of that and approaches things in a more standardized fashion.

Having said that, if I had my choice, I would get NGS testing done on everybody. I would like to know that information so I can inform my patient and myself.

 Dr Zhang, what is your experience, and what you guys are doing?

 At this moment, we are not routinely doing an NGS panel for early stage lung cancer. However, I am personally in favor of it. There are a couple of reasons why. No. 1 is because of neoadjuvant immunotherapy. We know that for patients with 

 mutations, for example, if they receive immunotherapy followed by osimertinib, they’ll be concerned with immune-mediated toxicity. It’s something that I would like to understand and try to avoid as well.

The second thing is, we don’t know whether other new immunotherapies—for example, other immune checkpoints—will have some value for this 

-mutant non–small cell lung cancer population, especially in the neoadjuvant setting. Having that piece of information will really answer this question. So yes, from my personal perspective, I would strongly recommend this approach.

 This has been a great discussion. Before we move on, I’ve gotten some second-opinion consults recently. I have a patient of resected 

 lung cancer. Should I just be using alectinib or osimertinib for 

? What are people’s thoughts on that? Again, we have a high rate of relapse. We have a known drug with great activity. Is this where we stop and pause, or is there a role for adjuvant targeted therapies for other genotypes in the absence of data?

 I’ll take that. My answer is, show me the data. We can extrapolate in certain circumstances. But that is a very slippery slope, and I certainly wouldn’t advocate for that approach until we have data in the 

 What about ALCHEMIST? Enroll them in the ALCHEMIST trial then. Would that be ideal?

 Yeah. This is an opportunity where we’re testing patients more commonly in the resected phase. We can boost accrual to trials like ALCHEMIST.

 Yeah. And just to call for trials in this space, ctDNA [circulating tumor DNA] at some point may also be leveraged in the adjuvant space to understand monitoring for minimal residual disease. I look forward to seeing some of the data coming out, hopefully in the next year or 2, looking at ctDNA. Scans are scans. We think there are things going on underneath those scans that we could detect in plasma. I don’t know if you guys have experience with this? Dr Salgia?

 Yeah. I love, Dr Levy, what your institution has done. There was a beautiful paper from Johns Hopkins and collaborative studies in terms of the science paper for screening for cancer, looking at it not only from blood biomarkers. I was very happy to see things such as CEA, CA 19-9, and CA 125 come back to fruition, in some sense. But then cell-free DNA as well, and PET scanning at the same time.

I’m always the biggest believer that you should use all the science and tools you must be able to arrive at an answer. We’re actually looking at ctDNA like there’s no tomorrow. No question about that. I hope we can get it approved through the payers—repeated ctDNA analysis. If somebody has a 

 alteration and you give them a specific therapy, and then the 

 goes away, that’s actually a very positive sign. But you have to do it in terms of clinical trials too, of course.

Patient Selection: Adjuvant Therapy and Testing for ES NSCLC

Let’s move on to our next section, which is the role of immunotherapy in early stage disease. All of us are aware of the immuno tsunami that has occurred in non–small cell lung cancer, specifically in the advanced-stage setting.

We now have 9 different approvals and different indications for advanced-stage disease without an actionable mutation. It’s incredible to think about how many options are currently available as single-agent I/O [immune-oncology], dual-checkpoint blockade, chemotherapy with I/O, dual checkpoint blockade with 2 cycles of chemotherapy. Of course, all these are approved for advanced-stage disease and lead to improved outcomes.

Similar to the targeted therapy paradigm, we’re trying to look at the role of these strategies in early stage disease. There is a role that we’re starting to learn about for perioperative immunotherapy and immunotherapy combinations. Clearly, 1 of the ways it has been explored first has been in the neoadjuvant setting, and it makes a lot of sense to look at this in the neoadjuvant setting.

Jarushka, you’ve worked a lot on this topic. Talk a little about the biological rationale for immunotherapy in early stage disease, and maybe even the clinical rationale for neoadjuvant immunotherapy.

 I’d be pleased to talk about that. I obviously worked with Dr Patrick Forde on his neoadjuvant study of nivolumab, and I have my own study that is looking at combining immunotherapy with radiation in the neoadjuvant setting for stage III disease. So I have some understanding as to why these approaches are interesting both clinically and biologically.

