SP: Dear colleagues, it’s my great pleasure to welcome you to this ecancer virtual discussion which will cover the latest news in lung cancer based on the new presentations and abstracts of the virtual ESMO 2020 meeting. I will chair this virtual discussion, my name is Solange Peters, I’m a medical oncologist working in Lausanne in Switzerland. My faculty, who will be the most important people there, are from everywhere in Europe but with a little accent on Italy. We have Federico Cappuzzo from Rome, we have Antonio Passaro from Milan and we have Sanjay Popat from London who will all bring their insight and their thoughts about how much the data presented at ESMO might impact our daily practice today and probably tomorrow. So, of course, it’s a selection of the abstracts we find the most relevant and the idea is to give you some take-home messages, some key messages, about innovation in lung cancer. So I will immediately dive, for the sake of time, into this most important abstract and, of course, we always start with what is Presidential, so what is the most practice-changing data. The LBA2 was offering a new opportunity in a niche disease entity which is the ALK positive non-small cell lung cancer where we could see the data, very positive data, of the phase III CROWN study comparing lorlatinib versus crizotinib. Very nice data but it is not the first time we have innovation in the ALK positive field and the question is to know how much we find this data innovative in changing the paradigm in our field. So maybe to start with ALK, Federico, you have been working a lot on targeted therapy, what do you think about the CROWN data and does it change the way you perceive the treatment of ALK positive non-small cell lung cancer in front line?

FC: The CROWN data is an important trial comparing crizotinib versus lorlatinib that is a new generation ALK inhibitor. The data from this trial are clearly positive, there is a significant improvement in progression free survival for patients receiving lorlatinib versus crizotinib. Importantly there is a significant advantage for patients with brain metastasis, so the control in the brain is one of the most important points of this trial. I think this is a clearly relevant trial proposing lorlatinib as an additional first line option in patients with ALK positive non-small cell lung cancer. This is not the first time that we have an agent showing superiority versus crizotinib because all the new generation ALK inhibitors are showing this effect. So I think that this is not the new standard of care but this is just a new option that we have in addition to the other agents that already we have available in the ALK positive metastatic setting. I think that one of the most important points for deciding the best first line therapy is represented by the adverse events. In general the presence of adverse events related to the treatment is of particular relevance. In the specific trial with lorlatinib the side effects were more frequently observed in patients treated with lorlatinib so this is something that of course we need to consider when we choose the therapy, the first line therapy, in ALK positive.

SP: Sanjay, just to complete that, we have been seeing wonderful data on lorlatinib as a subsequent line of treatment. It has been shown that even irrespective of the mechanism of resistance lorlatinib gives rise to a very nice response rate between 30-50% in patients who relapse under, for example, alectinib or under brigatinib. So my question to you is are we favouring, once again, the best drug first which, at some point, might be lorlatinib or when it is about new generation TKIs we are happy to sequence because all of these drugs, by the way, go to the brain and are very potent? What is your feeling? It’s risk-benefit – do you think we will sequence brigatinib or alectinib followed by lorlatinib in the future or do you think we have to pick the best drugs, the strongest drug, first irrespective of toxicities?

SA: (Sanjay Popat) I think this the fundamental question that we have now in ALK that has been posed by CROWN and I don’t think we know the answer to that question. Undoubtedly CROWN has presented the best hazard ratio for progression free survival in any of the trials against crizotinib but you have to balance that against the unusual toxicity profile that you get with lorlatinib. You also then have to recognise that whilst the other drugs which are routinely used, such as alectinib and brigatinib in the front line setting, whilst they’re highly effective many patients still progress with intracranial disease. In that setting lorlatinib is a very, very effective drug to use as salvage. So the key question, as you’ve pointed out, is do you use it as a salvage option or do you use it up front? I have to say, I think with this data cut, for me it’s just a bit too immature to rush straight into using lorlatinib as my first line preferred drug because I’m not convinced yet of the efficacy-safety ratio for a long period of time. Lorlatinib is a highly effective drug, undoubtedly. It’s given once a day which is very nice for patients in terms of preference. We saw some very good quality of life improvement data against crizotinib which is good, but we have to be careful because it has a number of interactions with medications; we have to be aware of concomitant medications. And it has a very unusual neurocognitive toxicity profile which I’m not convinced CTCAE can capture adequately well enough. This, for a long period of time, has the potential of being problematic. So, for me, I have to say my bias is to use another next generation inhibitor up front and reserve lorlatinib for the salvage situation but I think this is an area of debate and I really very much look forward to what other colleagues have to say about this as well.

