Welcome to today's webinar, the ISLC 2020 World Conference on Lung Cancer in Singapore, Highlights. Hi, my name is Ross Su, and I will be your moderator and one of the presenters for today's program. Let's begin by running through the housekeeping notes. If you'd like to download today's slides, you can access them by clicking on the link to the webinar page in the chat. You will also be able to find a video recording of the webinar at that link within the next week. An email will also be sent after the webinar with instructions on how to claim your CME credit. Your camera and microphone will remain off for this webinar. Please enter any questions you have for the Q&A discussion into the Q&A section at the bottom of the Zoom webinar. You may use the chat function for other discussions. We will not be using the raise hand function for questions. We plan to have a panel discussion and a Q&A after the presentations. Please enter your questions into the Q&A section at any point during the talks. We have made the WCLC simultaneous publication by Ben Hurhan available to you, and you may access it by clicking on the link in the chat. Here are the speaker disclosures for today's presenters. I would now like to introduce our first speaker, Dr. Daniel Tan, from the National Cancer Centre Singapore, who will be presenting on day two of the World Lung Conference. Thank you. Thank you very much, Ross. So, a very warm welcome to this session on highlights from the recent WCLC. I'm Daniel Tan, and one of the co-chairs of this year's meeting, and over the next 15 minutes, I will bring you through some of the highlights on the second day of the meeting, followed by Professor Wu and then Ross Su subsequently. So, the overview of the abstracts that I chose to summarise are going to be broadly categorised as shown on the slide, and for the very first topic, really, we're going to talk about high precision biomarkers for checkpoint inhibitors. And during this meeting, we saw the first report of the four-year follow-up from Keynote 189, where the three-year landmark analysis showed 31.3% of patients alive in the intervention arm versus 17.4% in the control arm, and there was increase in activity in PD-L1, or increase in survival in those patients stratified for more than 50% of PD-L1. And we did also see additional data from trials where we've had further refinement of potential IO biomarkers, and it is…and here is the first trial that was presented in one of the oral abstract sessions, MPOWER1, which was presented by Dr Kilcap, and it was a randomised phase 3 trial of semiplimab, a PD-1 antibody that had been previously approved for cutaneous squamous cell carcinoma versus chemotherapy in the first-line setting, and initially presented in ESMO 2020. At WCLC, data for substratification of PD-L1 groups, 50% to 60%, 60% to 90%, and more than 90% was performed, and this showed here… Sorry, let me go back one slide. And this showed very high response rates in the middle and upper band, particularly also in the PFS being most striking in the more than 90% band with PFS of 12.7 months and with hazard ratio of 0.33. Of note, this trial was unique in that it also only did not enrol individuals who had never smoked in addition to the usual criteria of excluding patients with oncogenic drivers, including EGFR, ALK, and ROS1, and this data has now been published in The Lancet just this month. The next studies were additional biomarker analysis specifically with regards to TMB, and this was presented by Dr Hirsch from the two lung studies involving metastatic squamous cell carcinoma. And of note, these analyses were derived from a randomised phase 2 trial of Nivo IPI versus Nivo, and a single-agent development trial comprising of over 320 patients. Now, the investigators did look at TMB as measured by the Foundation 1 T5 panel, and in this particular analysis looked at TMB as a continuous variable at 10-unit differences and observed an association with improved PFS and overall survival with different thresholds set ranging from 5.5 to 21.8 as shown on the right panel. And when we look into some of the subgroups of PD-L1 in the S1400 study where we looked at the impact of TMB in the high PD-L1 expression subgroup, it did seem this was less prominent as compared to that in the lower tertiles of PD-L1. And again, caveat, of course, is that sample size remains fairly small, and in this particular study, half the patients were on nivolumab, the other half on IPI-Nivo. Touching on stage 3, where ongoing efforts have been directed at improving beyond that of the PACIFIC trial, we see here the first report of Keynote 799, which randomized 216 patients, or at least enrolled 216 patients with stage 3 non-small cell lung cancer to either one cycle of induction, paclitaxel, CARBO, and pembrolizumab for squamous and non-squamous, which was in cohort A, and pemotrexate, carboplatin, and pembrolizumab for non-squamous carcinoma in cohort B. Patients then went on to receive cycle 2 and 3 concurrently, and with radical radiotherapy, followed by the remaining 13 cycles of pembrolizumab alone to complete one year of immune checkpoint inhibitors. With a follow-up of at least 13.6 months, the duration of response was 82.2% and 72.1% at