Biologically, when we think about how PD-1 or PD-L1 inhibitors work, the idea is that releasing this inhibition allows our immune cells to kill the tumor cells. But this requires antigen presentation by the tumor cells to generate a group of what we call 

Therefore, it makes sense to use immunotherapy in the neoadjuvant setting when the tumor mass is already in place. Imagining a large tumor mass with lots of different tumor clones, this presents us with an opportunity for a large volume of potential antigens to be presented and to generate antigen-specific T cells.

From there, the idea is that you generate this compendium of antigen-specific T cells, almost like a cancer encyclopedia. After you’ve had your treatment, these antigen-specific T cells can then act as your means of immunologic memory, so if a tumor clone does rear its ugly head, you have a specific T cell that can come and take that out and act as a silent and constant killer without necessarily needing repeated dosing.

That is something that has been looked at in tumor models comparing neoadjuvant vs adjuvant immunotherapy approaches. Investigators have looked to see if the generation of T cells is different when given pre- or postoperatively. This has certainly been corroborated in multiple different tumor models and different tumor types, not just long cancer. This has also been studied in breast cancer. So from a biological perspective, it makes a lot of sense.

From a clinical perspective, we talked a little about the downsides of giving a neoadjuvant chemotherapy approach. One was the toxicity of chemotherapy that may limit the ability to get to the definitive stage of surgery or incur certain surgical complications.

That’s not the case with immunotherapy. We have been really positive about the improved tolerability of anti–PD-1 and PD-L1 agents. Thus far in the neoadjuvant studies, which I know the rest of the panel will go through in due course, we haven’t seen any unacceptable safety signals in some of these early studies. When Dr Forde and my study were being developed, there was a concern for pneumonitis. That was the highest on our list. Thankfully, we have not seen that as an unacceptable rate of toxicity that has limited the ability to get to surgery.

None of those things appears to be panning out with immunotherapy—the tolerability question, the ability to get to surgery, the complications of surgery. If anything, it seems to be tentatively easier than giving neoadjuvant chemotherapy. So there are many clinical pluses associated with this approach.

A beautiful explanation. I’m sold. I’m ready to do it on all my patients. Let’s talk about some definitions that keep coming up on these trials: major pathologic response and complete pathologic response. Dr Naidoo, maybe you can walk us through what these are and how they have correlated with outcome, or if they have at all.

 With regard to pathologic complete response, way back when all of us treated breast cancer, a long time ago I’m sure, that was the Holy Grail that many patients were going for. Patients were treated with neoadjuvant chemotherapy. For breast cancer, we know that pathologic complete response correlates with survival outcomes. Was this the same or true for neoadjuvant chemotherapy in lung cancer? Unfortunately, the answer is no.

One of the reasons is that the incidence of a pathologic complete response—basically achieving complete tumor eradiation for patients treated with neoadjuvant chemotherapy—was very low. In the major published studies, this ranged for 0% to 16%, with a median of around 4%. Statistically, the incidence of this is too low to really be used as a real-time end point for neoadjuvant chemotherapy and, therefore, presumably other therapies as well. Therefore, it was not selected as a pathologic end point of interest in some of the early studies. Major pathologic response was based on a seminal study published in 2012. I think this was based on 192 surgically resected lung cancer samples from patients who had undergone neoadjuvant chemotherapy. A pathologist looked at all these samples and identified that this end point, major pathologic response—defined as less than 10% viable tumor cells—was significantly associated with overall survival in this compendium of studies.

That was the data for which, for example, Dr Forde’s study in the 

 used major pathologic response as the pathologic end point of interest. But this was with the understanding that this was based on a clearance of chemotherapy in the setting of, or lack of experience in, neoadjuvant immunotherapy.

Since then we have learned a lot, and the pathologists who were involved in this study and others have really come to the table and try to understand how we could potentially do better from a pathologic end point standpoint.

I would refer you to a great paper in the 

 that was published in 2018. In that study, the 20 patients who were treated on the 

paper with neoadjuvant nivolumab were assessed very carefully for their pathologic features.

What they identified was that certain pathologic features of the regression bed of the surgically resected specimens harbored specific features that could be combined in a score called the immune-related pathologic response criteria score. This included a number of factors, including immune activation, cell death, tissue repair, and a regression-based score. They were assisted by multiple pathologists and found that it was reproducible.

This has been looked at in a couple of different neoadjuvant settings. It has been looked at not just in lung cancer but also in melanoma and other cancers. It looks to be something that is going to be studied into the future. So there is a lot to be done here. I’m pretty sure it’s not going to be where we end.

