Listen to Dr John Heymach and Dr Solange Peters discuss key data presented at the 2025 World Conference on Lung Cancer regarding frontline maintenance for extensive-stage small-cell lung cancer and targeted treatments for non-small-cell lung cancer and how they may change the treatment paradigm.
In this episode, Dr John Heymach and Dr Solange Peters discuss key data presented at the IASLC World Conference on Lung Cancer including first-line maintenance in ES-SCLC (IMforte and DeLLphi-303 trials) and targeted treatment for NSCLC (FLAURA2, Beamion LUNG-1, and ARROS-1 trials).
Presenters:
John Heymach, MD, PhD
Chair and Professor
Department of Thoracic/Head and Neck Medical Oncology
Ruth Legett Jones Distinguished Chair
MD Anderson Cancer Center
Houston, Texas
Solange Peters, MD, PhD
Professor and Director of Medical Oncology
Department of Oncology
University Hospital of Lausanne
Lausanne, Switzerland
Content based on an online CME program supported by independent educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Jazz Pharmaceuticals, Inc.
Link to full program:
https://bit.ly/3L1eksI
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Expert Highlights From the 2025 World Conference on Lung Cancer
Amber Williams: Hello and welcome to the Decera Clinical Education Oncology Podcast. I’m your host, Amber Williams. Today’s episode features Dr. John Heymach, from the MD Anderson Cancer Center in Houston, Texas, and Dr. Solange Peters, from the University Hospital of Lausanne in Switzerland. They will discuss key data presented at the 2025 World Conference on Lung Cancer regarding frontline maintenance for extensive-stage small cell lung cancer and targeted treatments for non-small cell lung cancer and how they may change the treatment paradigm.
This episode is part of a larger educational program titled, “CCO Independent Highlights of the 2025 World Conference on Lung Cancer.” For more information on Dr. Heymach and Dr. Peters, along with a link to the larger education program, please visit the show notes for this episode.
Now let’s get started and hear what the experts have to say.
Dr. John Heymach: Hi. I am John Heymach, Chairman of Thoracic and Head and Neck Medical Oncology at MD Anderson Cancer Center in Houston.
Dr. Solange Peters: My name is Solange Peters, and I am the director of the Department of Oncology in Lausanne, in Switzerland. And I am focusing my research and my clinical opportunities in thoracic malignancies research. And it is my pleasure today to discuss with you some of the data.
Dr. Peters: presented at the World Lung Conference this year, trying to understand together how it may change the landscape and our practice on a daily basis.
Treatment Landscape in ES-SCLC
Dr. Heymach: We have seen a lot of changes in the landscape for extensive-stage small cell lung cancer, so maybe I can put them all into context.
Small cell lung cancer usually presents as extensive-stage disease or metastatic. For over 30 years, the standard of care was etoposide and platinum that was established back in the mid-80s. So really progress was very slow.
The first advance we had in decades was the addition of PD-L1 blockade. There we had the IMpower133 study, as well as the CASPIAN study, that is with platinum and etoposide with either atezolizumab in the IMpower133 study or durvalumab in the CASPIAN study.
The results were really pretty comparable between the two. There was an improvement of a couple months in overall survival. That was a clear advance. The range of numbers was from roughly 10 months to 12 months and change as a ballpark. There we see a hazard ratio for survival in the 0.7s overall. So clearly a significant advance, but something that was on the order of months for most people and not years of addition. This was really the first standard of care difference in decades, literally.
Right now we are starting to see additions built on top of this base regimen, if you will, of chemotherapy with PD-L1 blockade.
Dr. Peters: I have been running many, many trials trying to implement something more than the usual platinum etoposide. Now, with the checkpoints, durvalumab, atezolizumab, trying, for example, to add some different maintenance, immunotherapy maintenance, but all of the trials at the time being failed. What is quite interesting now is that we start to see data changing the paradigm, not only of second and later lines, but the paradigm of the maintenance after four to six cycles of platinum etoposide and a checkpoint. And one of the important, I would say, new data set really changing the practice today is the IMforte trial.
IMforte
Dr. Heymach: Solange, you were involved in this IMforte randomized phase III study. What are your thoughts about it?
Dr. Peters: IMforte is placing at the end of four cycles of platinum etoposide and atezolizumab, lurbinectedin in addition to the maintenance atezolizumab. In that trial, of course, it was compared to atezolizumab monotherapy, trying to show if the PFS and the overall survival could be improved.
This is a challenging trial because it is chemo after chemo. And we all know that there is some hematological toxicity at the end of platinum etoposide, thrombocytopenia, anemia, sometimes leukopenia, sometimes requiring GCSF. So we knew it would not be easy, but we also knew how fast the patient progressed, very often some weeks only after the end of chemotherapy in that specific aggressive disease.