one-year mark, and overall response rate of 66% and 64.5%, even in the low PD-L1 subgroups. And with the limitations of cross-trial comparison, this compares pretty favorably to the 28% that we observed in PACIFIC. And similarly, when we looked at the 12-month PFS rate, this was 67% in cohort A and 65.2% in cohort B, which again compares favorably to the 12-month landmark of just over 55% in PACIFIC trial. Perhaps the adverse events were of the highest interest, and those particularly with the rates of pneumonitis, and this was similar in both of these arms of 8% and 7.9%, as shown in this table. The, and this was just slightly higher, this is higher than what was compared if we observed in PACIFIC, which was approximately 3.4% in the devalomat arm. Now, comparing the different chemotherapy backbones, cohort A was associated with higher prevalence of grade 3 to 5 adverse events, including four deaths, and there were higher incidence of immune-related adverse events as high as 52%, with high discontinuation rates as well. So, I think at this point, the follow-up is still limited, and we await long-term efficacy data, particularly the progression-free survival. There are ongoing clinical trials now that include PACIFIC-2 to evaluate the role of concurrent devalomat, as well as additional combinations with CTLA-4 antibodies, for example, in the CheckMate 73L. Next, talking about adaptive designs for administration of radical radiotherapy, and this RTOG-1106 study presented by Dr. Kong, 127 patients were randomized, twos to one, to either 60 gray to the whole volume, or select boost to lesions that remain PET-avid midway through treatment. And in this particular study, we did not observe difference in local regional control by central review, but there was an increase in grade 2 or more esophagitis. A related abstract in the same session examined the role of two different approaches for dose intensification, again associated with higher toxicities. Overall, with the emerging landscape of combinations with systemic therapies, the role of radiation dose intensification may be increasingly limited. Now, one of the other sessions that now attracted some attention, or has been attracting increasing attention of late, has been in the novel cytotoxic space, in particular with the advent of antibody drug conjugates. Here, I provide you a glimpse of this with the HERD3 antibody drug conjugate, Petritumab, Derextrican, in EGFR TKI-resistant non-small cell lung cancer, showing encouraging response rates of 25%, with activity seen in both T7IDM positive and negative disease, and nearly half the patients on this study still on follow-up. In the bottom panel, we see the TROPE2 antibody drug conjugate, Datapetumab, Derextrican, again showing response rates across three dose levels at 4mg, 6mg, and 8mg per kg, or sorry, 8mg per kg, and this actually showed significantly higher rates of toxicity with the highest dose levels. And one of the emerging observations is the risk of treatment-related interstitial lung disease, which seems to be occurring across this class of agents, and there remain specific aspects of understanding the PK variability, internalization of the payload, as well as defining appropriate biomarker thresholds in this new class of compounds for which are not fully resolved yet. Another new class of agents that were presented this time was the bispecific antibodies in this example here, with Amiventumab, which is an EGFR MET bispecific antibody, and beyond targeting both EGFR and MET, they are thought to also result in direct inhibition of tumor growth through ADCC. Here, the focus of the CRISALIS trial was exon 20 mutations, for which we've not seen any approved targeted approaches yet, and the 81 patients were reported here that were evaluated for efficacy. This waterfall plot demonstrates the response rate of this bispecific antibody of 40%, with a median durational response of 11.1 months, and a seemingly manageable toxicity profile with grade 3 toxicities, mainly related to EGFR MET inhibition of approximately 16%. And these results are especially significant as this remains a population with higher MET medical need, and similarly higher prevalence in Asia, given the preponderance for activating EGFR mutations. Now, notably, exon 20 insertions are heterogeneous, and location may influence the kinetics of drug binding, and you can see in this particular instance, those mutations close to the near loop were associated with better responses. Now, moving on to another exon 20 targeting strategy with a small molecule, mobicertinib. This was one of the largest post-platinum cohort that was presented, showing a response rate of 26%. But again, one of the challenges here would be maybe the toxicities associated with chronic inhibition of wild-type EGFR, and there's an ongoing randomized phase 3 trial comparing now mobicertinib versus platinum chemotherapy in the frontline setting. The last studies I wanted to highlight with this day 2 was the data around resected early-stage EGFR mutant lung cancers, where we saw much-anticipated data on the impact of adjuvant chemotherapy presented by Professor Wu. Here, it did turn out somewhat underwhelming, to some extent, given the significant