Yeah. As with everything else, we’re just beginning to scratch the surface of all this. Identifying the right end points takes a lot of scientific, deep work, which you’ve gone over. I’d be curious to see what that end point is at 5, 10 years down the road vs what it is now, and whether these end points will lead to drug approvals.

Role of Neoadjuvant I/O in ES NSCLC

 Dr Leal, we’ve had several neoadjuvant studies that have been published or presented that are starting to look promising. Maybe you could go over some of the ones that we’ve had up to ESMO [European Society for Medical Oncology Congress], and Dr Salgia will talk about some of the neoadjuvant immunotherapy trials presented at ESMO. Can you discuss the current state of affairs for neoadjuvant immunotherapy? Just provide a high-level overview of some of these trials.

 We’ve had really promising trials that have been completed on the use of preoperative nivolumab in patients with early stage non–small cell lung cancer who underwent resection following 2 doses of nivolumab. The primary end point of this study was really safety and feasibility. This was a small study. There were about 21 patients who had tumors removed. These was very interesting data because they demonstrated a very high response rate in these patients. Nine of 20 patients were resected, and they called out a major pathologic response [MPR] of 45%. That really caught everybody’s eye and interest, in regard to this strategy. Interestingly, in this study, this was independent of PD-L1 expression. In the pilot phase of the study, there was no delay in surgery. This was concluded to be something that was feasible and safe, and it really opened up the path for the up-and-coming neoadjuvant strategies we’re seeing.

Another promising strategy was the LCMC3 study, which looked at preoperative atezolizumab in resectable patients. In this study, adjuvant chemotherapy was also allowed. Again, we saw similar safety and tolerability with atezolizumab in the neoadjuvant setting. We also saw that it did not delay patients going to surgery. The major pathologic response was lower, at 19%. This was encouraging but lower than what we saw in the nivolumab study. The pathologic complete response rate was 5%. Again, the major pathologic response was independent of PD-L1 expression.

We also saw presented data on the NEOSTAR study. This randomized patients in the neoadjuvant setting to nivolumab vs nivolumab plus ipilimumab. Again, this study showed the feasibility of this approach.

As one can expect, there were higher MPR rates in the nivolumab-plus-ipilimumab arm—33% vs 17% in the nivolumab arm. I will say this study reported out that there were no unacceptable toxicities. However, there was a death on the study because of complications in the postoperative setting. This leads us to understand that, so far, there haven’t been any unacceptable toxicities. But as you roll out surgery in the post immunotherapy and immunotherapy-chemotherapy setting to general practice, the safety needs to be demonstrated better in this patient population.

Most recently, the most provocative results that have been presented are from the NADIM study. The NADIM study actually looked at a chemotherapy with I/O combination for patients in the resectable setting and showed a very high overall response rate of 78%, with a complete pathologic response in about 60% of patients. Again, it’s going back to looking at safety and tolerability and feasibility of rolling this out to practices as the data come out and really validate this end point. Certainly, the MPR end point is a very good 1 to use if it really is validated because you can get results quicker. Overall survival would be looked at in a longer study and would take more patients. So I can understand why we’re using this end point, but I would like to see that it’s a validated end point that we can trust to roll out to our patients.

Moving forward, just to summarize, neoadjuvant strategies are here to stay. I’m excited to see the results from ESMO. Chemotherapy and I/O is probably the way to go, as long as we can demonstrate safety, feasibility, no delays getting to surgery, and no increase in postoperative complications.

 That was a very nice overview of very complicated studies. These trials are really landing front and center. I did a double or triple take with a pathologic complete response of 60% in the NADIM trial. That is quite high with just 3 cycles of chemotherapy and I/O followed by surgery. I’ll be very interested to get people’s take on that, because that’s 1 that really stood out to me, especially coming from our institution, which has done a lot of neoadjuvant studies.

Key Trials in Neoadjuvant I/O for ES NSCLC

 Let’s talk about some of the data, Dr Salgia, that came out of ESMO [European Society for Medical Oncology Congress]. Although maybe not as promising of activity from the trials that Dr. Leal went over, but let’s get your take on the ESMO presentations.