So the trial met the end point of improving progression-free survival, but also overall survival. And in a very meaningful and statistically significant, of course, manner, we have had a ratio of 0.54 for PFS and 0.73 for survival, which I can tell you in small-cell lung cancer is absolutely amazing.
Dr. Heymach: And I’ll note there had been regimens that had been tested in this maintenance setting previously, but this was really the first one that showed a striking benefit.
Dr. Peters: At the World Lung Conference, we did revisit all together how we can manage the toxicity. We know that sometimes we need GCSF, and some centers decided to give GCSF upfront for all patients not to have trouble because in the first three months of treatment, you can observe thrombocytopenia, neutropenia, and febrile neutropenia, but in a very small number of patients, the febrile neutropenia.
So we have to keep in mind that this chemotherapy has a usual paradigm of chemotherapy toxicity, but mainly concentrated in the first three months of treatment, way less observed later on.
The overall rate of adverse events leading to study treatment discontinuation was, at the end, relatively and surprisingly low in both arms, meaning that by managing these hematotoxicities we know well, as well as some now the GI toxicity, we are able to continue the treatment and get the benefit in terms of survival and progression-free survival. So although, a higher incidence of adverse events by adding lurbinectedin, this is manageable, mainly observed in the first three months, mainly hematotoxicity and not leading to discontinuation.
So I think, like any new strategy, we need to get acquainted to this additional toxicity. We need to inform the patient for no surprise to happen, and sometimes to consider some local management, depending also on the patient, for example, giving GCSF if you feel like it is useful after one cycle or at baseline of lurbinectedin. But I think it is a very reassuring abstract telling that with the art of oncology, this is manageable.
Dr. Heymach: On that basis, the IMforte regimen has now been approved in the US, and I think justifiably so. This is, from my perspective, the first real advance building on top of the IMpower133 and CASPIAN studies we have seen now in several years.
DeLLphi-303
Dr. Heymach: The second big advance. Now, this is one that has not yet been formally approved, but it really shows us that T-cell engagers, like tarlatamab can be a game-changer. This is the DeLLphi-303 study.
Here in the DeLLphi-303, this is not a randomized study versus standard of care, but this is taking tarlatamab and adding it as maintenance therapy. So the same setting as we saw for the IMforte study. This is for people who have had four to six cycles of chemoimmunotherapy and not had disease progression.
Then they received either tarlatamab and atezolizumab or tarlatamab with durvalumab. In other words, building on top of either the IMpower133 or the CASPIAN regimen, which, those two regimens tend to yield very similar results. This is not compared to standard of care of chemotherapy with immunotherapy alone.
Really the results were pretty striking. The number that really got my attention, most other people's attention was the median overall survival from this study. The median overall survival in the atezolizumab arm was 25 months. In the durvalumab arm, it is not yet evaluable, but we can see it is going to be a long number, presumably in excess of two years. The overall survival for the entire group, when you combine the two arms is 25.3 months.
Now, I will tell you that I was in the room as this was presented for the first time. There was really a gasp in the air. That is because for years, those of us who have been studying small cells, actually decades, we really have been stuck in that 10-month range, getting up to 12, perhaps with immunotherapy now getting up past 13, when we saw the IMforte results. This is a game-changer in that respect because now we are seeing in excess of two years.
Extensive-stage small cell is something where you do not tend to see a lot of outliers like this. Unlike in non-small cell, where you might have a favorable group that have a lot of driver mutations or something, we do not tend to see any particular group of extensive-stage small cell that is particularly favorable outcomes. Now you have got pretty good size study showing a survival in excess of two years. That is from the time of maintenance therapy. That is not from the time beginning.
Even though, right now tarlatamab is approved in the second-line setting in the US, when we look at the strength of these results, it is hard for me to imagine that this would not become part of the first-line regimen at some point in the near future.
So, excited to see the results with lurbinectedin. I think a very solid step forward, that should become a standard regimen in the United States and is now FDA approved. But I think with tarlatamab, we are seeing something that may be more of a game-changer, assuming the results hold up when we get to randomized studies. There is no reason I can think of that they would not hold up. I did not see any factor with patient selection or anything that would make me think this was an atypical group.
Targeted Agents for NSCLC
Amber Williams: Dr. Peters, can you tell us about recent advances in non-small cell lung cancer?
Dr. Peters: Today, we have been developing this pie of non-small-cell lung cancer and speaking and focusing first on advanced disease, making us understand that in Caucasian patients in our environment, probably a third, up to half of the patients, might benefit to something else than the classical chemoimmunotherapy. And this subdivides 30-50% of the patients into very small subgroups, where at the end, we start to develop precision oncology and targeted therapy in almost all of the circumstances.