impact conferred by adjuvant osimatinib in patients that relapsed, and, you know, I think we did see similar magnitude of benefit regardless of whether patients were exposed to adjuvant chemotherapy. And similarly, this was – PRO patient-reported outcomes showed minimal impact of osimatinib, again, testament to the excellent tolerability of this third-generation drug. And I just want to conclude now, just also pointing out that although this is very tolerable and we do know that there were – the potential high risk of relapse in the ADORA trial, it's worth pointing out that in the more mature cohort of resected EGFR mutant lung cancers, this was a cohort of 389 samples. We confirmed that there were high rates of relapse in stage 2 and 3A disease at 2 years, and even in stage 1B and 1A. But ultimately, we also highlight in this long-term – this cohort with long-term follow-up data, a fair proportion of patients are actually also cured even without a TKI. And this underscores the need for continued improved patient selection, particularly for adjuvant osimatinib. And with that, I conclude my – this day two of WCLC, and we'll hand the time over to Professor Wu. Hi, good morning, good evening and good afternoon. I am Dr. Yilong Wu. So today I will give the talk about the lung cancer screen and the adjuvant treatment and the KLAST and immunotherapy combined and the immunotherapy and the platelet-from-a-child totally. Several attracted were the selector. The first objective was the top of lung cancer screen, the Thailand study from the Taiwan by Professor Pan-Chi Yang. So this is the study design. Please know the Thailand study target the population with the non-smoker page population and the familiar history of the lung cancer. More 12,000 people were screened in the four year and the half people had a family history of the lung cancer. So what are the discovered from the Thailand study? Comparison with the two important lung cancer screen trial NIST and the Nielsen study. More than early cases with the lung cancer were discovered from 0.9% in the Nielsen to 2.6% in the Thailand. The most cases about 96.5% were the JILO or the state 1A to state 1B. The prevalence of the lung cancer with or without the family history, 3.2 versus the 2.2% the p-value less than 0.01. So the Thailand also confirmed that the familial cancer history is supposed to be the first degree family with the female is the higher risk for the non-smoker lung cancer. The risk ratio was a 1.61 to the 2.0 point. The data is the consist of the 2 to 2.5 to 7 in our study and others. So what is the clinical significance from the Thailand study, the lung cancer study? The highest effect of the lung cancer, not only for tobacco exposure, also for familial lung cancer should be included in lung cancer screen program, especially in the east of the population. The second and third objective were the pre-operative adjuvant chemotherapy. ITK trial was the generally based adjuvant trial reported by Dr. Navarro from the Italia. So this is a study design. This was very complex, the study design. Totally 773 patients with the completely set the stage 2 to stage 3A non-smoker lung cancer were divided to arms. One arm was a higher ERCC1 mRNA inspiration cohort in the future, cisplatin not allowed in the thyroid arm. Another one was a lower ERCC1, the cisplatin low in the thyroid arm. Based on TSM-RNA inspiration, two arms were divided for the profile. Each priority was randomized to VIF or V-LOUD cisplatin combination regimen or the standard cisplatin doubly chemotherapy regimen. So this is the LC-MC3. It also was a new adjuvant trial of the PD-L1 inhibitor report by Dr. Li from the USA. The study design, 181 patients with the receptor stage 1B to stage 3A and select the 3B non-smoker lung cancer received the artesial ligament melanotherapy quarter to two cycle, then received the surgical recession. The primary endpoint was a major pathological response defined as less than 10% of the viral tumor cell in receptor tumor tissue. What are the discoveries from the Itaka study? The event were less than expected. Only 22% of the ITT population. The over-survival was longer with a 96.4 mark in the thyroid arm and 83.5 in the control arm. No significant difference was seen in the heart ratio, 0.76. How about the LC-MC3? The benefit of the waterfall plot. Almost all the patients with the tumor shrunk. Major response rate was 21% and the PCR 71%. What is the significance of the Itaka and LC-MC3 study? Since the beginning of this century, adjuvant chemotherapy became the standard of the care of adjuvant treatment or the receptor stage two or stage nine cancer based on ANIMTA, BR10, and the laser meta-analysis. And the SEPRI trial is a part of how to select the patient who customized the chemotherapy based on the ERCC1, RN1, and beta-tubulin, and so on. But all for a failure. The Itaka trial once again confirmed that it is impossible for thyroid adjuvant chemotherapy will convert the receptor lung cancer patient selected by genomic orientation. Monotherapy with the PDR1 inhibitor, T-jolitumab, as the new adjuvant treatment achieved the promised result with a major response rate of 21% and the PCR of 70%. The third topic is targeted KLAS. Cobraker-100 was the first clinical trial of the KLAS inhibitor, Sotarespine, reported by Dr. Lee from the USA. The study design was simple. Patients were treated with Erbanzo-Nansimov-Cellar lung cancer, and KLAS-G12C were enrolled. The primary endpoint was the response rate received 1.1. 