 Thanks, Dr Levy. Beautifully summarized, Dr Leal and Dr. Naidoo. I enjoyed that discussion. There were 2 abstracts that were presented. One was by Dr. Marie Wislez, and this was the IFCT-1601 IONESCO study looking at durvalumab. This was given on days 1, 15, and 29, and it was relatively very well tolerated. The partial response rate was 8.7%, with a major pathologic response [MPR] rate of 18.6%. There were about 46 eligible patients, but the issue was it was stopped early. The trial was stopped early because 9% had observed deaths. This was most likely related to not the immune checkpoint inhibition but comorbid disease, and that’s what the author stated.

The second study, PRINCEPS, was presented by Dr Benjamin Besse and colleagues. This study looked at using atezolizumab. Only 1 dose was given, and then surgical resection was 4 weeks later. That’s an important end point. They looked at 30 patients. Four of 30 patients had MPR. That was 14%.

This summarizes that for these 2 abstracts that were presented, I don’t negate what’s been done in the past, but we always tend to come back, with the pendulum coming back to normalcy. The initial trials may show a great response rate, but this one is showing major pathologic response. But these ones, not necessarily. I agree with all of you that it may be about not just using an immune checkpoint inhibition strategy by itself, but is it a combination? Let’s say nivolumab with ipilimumab gives you better outcomes, or is it chemotherapy plus immunotherapy?

My only editorial comment here is that we have to be cautious. We have seen patients who have gotten immune checkpoint inhibition or chemotherapy combinations and have had hyperprogression. We have to really consider whether we should do next-generation sequencing on those patients up front to see if there’s a negative predictor, like STK11 or MDM2 or something else, that will help us prevent that. It would be a terrible shame, even if 1 patient had hyperprogression in our clinical trials or in our clinical experience. That would really negate a lot of things. I do think we need some predictive values as well.

 Yeah, I think you’re right. Understanding the underpinnings of the tumor as well as trying to understand end points for these trials and harmonization of end points is going to be important. I’ve kept a tally in my head as everyone has gone over all this data. My head is spinning. Dr Patrick Forde’s data are around a 40% to 45% major pathologic response. The other single-agent immunotherapy neoadjuvant trials elicit a major pathologic response rate somewhere between 15% and 20%. From the NEOSTAR data, it looks like dual-checkpoint blockade elicits a major pathologic response, around 18% to 20%; maybe a little bit higher—30%. And with chemotherapy and I/O [immuno-oncology] as neoadjuvant therapy, we have a pathologic complete response of close to 60%.

Dr Zhang, you’ve been quiet, but I know you’re taking notes. I see you’re ready to distill all the confusion and simplify this. What is your take on all these trials? What do you think about them? How do we put this all together?

 These are really good summaries. I have learned a lot from everyone’s comments. My take-home message is that we’re seeing a similar trend like what we’ve seen in the metastatic setting. Single-agent immunotherapy has some response but is pretty limited. When we combine that with chemotherapy, the response is higher, especially when we use the major pathologic response. When we combine with another I/O therapy, I/O plus I/O, it seems like the response is higher as well. I would say that if we’re really serious about considering this in the neoadjuvant setting, if we are going to use MPR as 1 of the end points, then the combination of I/O plus chemotherapy might be something that I would favor.

Having said this, what we also know from the NADIM trial is that when we combine chemotherapy and immunotherapy, we have a higher incidence of grade 3 and 4 toxicities. Whether those things would really delay surgery in the real world is another question.

Another point Dr Salgia mentioned is that we actually need to know the molecular profile of those cancer cells as well. For example, if a patient has an MDM2/MDM4 application, 

 application or mutations, there’s a chance of hyperprogression. In clinical trials this would be rare, but we cannot really afford for any patient in our lives to get to hyperprogression. Certainly, these are things that need to be investigated as well.

 Yeah, it’s getting exciting and complex at the same time.

Neoadjuvant I/O for ES NSCLC: Key Trials from ESMO 2020

 Where do we go from here? What are the trials that we need, or what trials are currently going on in this space that hopefully will help answer these questions? Do we have phase 3 trials coming out in this space? If so, when will we know answers? Does anybody on the panel want to take the lead on general approaches for the neoadjuvant setting? We’ve got a lot of phase 1/2 trials here. Where do we go from here?

 There are certainly large, international phase 3 studies that are looking at this. The differences in the approaches between countries will matter. Obviously, patients are generally sold on immunotherapy and the activity of immunotherapy in lung cancer. These studies, where available, are going to be taken up with a great deal of enthusiasm.