SP: Thanks a lot. The second abstract which was a very important one, it was already presented twice in international conferences and twice in the plenary sessions, is the role of adjuvant TKI in oncogene addiction. Here we have the ADAURA trial, which has been now published simultaneously to the ESMO meeting, which was completing the dataset presented at ASCO by having some updates in number which still remain amazing in terms of response rate, preventing the relapse of the disease with a hazard ratio of 0.17 but also showing how much this impact affects the systemic disease but also the brain with impressive hazard ratio at the brain level. Adding here a consideration about the burden of brain disease – quality of life, costs related to brain treatment. So, suddenly completing the clinical picture. So, Antonio, what is your take-home message out of ADAURA and if we were living in an ideal world would you prescribe osimertinib in the adjuvant setting to all stage 1b to 3a operating in surgical non-small cell lung cancer? Would you do that? Would you skip chemo? Would you keep chemo? What is your ideal world? We know it will take time but if you could choose what would you do?

AP: Of course the ADAURA trial was, I think, the track trial for the lung cancer community this year with a very, very high weighting for all of us. The trial was a very robust one with more than 1600 patients enrolled. So we have some limitations in the trial. Of course the role of brain evaluation before being enrolled with the brain MRI on CT scan but the important topic is not only the survival but also the quality of life for our patients. The data presented during the ESMO are based only in a small part of patients that show disease free events, I think in about 11% for osimertinib and then about 45% for the control arm. But this is very interesting because we can see that patients that develop that progressive disease, most of them in the control arm, have local regional disease but also brain metastasis. We know that the development of brain metastasis is a very important topic for the long-term survival, long-term quality of life. So, of course, the use of up front treatment with osimertinib in the first line setting is very, very heartening for these patients. But I’m a great believer in the use of the TKIs in the adjuvant setting to improve not only the survival that at the present time is difficult to balance compared to the up-front in first line but also for reducing the rate of patients with a progressive disease and eventually death in the years after the surgery. The role of chemotherapy plus or not is interesting but I think this is not influenced by the data that are coming out from the ADAURA trial. So patients were not well balanced for adjuvant chemotherapy received or not. The important question that is highly debated from the MRI at the baseline setting of course is very, very important but this is not clinical practice worldwide to date. The indication in the ADAURA trial was that the patients can receive a CT scan or brain MRI or not in the absence of clinical symptoms that I think is clinical practice for all of us. So I’m a believer in TKIs but I think that a brain scan at the baseline after surgery before starting a treatment is of course recommended today.

SP: Thank you so much. Federico, of course the question of chemo/no chemo hasn’t been addressed in this trial and would deserve, if it is really a question, a dedicated trial in order to answer with accuracy. But maybe your feeling too about this wonderful magnitude of benefit by osimertinib and would you discuss with the patient first on osimertinib but also would you reopen the debate about chemo/no chemo? Honestly, are you read to embark into that in all patients with EGFR mutations? Are you testing these patients for EGFR mutation, by the way? Are you buying that, Federico?

FC: Of course the ADAURA trial cannot answer the question of whether we should use chemotherapy or not. But I know what happens in clinical practice so when patients come to my clinic they prefer not receiving chemotherapy. They ask for not receiving chemotherapy and I think this is what we need to consider. So today, based on the ADAURA trial, first we need to screen all patients for the presence of the EGFR mutation. Second, in patients with an EGFR mutation I think that giving osimertinib is the best option we can give after surgery. I think that unless there are some specific situations I prefer giving the drug without chemotherapy. This is what the patients want and we need to consider this option. Of course we need additional investigation because we know that probably chemotherapy plus an EGFR TKI could be superior to an EGFR TKI. These are the data emerging in the metastatic setting. But I think that we need a specific trial to address this question.