We had some missing players, or not really satisfactory treatment options. Remember KRAS, which was called for a long time undruggable and HER2, which was not druggable by nature of the mutation and by nature of the compounds we had. And today, we have an abundance of HER2, I would say targeted therapies, and even more on KRAS off, right, blockers that come and meet the paradigm of best treatment first, meaning that they escalate the lines of treatment to go frontline.
So I think all of these now low-hanging fruits, this oncogene that our NGS small panels identify and identify better, remember, if you have an RNA component for the rearrangement, all of these mutations now have targeted therapies, which should be given frontline. We are even revisiting this targeted therapy in the adjuvant setting, like it was done for ALK and for EGFR. So I think really changing and dividing the world of non-small-cell lung cancer into this oncogene addiction with actionable genomic alterations and the non-oncogene addicted, which again, has also seen lots of advances with the confirmation of the efficacy of immunotherapy, dual or mono checkpoint inhibition.
So I think we have been, and it is nicely seen, by the way, in a recent review from the French environment, we have been seeing massive improvement in survival of these patients. If you look at the whole population of a country, decade by decade, during the last 30 years. And this really proves and showcases how much we have advanced in all circumstances of non-small-cell lung cancer.
FLAURA2
Dr. Peters: There is another abstract just presented at the World Lung, which is absolutely, I would say, changing the landscape, even if we suspected it would happen. This is the FLAURA2 overall survival abstract. Remember that in the field, and we are here, non-small-cell lung cancer in patients suffering from classically mutated EGFR, non-small-cell lung cancer, exon 19 deletion, exon 21, L858R. These patients usually receive osimertinib frontline. This had been compared to first-generation TKI. Osimertinib is a standard of care, better PFS, better overall survival.
But since some six months or a year, we challenge this by trying to escalate this osimertinib or by adding chemotherapy on the top, which is FLAURA2, chemo-osimertinib, or by switching to lazertinib-amivantamab. It is interesting, it is a real competition between the two escalation processes. But the elephant in the room is why and for which patient you need to escalate.
So basically, this is a very important and awaited data set because we knew already from previous presentations that the amivantamab-lazertinib was improving survival, but with the median not being reached and just projected, but with a significant hazard ratio at the final analysis for survival. Here we, for the first time, see the survival data of osimertinib-chemo versus osimertinib in this more than 500 patient population randomized.
In that trial, remember that the PFS was showing a hazard ratio of 0.62 in favor of the combination. And in the presentation of the World Lung, we could see a quite amazing hazard ratio for survival of 0.77 being statistically significant and making a difference, which we should not neglect in our field of research of 10 months. So 10 months gain in terms of survival by adding the chemo.
So here the main question comes to me. Later on at the ESMO meeting, for example, we could see that this hazard ratio is found across all subgroups you can imagine: type of mutation, brain mets, p53, ctDNA measurement by baseline. The same magnitude of benefit as translated by hazard ratio is seen across subgroups.
So the main question is, are they very good prognosis patients for whom you cannot escalate? I am still not convinced myself, because it will be the first time in my career that we decide to ignore a benefit in overall survival of 10 months. I mean, for most of the things we have been doing, we would have found it absolutely amazing. So I think we need at least to discuss this FLAURA2 escalation in all patients.
And of course, like usual, some patients will reject the chemotherapy, and that will be fine, and we give the osimertinib. But I think this educated discussion has to happen with every patient. And last but not least, I think that chemotherapy and osimertinib is still better tolerated than the amivantamab toxicities, which is a class effect of EGFR with the rash, paronychia and GI toxicity, which probably makes this combination slightly easier to use.
So, I think this overall survival data confirms that probably we have defined a new standard of care, which might not please all patients, but which might and has to be proposed to all patients.
Beamion LUNG-1
Dr. Peters: There are also two abstracts, which go into the niche of oncogene-addicted, very small subgroups of patients. First one, let us go and look at the HER2-mutant. So Beamion LUNG-1 John, you were involved and treating patients. So, what are your thoughts about the benefit you can expect from such a strategy?
Dr. Heymach: Well, we have had a lot of new exciting findings in the HER2- mutant non-small cell lung cancer space. I can briefly review those, having to do with zongertinib.
Just to remind everybody, HER2-activating mutations are roughly 2% to 3% of non-small cell lung cancer cases. These are not amplification or overexpression. HER2 overexpression is something that can potentially be treated with trastuzumab deruxtecan. These are activating mutations.
The vast majority of these are exon 20 insertions. In fact, 70% of them tend to be one particular HER2 exon 20 insertion. It is what we call the YVMA insertion that happens at the 772 location. Anyway, that is the population we are talking about for HER2-mutant non-small cell lung cancer.
Earlier drugs that were tested in this space - and we had done a lot of work with poziotinib, for example - had the challenge that while they may inhibit HER2 mutations or tumors with HER2 mutations, they had a lot of EGFR-related side effects, rash, diarrhea and so forth.