It’s not the same cancer, but there’s a cooperative group study of limited-stage small-cell disease using immunotherapy. You know, a rare beast. But that study is over accruing. It is accruing faster than they thought was possible. So I think there will be a lot of excitement for these studies.

Obviously, only 20% to 30% of our patients, on a good day, have early stage or resectable disease. The other factor is that we need to do better in identifying earlier-stage lung cancer patients if this is really going to be an effective treatment. That goes hand in hand with this. The majority of our patients have stage IV disease. The advances here are going to need to be coupled with advances in lung cancer screening and those kinds of studies.

 Yeah. I want to see—and there are trials ongoing—neoadjuvant chemotherapy vs neoadjuvant chemotherapy with I/O [immuno-oncology]. We can consider neoadjuvant chemotherapy the standard of care if you’re going to consider neoadjuvant therapy. Having randomized trials such as ones that explore chemotherapy vs chemotherapy with I/O would be the most relevant to me to help answer questions about toxicity, major pathologic response, complete pathologic response, and outcomes. We’ve run into this in our own centers, and we don’t like to talk about it, but sometimes it takes the surgeon’s buy-in. Is this something that you guys experience at your institutions? Dr Leal, you’re smiling a little. Do you have to have the surgeon’s buy-in here?

 Yeah, for sure. It requires multi-D [multidisciplinary care] to the max. The reason why I’m smiling is we have a recent neoadjuvant trial in which the surgeons are coinvestigators. We actually persuaded 1 of the surgeons to sit through an SIV [site initiation visit] with us and be a part of every step. Obviously, they buy into it. We have a great multi-D team. We have a great group of thoracic surgeons. It’s not something that has been historically on their radar. It’s really a shift in how you think about clinical trials and really work together to advance the field in a meaningful way. We need buy-in from the thoracic surgeons, and we need buy-in from the pathology group. This has really been an incredible effort to get everybody on board to get these trials up and going.

 It takes a village on so many levels. Dr Salgia, your thoughts on this and getting the surgeons to buy in to this strategy?

 I like what you said, Dr Levy. It takes a village. And I like the new term, Dr Leal. I’m going to say multi-D rather than multidisciplinary. It absolutely takes that communication. What I love is that we’ve come a long way. In the old days, it used to be 1 specialty vs another specialty. It really is a combined effort now. Our surgical colleagues see that early stage patient, and then we all do clinics together. It makes it easier. Our surgical colleague might say, “Hey, Ravi, are you able to see this patient today? You’re in clinics and so forth.” It makes it so much easier.

Those days where it took weeks and weeks to see a patient are gone. With this cross-communication, having the cross–multi-D clinics altogether, it makes things so much easier. That’s really what we envisioned as the future in the past, and it’s here. I’m very happy with that.

 That’s a great summary. Just going back to Dr Leal’s comment, I would propose that the surgeon who attended the SIV should get an award. I’ve never heard of such a thing. That’s just emblematic of the need to communicate and all be on the same page with not only the clinical care but the science. Everyone is right on target with what we must do moving forward. Dr Zhang, what is your experience with this? Discuss your interface with the surgeons and how to pull this off.

 Our surgeons have had concerns about whether immunotherapy induces some toxicity, so that a patient would no longer be a perfect candidate for surgery or that there’s some delay. But based on those clinical trials, they are now more convinced. We need to do something in early stage lung cancer. But for surgery, there’s a big change, and they’re really into it now. In fact, we also have clinical trials using neoadjuvant immune checkpoint inhibitors.

 For those patients who are going on neoadjuvant trials, is there patient reluctance? Or are patients saying, “I just want this out. I don’t want to wait to get the treatment.”? We’ve run into this issue before. We thankfully got the surgeon and the medical oncologist on board. But the patient said, “I don’t want to wait. I’ve been taught that this needs to come out. I’ve always been told cure is achievable through surgery.” Is that happening at other institutions? Dr Zhang, go ahead.

 Yeah. In fact, I have patients like this. I have a guy who just wants to get this done as soon as possible. Of course, when you discuss neoadjuvant clinical trials, mention potential risks, etc, they don’t want to lose any chance that their cancer can’t be resected. Certainly there is, but I would say the majority of patients are interested in participating in a clinical trial that hopefully offers longer survival or a chance for cure.