SP: Yeah, and probably to address also the very early stage, we need to address these dedicated remaining question marks in the future to refine our conviction but I think we’re convinced about a role for TKI there. Let’s move to the third Presidential and I will give it to Sanjay. It’s a topic which is quite complex about multimodality. It’s a very strongly awaited trial, it took some years to have the first evidence-based data about the role of giving adjuvant radiation in patients who have received standard of care surgery and chemo for stage 3a disease and to completely resect it, meaning no capsular invasion. Following the standard of care for the definition of complete resection of a stage 3a and 2 disease. This trial, the LungART, led by Cecile Le Pechoux who was very courageous there in continuing the effort with many collaborative groups, was basically, and despite some wording I found a little bit borderline in the conclusion, was basically showing that a benefit could not be proven. It could not be proven by adding radiation in addition to well-performed surgery, perfect surgery I would say, plus chemo in stage 3. So is it the end of the story, Sanjay? So if you have one good local modality performed optimally plus a systemic treatment it’s enough in locally advanced disease?

SA: I think that’s what the trial would suggest is that optimal surgery is the best local modality and doesn’t need additional consolidation with radiation. We have to be clear with what the trial showed is that there was a small DFS advantage, because that was the primary endpoint of the trial at three years, 15% DFS advantage, but not significant in the way the trial was performed. But with that advantage was the significant disadvantage of increased cardiopulmonary deaths. That is really of concern, actually. Really with that rather debatable benefit but with that strong evidence of harm, I’m really struggling to see a routine role for adjuvant radiotherapy in this setting. Of course, those nodes which have extracapsular spread, which we see from time to time, those patients were not included in the study. So there still remains a question for the high risk group – do they need adjuvant radiation or not? Of course the R1, R2s are still a clean indication. But routinely I think that trial has really put that indication to rest.

SP: Yes. In Switzerland, in France, in Germany, we are complete fans of surgery; we have these very aggressive surgeons. You’re from the UK, and Cecile Le Pechoux in the discussion of the abstract was stressing the fact that basically this data shouldn’t make us forget that surgery might not be the best option in this stage 3a and 2 disease. So what is your standard practice in the UK? Do you have a limit? Do you have a definition of who should receive definitive radiochemotherapy versus chemo plus surgery in this stage 3a specifically?

SA: This is a very open question in the UK and, of course, N2 disease is a heterogeneous group of diseases and there is wide variation in practice. In general, definitive concomitant chemoradiotherapy is the preferred option in the UK for N2 positive stage 3a lung cancer, other than exceptional cases where you might consider it in fit patients with single station disease. However, we’re moving to the era of immuno-oncology and in this new era where we’re considering neoadjuvant treatments we have to reconsider all our stage 3 paradigms.

SP: Thanks for that. Antonio, let’s move to the next abstract. The next abstract is trying to identify… I found it first of all confirmatory but a little frustrating. We’ve switched to immunotherapy, we’ve switched to immunotherapy in small cell, extensive stage small cell lung cancer, where in the context of the trial adding atezolizumab to platinum-based chemo, the IMpower133, the authors have tried to identify characteristics which would allow us to identify long-term survivors, LTS, trying to help us and guiding treatment and maybe even sparing money, time and effort. What I find so frustrating is they couldn’t really identify a subgroup not benefitting or a subgroup benefitting from the addition of atezolizumab. At the end I would say what is important is that the magnitude of benefit is not the one which was observed in other diseases with immunotherapy. So what is your uptake of this one, of course also of the CASPIAN trial, all of these two trials adding… or even the KEYNOTE-604, adding an anti-PD-L1 in small cell? Is it worth the effort and are we going to be able to identify who should be treated like that? What is your standard and what is your feeling about extensive stages in immunotherapy, Antonio?

AP: Of course to date our standard is chemo plus immunotherapy in small cell lung cancer but these data are very, very interesting, confirming that we need biomarkers in small cell lung cancer and our need is very, very high. These data confirm that the combination is active with regards to the biomarker, the PD-L1 or the [??] tumour mutational burden and also regarding of the clinical characteristics of our patients. But we know that we can find patients that have a long-term performance with a combination compared to other kinds of patients that have a standard performance like with chemotherapy alone. So in this kind of patient population as we saw in the similar trial, the ETOP, we understand that the small cell lung cancer is a very, very difficult disease with a very intriguing microenvironment and we need to improve our understanding of the biomarkers. To date, of course, our standard should be the chemo plus immunotherapy in the first line setting for the small cell lung cancer because the improvement in the median overall survival by three months is a great achievement if we look back in the last 15-20 years. But if we compare these results, this achievement with the survival of patients with non-small cell lung cancer, we know that this is only the first step in the improvement of survival in the immunotherapy era and small cell lung cancer.

