Good day everybody, my name is Luis Raez, I’m the Medical Director of Memorial Cancer Institute here in Miami, Florida. It's a pleasure to accept this invitation from ecancer. We’re going to review four of the most important presentations of ASCO 2025 in the area of lung cancer.

We are going to start with a review of CheckMate 816 and if you were not there Dr Patrick Forde presented final survival analysis data of this study. If you remember, CheckMate 816 is a very important study because it was the first time that we had a randomised study for neoadjuvant immunotherapy with chemotherapy for early-stage non-small cell lung cancer. Remember, he was the first one to present years ago showing a benefit to chemoimmunotherapy versus chemotherapy alone for neoadjuvant therapy – three cycles of chemotherapy with nivolumab for patients with early-stage non-small cell lung cancer that are going to go for surgery. That was some years ago but the importance is that we didn’t have the survival at that time; that regime was approved by the FDA based on the disease free survival. Now we have finally survival data. So the survival data that they presented showed a hazard ratio of 0.72, meaning that there is a 28% benefit if we add immunotherapy to this neoadjuvant intervention to the chemotherapy.

To make it easy to visualise, what we can tell you is that at five years of follow-up there is 10% more patients alive having immunotherapy with nivolumab instead of having chemotherapy alone.  So that’s an easy way to see the benefit of this intervention – 10% more people alive having immunotherapy instead of only chemotherapy alone. So there is a benefit and, remember, we’re talking about only neoadjuvant. This study doesn’t have any adjuvant portion, we only give the three cycles of chemoimmunotherapy, surgery, that’s it.

During the same time that we were waiting for this data to come, as you know, we had three other studies, one with durvalumab, AEGEAN, one with nivolumab also similar to this one – CheckMate 77T – and one with pembrolizumab, KEYNOTE-671, that showed that if we do neoadjuvant chemoimmunotherapy and we do adjuvant immunotherapy after, there is a benefit in survival. So that’s why this study is different from the other three – the other three studies, we call them perioperative. Perioperative means that we give the immunotherapy before and after the surgery. So we have three perioperative studies, again CheckMate 77T, KEYNOTE-671 and AEGEAN, the one with durvalumab, and everybody knows that also there is a study called Neotorch in China with another PD-1 that we don’t have here. So all of these studies, perioperative, show benefit giving the immunotherapy before and after and that’s also FDA approved.

This study is interesting because, as I said, the benefit is only when we are doing the neoadjuvant portion, there is no adjuvant. So then the question, of course, the most popular question, is do we need adjuvant? So if there is a benefit in survival only giving three cycles of chemoimmunotherapy, why are you going the patient for one year extra? Remember, after surgery we don’t know which patients need adjuvant. We give it to everybody but some patients may not need it because they may be cured. A lot of the stage 1b or 2 patients may not need it because they may be cured already. So that’s the benefit of the neoadjuvant intervention – everybody needs immunotherapy and chemotherapy but if you do adjuvant not everybody needs it.

So one way that we can settle this is Dr Patrick Forde, as he did before, this is not the first time he showed, he showed that there is a survival benefit for the people that have a complete pathological response. In other words, if you get three cycles of  chemoimmunotherapy and you get a complete pathological response, you may not need adjuvant because the patients in the study, in this study, practically all of them at five years are alive if they achieve a complete pathological response. If they didn’t achieve a complete pathological response, of course, there is a group of patients that are not here.

The other group that benefit tremendously is the patients that have a DNA clearance. ctDNA in the blood is not standard of care but it’s going to be standard of care soon because we are starting to monitor ctDNA in many indications – in lung cancer and other cancers. If you have a DNA clearance your survival is much better than if you don’t have a DNA clearance. So that’s why, in conclusion, this study is very important because obviously there is a possibility that maybe if you get neoadjuvant chemoimmunotherapy you may not need adjuvant therapy if you have a complete pathological response.

Not all of us are 100% in agreement with that because the scientific way to do that, to deny people adjuvant therapy, would be to do MRD and find an MRD test that is 100% accurate so we can tell the patient after surgery, ‘Your MRD is negative, you don’t need anything.’ We don’t have a test of that sensitivity yet; we have a very good test that we’re testing now for many industry partners but we don’t have details yet. That’s why it’s still a controversial topic. But it’s up to you – your patient gets a complete DNA response maybe you don’t want to give adjuvant immunotherapy because, as I said, both of them are approved.

The other abstract that was very interesting is the one with the combination of lurbinectedin and atezolizumab as a first-line maintenance, maintenance for patients with small cell lung cancer extensive disease. This was presented by Dr Luis Paz-Ares. If you remember, the standard of care in extensive disease small cell lung cancer is we give four cycles of chemotherapy – carboplatin etoposide – followed by maintenance atezolizumab, that’s standard of care. In this study people were randomised in the maintenance part, so everybody gets the chemotherapy. In the maintenance part instead of having atezolizumab alone, 200mg every three weeks, as the standard of care until progression, they gave atezolizumab at the same dose, 200mg every three weeks, plus lurbinectedin, 3.2mg, we use lurbinectedin every three weeks. To make the story short, you know probably that the results were positive – there was a hazard ratio of 0.73, meaning a 27% benefit if we add lurbinectedin to atezolizumab.