 I agree completely, Dr Zhang. In the old days, it used to be much more of an issue. If it were some cytotoxic therapy, or given in combination with bevacizumab, patients were reluctant. But this doesn’t happen as much now because patients are seeing this information flow through on social media. You even commercials on TV. Patients want to be part of an interesting and important clinical trial, and I certainly think it will become standard of care for us in the next few years.

 One last question. For patients who are 

 mutant, is this the right modality? Let’s say we know that they’re 

 mutant from the biopsy, not necessarily from the surgical resection. Do we pump the brakes on neoadjuvant immunotherapy given that we’ve got a great adjuvant drug? Do we not have enough data? This is a tough one. Dr Naidoo, I see you’re thinking hard about this one.

 Yeah, no data. We encountered this a couple of times in various different patients who were being considered. In many of the neoadjuvant studies, these patients are not necessarily excluded. We know this was the case for PACIFIC as well, which I know we’ll get to. It opens up a bit of a quagmire for what to do next in the patients who have received immunotherapy. It’s an evolving experience. Obviously, we’ll discuss that in the context of PACIFIC. But right now, these patients are definitely being enrolled, and we will have to see whether they derive equivalent benefit, don’t derive the same benefit, or have different toxicities. Until we have the data, it wouldn’t behoove us to exclude these patients from this opportunity in case they may benefit.

 Any parting words on the role of neoadjuvant immunotherapy for 

 Yeah, I’m not a fan, to be honest. I think these tumors are cold tumors. Are we doing a service for our patients, knowing the data for stage IV disease and then applying it to early stage disease? I’m not necessarily sure. It’s clinical-based evidence rather than evidence-based medicine. Without haing that trial, I just don’t know if it’s appropriate to put your 

 or ALK patients on these trials. We have to be very concerned about that. That’s why we do next-generation sequencing for everyone. Then we have that discussion with our patients.

Future of Neoadjuvant I/O in ES NSCLC

 Let’s move on to the final section, where we will discuss the role of immunotherapy in unresectable stage III disease. We’ve talked about the role of targeted therapy in the adjuvant setting and the role of neoadjuvant immunotherapy in the resected setting. But in the unresected setting, even for cure, we’ve obviously got new treatment paradigms that have evolved over the past 2 years. We have an FDA approval for durvalumab based on the PACIFIC data.

The PACIFIC trial has been presented multiple times. It has been published twice in the 

, once for the PFS [progression-free survival] end point and then for an OS [overall survival] end point. We’ve all attended these historical meetings in which we showed up in person. It was presented at ASCO [American Society of Clinical Oncology Annual Meeting] and at the World Lung World Conference on Lung Cancer in Toronto in 2018, and we have some data from ESMO [European Society for Medical Oncology Congress]. Dr Leal, do you want to talk about the PACIFIC data at high level, and then share some updates from ESMO too?

Yeah, definitely. It is great to have this update regarding the 4-year survival for the PACIFIC data. It’s very encouraging. It brings with it a lot of optimism for patients with resectable stage III non–small cell lung cancer, especially if you compare it with historical controls. We had 5-year overall survival rates, despite multiple randomized phase 3 trials, of about 10% to 15% at best.

The PACIFIC trial was a phase 3 trial that randomized patients after completion of concurrent chemoradiation with at least 2 cycles of platinum-based chemotherapy to durvalumab every 2 weeks or placebo. The initial report was an improvement in progression-free survival. The hazard ratio was 0.52. There was an improvement in overall survival, with a hazard ratio of 0.68. As you said, it’s been presented multiple times, and the good thing about having the updates is that it’s been reassuring to see that the data are holding up, and we’re seeing consistent improvements in PFS over time, as well as OS. 

This leads us to think that at the 5-year overall survival update, perhaps we’re actually going to be talking about cure rates. Are we curing patients with stage III disease with consolidation durvalumab?

The update now is a 4-year OS update. We have a median follow-up of 34 months with durvalumab. This is the first time there is a median overall survival in the durvalumab arm. We’re seeing a PFS of 17.2 months vs 5.6 months, with a hazard ratio 0.55. We’re seeing an overall survival benefit as well—a median of 47.5 months vs 29.1 months and a hazard ratio 0.71. There are really impressive results.

The tolerability of durvalumab has been well known to all of us, and it is well demonstrated in the trial. It really is a game changer, and it is reassuring to see these updated 4-year overall survival updates.