SP: Thanks a lot. Let’s continue on immunotherapy, Federico, we had the opportunity to discuss it yesterday, the EMPOWER-Lung 1. Let’s be very transparent and straightforward, this is an encore trial. EMPOWER-Lung 1 is looking at cemiplimab, an anti-PD1, versus platinum-based chemotherapy in patients with high PD-L1 as defined by TPS by the expression of PD-L1 on tumour cells of more than 50%. So this data is an encore and shows encore  and still the very, very strong superiority of immunotherapy versus chemo in that context. We said during the ESMO meeting we also were able to see the long-term benefit in KEYNOTE-24 of pembrolizumab in the same patient group, very impressive. So I’d like, Federico, that you tell me your specific feeling about this EMPOWER-Lung 1 which had some specificities, first of all, to allow to continue the immunotherapy adding chemo in the arm of IO for the patients who wanted, allowing for a crossover which was quite high, but also was performed in countries where probably specifically accessibility to IO was limited. So very specific features with a wonderful hazard ratio. So did we learn something, Federico? Is it better than the other checkpoints? Is there something new or is it just an encore trial?

FC: Difficult to say if this agent is better than other agents we already have in our practices, specifically pembrolizumab. Certainly these data are in the same range of other trials such as atezolizumab or pembrolizumab with a very good hazard ratio in terms of reduction of the risk. Of course there are some factors reinforcing the hypothesis that this agent is of interest, particularly the very high rate of crossover and the fact that also was allowed the combination of immunotherapy and chemotherapy in second line on patients progressing. So I think that these factors reinforce the hypothesis that this agent could have more activity even than other agents, even if, of course, we don’t have any direct comparison. But anyway, I think that based on the data we have this is an additional agent we could potentially have in the first line setting in non-small cell lung cancer and reinforce the concept that immunotherapy is the new standard of care in non-small cell lung cancer. But I don’t think that we need this data for learning that immunotherapy is the standard of care.

SP: The next topic, Sanjay, for me would be to continue in the same slot of patients with high PD-L1 expression, more than 50% on the tumour cell, trying to envisage a cross-talk which is well known between antiangiogenic and immunotherapy. Basically even antiangiogenic and targeting VEGF is sometimes considered as being an immunotherapy per se. Our colleagues from Asia, from Japan, decided to focus on this 25% of patients with high PD-L1 and to combine atezolizumab and bevacizumab. Of course it’s just an attempt, it’s descriptive by nature, but I found the results exciting, even interesting in this Japanese phase II study. So what is your feeling about making more than monotherapy front line in these patients and adding bevacizumab, Sanjay?

SA: Yes, I was really excited to see this data Dr Seto presented and this is the @Be trial, a small phase II, I think there were about 38 patients odd treated with a combination of atezolizumab and bevacizumab. The primary endpoint was the response rate and the response rate was really quite high, about 60%-odd, which is much higher than we’ve seen for that comparative population with atezolizumab monotherapy in IMpower110. So potentially a signal for increased efficacy with the addition of bevacizumab and that interplay between VEGF and IO; we know these are complementary strategies from the immunotherapy viewpoint. But we have to be careful because in that trial we had 15% grade 3 or more hypertension, no grade 4 events but this is a significant amount of hypertension. Indeed, this is a signal that seems to be coming through. There was the other study which we will come on to talk about with bevacizumab and nivolumab in conjunction with chemotherapy which also had hypertension as a significant feature. So very exciting, I think this is a combination definitely worthy of further evaluation in different thoracic tumour types. As you know, Solange, we’re evaluating this in the BEAT-meso trial which therefore had a great passion to my heart, this combination. But we should also be aware of the adverse event profile as well.

SP: Yes, you evoked it, Antonio, this kind of important trial, randomised trial, phase III, of nivolumab in combination with carboplatin, paclitaxel and bevacizumab as first line treatment with advanced non-squamous, of course, non-small cell lung cancer. It was a Japanese trial, it was the LBA54, which was showing quite nicely a benefit of PFS. Of course, I think if I remember well, still no OS data, it was still immature which is a little disturbing for us. But already a trend in favour of the nivolumab arm there but needing more follow-up. So what is your feeling now? We had, of course, the IMpower150 as the background for combining VEGF inhibition with atezolizumab and chemo and now we have nivolumab, so what’s your feeling about having four drugs on board to start? And what’s your feeling about toxicity? Will it be feasible practically, financially and are we really seeing a benefit of piling the drugs, Antonio?