Why do we need to do this? Because, remember, even doing standard of care atezolizumab maintenance pretty much we lose half of the patients in the first year. That’s why in this presentation the maintenance with atezolizumab alone is only 44% in one year, so 44% of the patients are alive at one year if you are doing standard of care maintenance atezolizumab. That’s an improvement from before when there was no maintenance but it’s not enough. If you do lurbinectedin plus atezolizumab the number of patients is 56% so there is a 12% increase in the number of patients that are alive if you do maintenance with both agents instead of doing maintenance with one agent.

Of course the overall response rate, complete response, partial response, everything is in favour of the combination. Of course also there is an increase in toxicity because we are using now two agents instead of one so there is more toxicity but the patients live longer. The extra toxicity is nausea, fatigue, so in other words the extra toxicity is a toxicity that can be managed. I’m not discouraging the toxicity but it’s a toxicity that can be managed because these are side effects that we can manage like nausea and all these things.

The other presentation that was very important, this was a very good ASCO for small cell, was tarlatamab. Tarlatamab was approved last year in May for use in small cell lung cancer for people that have failed front-line therapy. But we didn’t have a phase III study, this was some sort of conditional approval, everybody was waiting for the phase III. The phase III study was the DeLLphi-304, that was presented by Dr Rudin in ASCO.  So basically remember that tarlatamab is a bispecific T-cell engager and the other arm of the antibody, the target, is DLL3. DLL3 we are researching for a while now in lung cancer and we were unable to get a drug approved, there were other drugs before tarlatamab but they were not bispecific antibodies so this is a successful story.

Basically patients that have failed first-line therapy with platinum-based therapy and now standard of care is anti-PD-L1, they were randomised for chemotherapy versus tarlatamab. Remember chemotherapy for 20 years is the second-line standard of care. We use a lot of topotecan, some people don’t like it, the toxicity, and prefer to use irinotecan off-label, now we have lurbinectedin, have now for the last two years, and in Asia they have amrubicin, these are the options. But second line and third line for small cell is very short outcomes but not very good outcomes.

So in this study, DeLLphi, patients were randomised for tarlatamab versus chemotherapy, as I said, in second line and basically the study met its primary endpoint. The overall survival increased 5 months, the median overall survival increased 5 months from 8.3, that is usually what we get, and that was actually even better than what we get with standard chemo, to 13.6. So the hazard ratio was 0.6, that is a 40% improvement in survival. 40% improvement in survival and, again, making it easy for the audience, in one year we have only 37% of people alive with chemotherapy, when we use tarlatamab it was 53%. So there is a tremendous 16% improvement in survival numbers if we are using tarlatamab compared with standard chemotherapy.

That’s why now tarlatamab is moving to second line. We knew that from last year but remember last year we only had data from a phase II study and not everybody agreed to put tarlatamab second line, they preferred to give it third line because tarlatamab, remember, the first two infusions of tarlatamab need to be done in the hospital because there is a chance of ICANS and there is a chance of CRS, cytokine release syndrome. So that’s why the first two infusions we do in the hospital; by the time that patients are getting infusion number three we bring our patients to the cancer centre because they don’t get really this ICANS or this cytokine release syndrome, it’s the first two infusions. So that’s why a lot of people last year were not happy using tarlatamab yet but now that you see this tremendous benefit in survival I think that there should be no doubt that we should be using tarlatamab as a second line.

The logistics, again, are challenging – there are publications already on how to use tarlatamab outpatients but in general most of us prefer to infuse the first two infusions in inpatient and then we move to the outpatient setting.

Finally, the last abstract that we want to discuss today is the NeoADAURA. The NeoADAURA is very interesting because it’s osimertinib with chemotherapy for EGFR patients before surgery. Everybody is familiar with the use of osimertinib after surgery with ADAURA, but this NeoADAURA was expected because, as I mentioned in the first part of the presentation, immunotherapy now is standard of care as a neoadjuvant, if you’re going to use immunotherapy, with chemotherapy standard of care. Everybody had a high expectation of how well the TKIs – can we use the TKIs up front? That’s why this NeoADAURA was very important, it was presented by Dr Jamie Chaft from Sloan Kettering. Basically this was a three-arm study, they gave osimertinib alone neoadjuvant, everything neoadjuvant, they gave osimertinib with chemotherapy or they gave chemotherapy alone, the three arms. Basically what she presented, if you remember, is the major pathologic response is very high – it’s 26% osimertinib plus chemotherapy, 25% osimertinib alone and 2% chemotherapy.

The reason why in lung cancer chemotherapy is not standard of care alone as neoadjuvant is because exactly this – complete pathological responses or major pathological responses are very low so that is why we don’t use it. We’ve just started to use now chemotherapy [??]. So chemotherapy alone is not standard of care neoadjuvant, it’s chemoimmunotherapy and maybe with this data that we just had with NeoADAURA you can debate that maybe we don’t need the chemotherapy because the osimertinib alone causes the same major pathological response.

We don’t have the event free survival data because it needs to mature; the curves are separating, that’s what she’s showing in ASCO, but the data needs to be mature. Of course the overall survival also needs to mature so we’ll be seeing that in another meeting. It’s obvious that if we use chemotherapy with osimertinib there are more adverse events than if we use osimertinib alone but we are used to because everybody has been using FLAURA2 for metastatic disease so we know if we mix osimertinib with chemotherapy there are adverse events but they are very manageable too.

So that’s a very interesting presentation, maybe we are very close to moving TKIs, at least osimertinib, to the front line, at least for stage 2 or 3 non-small cell lung cancer.

Anyway, this is all the time now that we have. Thank you very much for your attention, thanks to ecancer for this invitation, it will be until the next time.