 Great summary. How do you put this data into clinical practice? I’ll put you on the spot. The PACIFIC trial did not allow consolidation chemotherapy, which we were generally doing; at least I was for some patients. A third of patients got induction chemotherapy, which no one really ever does, at least in our institution, or at least until recently. Which chemosensitization regimen are you generally using for these patients? Do you always start durvalumab right after the radiation is done, or do you give consolidation treatment?

One of the things I think about, even seeing this update, is that half the patients were alive at 4 years. When I start a patient on concurrent chemoradiation, I think about how I get them to the finish line. How do I get them to durvalumab? I want to make sure we don’t rock the boat during chemoradiation with extra toxicity. In general, I’ve preferred to use the carboplatin-paclitaxel regimen on a weekly basis during radiation. There are patients for whom I may alter the regimen for 1 reason or another. Say somebody has really bad neuropathy. If I feel they can’t handle Taxol, I may change the regimen. This is all based on comorbidities and certain clinical characteristics of that patient. But in general, I favor carboplatin-Taxol with concurrent radiation.

I have gotten away from using consolidation chemotherapy. I don’t think we have strong data for that. We did that in select patients because we had intuitively thought that more is better. But really, we have not seen that pan out in phase 3 clinical trials. So I don’t use consolidation chemotherapy. I am happy to let that go, and so are patients. That added toxicity and might take patients away from being able to get to the consolidation with durvalumab, which is really the main goal. That seems to be the main treatment that has really improved survival and outcomes for patients.

 Yeah. Are there any differences in how the rest of you manage the chemosensitization regimen and the timing of durvalumab for patients, or is that generally what everybody is doing—weekly carboplatin-paclitaxel with radiation, followed by durvalumab within 2 to 4 to 6 weeks after the completion of radiation?

 On the PACIFIC trial, a specific chemotherapy regimen wasn’t necessarily mandated. I do use carboplatin-paclitaxel, as Dr Leal explained. I also use platinum-pemetrexed for patients with adenocarcinoma because it is very well tolerated. I am less of a fan of the classic SWOG regimen. I’ve been burned a number of times with that regimen. However, there are purists who use it and use it well, and there would be no reason not to use that regimen. But generally, patients do find it to be a tougher regimen.

In terms of the timing of beginning durvalumab, there was a lot of discussion regarding optimizing the timing—a change in the protocol to allow for a wider window in commencing treatment. It changed our paradigm slightly, in requiring a scan to rule out progression. Beforehand, this was something we weren’t necessarily doing until later. The timing has become more of an issue and requires us to have seamless communication with our radiation oncology colleagues. That might change the workflow for many oncologists in settings where they don’t have real-time access to their radiation oncologists.

 Are there any other thoughts on the management of this, in how we apply these data into clinical practice?

 The every-2-week dosing is a bit tougher for patients, in regard to coming in each time. Of course, we look forward to the q4 week dosing. The other question always becomes, why only 1 year? Should it be 2 years? Is it going to be 3 years? Or is it going to be 6 months vs a year? All those are important questions. We want to make it as palatable for patients as having a great overall survival but make it as less chemotherapy, less immunotherapy, less surgery, less whatever we can get away with by not having this toxicity. Those are all important questions as we go forward. But this is 1 of the first landmark studies that has revolutionized our practice.

Updates in Systemic Therapy for Non-Metastatic Lung Cancer | Peer Exchange

EP 1: Treatment of Early-Stage NSCLC: Current Standard of Care

EP 2: Neoadjuvant Chemotherapy in Early-Stage NSCLC

EP 3: Role of Postoperative Radiotherapy in Early Stage NSCLC

EP 4: Phase 3 ADAURA Study: EGFR-Mutated NSCLC

EP 5: Patient Selection: Adjuvant Therapy and Testing for ES NSCLC

EP 6: Role of Neoadjuvant I/O in ES NSCLC

EP 7: Key Trials in Neoadjuvant I/O for ES NSCLC

EP 8: Neoadjuvant I/O for ES NSCLC: Key Trials from ESMO 2020

EP 9: Future of Neoadjuvant I/O in ES NSCLC

EP 10: PACIFIC Trial in Stage 3 NSCLC

EP 11: Considering PD-L1 and EGFR Status With I/O in Stage 3 NSCLC

EP 12: Risk of Pneumonitis Post-Chemoradiation in Stage 3 NSCLC

EP 13: Takeaways on Treatment of Early-Stage NSCLC