Dr. Peters: we tried, I mean, many trials also to put a TKI in the setting, with a very low level of rate of response and kind of huge toxicities. And there is a whole list of drugs, which I would say, did not pass the bar of significance.
Dr. Heymach: Zongertinib is really the first drug we have got in the clinic that is able to inhibit HER2-mutant tumors, but is wild-type EGFR sparing. It avoids the toxicities that go along with inhibiting wild-type EGFR. This, in August of this year, received FDA approval for previously treated patients. That was based on an objective response rate of 71%, median progression-free survival of 12.4 months.
What was not described in detail in that initial New England Journal manuscript was the activity in brain metastasis. At the World Lung meeting, Dr. Ruiter and our team presented the results of patients with brain metastasis. There were really two cohorts that were involved here. Cohort one was the cohort involving the FDA approval. Those were previously treated patients, but who had never had a HER2 inhibitor before, but they had received prior platinum immunotherapy. In particular, this was the presentation of the patients who had brain metastasis at baseline from cohort one.
Then the second group was cohort four. And cohort four consisted of patients who had brain metastasis that was measurable by RANO-BM criteria that we like to use for assessing brain metastasis.
To summarize a lot of this data, the overall pooled analysis, the objective response rate from 58 patients with brain metastasis was 41%. If you looked at the cohort that had not received prior brain radiotherapy, the objective response rate was 44%. Disease control rate was 83%.
At the end of the day here, this shows that zongertinib clearly has CNS activity. Now the response rate is moderate. Response rate of 41% is a little bit lower than the response rate systemically, but it is still clear evidence of CNS activity.
Dr. Peters: So really showing that this is a compound, which can be used like osimertinib for EGFR in patients with asymptomatic brain mets and probably allows us to push to a later time point the opportunity of giving radiation. At least that is what we prefer to do in asymptomatic patients. But there was a continuation of the story.
Dr. Heymach: At the ESMO meeting, Dr. Popat and rest of our team presented the first-line data for patients who were previously untreated with zongertinib. Here the activity was really outstanding. Objective response rate was 77%. The median PFS had not been reached at the time of that presentation, but appeared to be well in excess of the 12 months that had been seen in the second-line setting.
The safety and tolerability showed that it had a very manageable safety profile, as had been seen in the second-line setting with low rates of grade 3/4 AEs, low rates of significant diarrhea, and virtually no rash of significance seen there as well.
The bottom line from all that is zongertinib has substantial activity in the first-line setting for patients who have not been previously treated. It has got clear evidence of CNS activity with the response in the brain of 41% from the pooled analysis of the cohort four and cohort one patients.
ARROS-1
Dr. Peters: In the same sort and line of thinking and perspective, we had another niche, which is ROS1-positive non-small-cell lung cancer. Again, something like 2-3% of our non-small-cell lung cancer population, which now is targeted by many compounds, taletrectinib, repotrectinib, we have many ROS1 inhibitors. But probably recently, taletrectinib was showing the highest, I would say, efficacy and has a competitor. The competitor is zidesamtinib, NVL-665 is sometimes easier to pronounce, which was presented with a lot of data by Alex Drilon at the World Lung Conference.
To make a long story short, Alex was able to present three cohorts of patients. One cohort was these patients having received more than one prior ROS1 TKI from one to four, very often new-generation ROS1 TKI, meaning resistance mechanisms, which are difficult to address. A second cohort was only one prior ROS1 TKI, crizotinib or entrectinib, so not the most powerful one like taletrectinib, for example, and a third cohort, TKI-naive, so frontline, a bit like we discussed before.
All of these patients could have received chemotherapy, at least for the cohorts one and two I described, and this is not a problem. But basically, if you are naive from any treatment, the response rate to zidesamtinib is 89%. So the duration of response at 12 months is 96%. And again, to discuss precision oncology and new TKIs, the intracranial response rate, as centrally reviewed, was 83%. This is for naive patients.
So let us go to only one line of TKI, response rate 51%. At one year, the duration of response is 93%. And still, the intracranial response is 85%.
Let us go later on in the patients having received one, two, three or four prior lines of TKI, meaning some new generation, response rate is still 44%. 78% still in response at one year. And the intracranial response rate, again, matching the systemic response, is 48%.
So, conclusion, this is a very active drug in the resistance setting, whichever line of treatment you are in. But more importantly, and again, like discussed before, for the zongertinib, right, giving it frontline, develop the whole paradigm of the best efficacy. And remember, confirms the idea we always have of the best treatment first. So let us try to always position the best treatment frontline.
Amber Williams: Thank you, Dr. Heymach and Dr. Peters, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “CCO Independent Highlights of the 2025 World Conference on Lung Cancer,” please click the link in the show notes. And be sure to check back regularly for more episodes on important oncology topics!