AP: Yes, we have both feelings. The first feeling is if we evaluate only the efficacy data and the second feeling is if we push up the efficacy data, the financial toxicity and the toxicity related to the combination. So we have a lot of data there to confirm that the combination of bevacizumab plus immunotherapy and chemotherapy has a good performance in patients in the metastatic setting. But the data presented by our colleagues, Japan colleagues, are very strong if we evaluate the toxicity profile. So in the first line setting which we have a good performance for chemo plus immunotherapy or immunotherapy alone, looking to this combination for a higher rate of toxicity is not the best way for our patients looking at the long-term quality of life. So the trial, of course, is positive but I don’t see a window for this kind of combination in our clinical practice.

SP: Thanks a lot, I think it will also raise some questions of feasibility and sustainability, having these combinations coming later on. We will have to do there some inter-trial comparison. Last but not least, I will not ask Sanjay because he was involved there too, the STIMULI trial. It’s a large phase II, it could have been called a phase III at the end because the endpoint was changed. It’s the idea of giving an immunotherapy in limited stage small cell lung cancer. We know, remember, that in extensive stage we failed the second line nivolumab versus chemo, we failed the maintenance with ipilimumab nivolumab or nivolumab after chemo in the front line setting but always seeing this shape of the curve which is telling us that, of course, the endpoint was not met so new standard. But some patients benefit from immunotherapy. Some of them, a small percentage, benefit in terms of extracting a long-term benefit, the tail of the curve, but we fail to know who they are and we fail, therefore, to apply the strategy to the right patients. STIMULI, a PFS reshaped endpoint for a trial randomising ipilimumab nivolumab versus nothing in consolidation after the full standard of care of radiochemotherapy, PCI completed, in limited stage small cell lung cancer. This trial again failed to meet the PFS, failed to meet the OS, which was a secondary endpoint, but did show that we have this feeling that some patients will benefit. So how to move, Federico? Do we need better IO? Do we need to start to develop IO without chemo differently in small cell lung cancer? Have we done everything we can there? What’s your feeling about STIMULI in limited stage? The opportunity of continuing – there are two big trials ongoing at least in that slot – and how to continue with IO in small cell?

FC: Unfortunately the trial was negative because, of course, we would like to see positive data in small cell lung cancer. The point is that the current therapies, current immunotherapies, are marginally effective in small cell lung cancer. Even in metastatic the benefit was statistically significant but was marginal, meaning that we need new drugs in this disease. I think that immunotherapy could have a place in small cell lung cancer but not these agents. The benefit with these agents is clearly marginal and this is also the reason why we have such difficulty in detecting the sensitive, the few really sensitive, patients.

SP: Sanjay, you have the final word because we unfortunately reached the end of our time, but the final word about small cell. Can you give us a feeling about your subjective assessment of what do you believe in? We know now, for example, that we have some phase III with some new compounds, TIGIT, for example. We also have this STIMULI type of trial where immunotherapy is introduced earlier in the course of the treatment. So what do you believe might really allow for a statistically significant and clinically meaningful difference in small cell? Where would you develop or where would you put your belief and your energy in trying to further develop IO in small cell?

SA: We shouldn’t give up, that is clear. We have a survival advantage in the metastatic setting and what we have seen is that in the refractory metastatic setting there’s no survival benefit. So, to me, the earlier you can treat this disease perhaps the greater the benefit you are going to see from checkpoint inhibitors. That’s a theory and I hope that the trials will prove this. What is clear is that we just don’t know from an individual patient clinical data level or a biological data level who benefits from these drugs. So for the time being we have to recruit everybody. We have to recruit everybody and it has been large enough trials so we can then tease out the other clinical and biological factors thereafter to then work out who needs it and who doesn’t need it. But, for me, this is still game on for checkpoint inhibitors and novel IO combinations in small cell, particularly in limited stage. I guess when these trials that are ongoing and recruiting read out that will really help determine the nature of the next 5-10 years in that space.

SP: Thanks a lot. So ultimately we will have to skip a lot of other interesting abstracts for the sake of time. But it was a pleasure to discuss with you; I think we have very important key take-home messages already. I’d like to thank you all for your participation and all of you for listening to this conversation. Have a good day.