121 patients with the KLAS-G12C were treated with the Sotarespine. Response rate was 37.1%. The tumor shrink was observed in the 81% of the patient. Median percent of the benign patient was 61% patient. Median percent of the benign tumor shrink among all the respondents was 60%. Median PS was 6.8 months. Comparison of the Sotarespine. Phase I trial, the response rate, duration of the response, and PFS were similar. The result of Phase II confirmed the result of Phase I clinical trial. What is the clinical significance of the COVID-100 study? FDA approved the Sotarespine for the KLAS-G12C mutated Erbanzo-Nansimov-Cellar lung cancer on the last year, the December. We are awaiting approval, and we changed our clinical practice for KLAS-G12C, the mutation. Now, moving on to immunotherapy. Kino-59A was a Phase III trial to explore the efficacy of PDR1 pain ball plus the CTL4 inhibitor EP in PDR1 high inflation patient with the Nansimov-Cellar lung cancer. It was reported by Dr. Boyer from Australia. In the randomized double phase Kino-59A trial, the 568 patients with the PDR1 more than 50% of Nansimov-Cellar lung cancer were randomized to IO plus IO pain ball monotherapy. The primary endpoint were the over-survival and progressive free survival. Median survival in this trial was 21.4 months for the pain ball EP versus the 21.9 months for the pain ball placebo. Heart ratio 108, P value 0.74. Median progressive free survival was 8.4 months versus 8.4 months. Heart ratio 106. Grade III to V event occurred at 62.4% of the combination of the combination R versus the 50.2% of the placebo R. And led to data in the 13.1% versus the 7.5%. The action data accepted monitoring committee recounted that the study was stopped for a few weeks and that the participants discontinued the epidemia and the placebo. Interesting. Combo in the therapy group and the KNO59A and the treatment 227 demonstrate a comparable efficacy data, but one is the negative and the one is the positive. So what is the significant concern? Adding the EPD-Lumima to the pain ball does not improve the efficacy and is associated with the greater toxicity. These data do not support the pain ball epidermis in the pain ball immunotherapy in this population. Single agent immunotherapy is the standard care of the PDR1 model 50% of the advanced non-submersible cancer. So the misogynistic trauma confirmed the trial was the phase three trial to explore the efficacy NEBO in the relapsed malignant mesothelioma reported by Finner from the UK. The study design also was very simple. The previous treat the malignant mesothelioma patient with the PSG0-1 were randomized NEBO, monotherapy or the placebo. The treatment was an anterior progression unacceptable to toxicity all the one year. Time endpoint was over the survival and the PFS. The median over survival data was the 9.2 month for NEBO versus the 6.6 month for placebo. Heart rate 072, P value 001A, median PFS was a three month versus the 1.1 but ratio 061, the P value less than 001. The study met both the PFS and the OS endpoint with the 12.6% improvement in 12 month survival break. On the 2020, the President's Symposium of WCRC by Dr. Park's report resolved the treatment 743 the NEBO plus the EP and the unreceptable the malignant mesothelioma. Oversurvival was 18.1 month. FDA also approved the NEBO combination with the EP as the fourth light treatment for this indication. Taking together recommendation for the clinical treatment for malignant mesothelioma, the fourth light treatment should be the NEBO plus the EP. If the fourth light treatment without the IO-NEBO should be as the second light drug. Final method was a platform trial. The fusion was a first to the platform study to explore the biomarker guide, the treatment the patient for progressive antibody therapy for the Dr. Bessel from the France. The study design, the patient treated with the PDA1 failure with the new biopsy. Then divide the two, group A biomarker match and group B biomarker non-match. Biomarker including the homologous recombinant repair and STK11 for the PARK inhibitor, ATN-ATR pathway for ATR inhibitor, CT73 for the CT73 inhibitor, HER2 for the HER2 inhibitor. Non-match the biomarker was treated with a DUOVA plus a different homologous inhibitor. Primary endpoint was the overall response rate. Response rate was from the zero to the 11%, the PMS1.41 to 7.43 through a rest limit and the ATR inhibitor showed the preliminary activity. This is the overall survival. The sero result rate was the best. The fusion demonstrate the molecular strategy that enrollment in the immunotherapy failure setting is the feasible. Thank you so much. This is the third day our select for highlight. Now, please invite Dr. Ross Hsu for next talk. Thank you. Thanks very much, Dilong. Okay. Right, so I would like to start off, finish off, sorry, with selected abstracts from day four. Here are my disclosures, I've shown that before. So the first abstract I'd like to present, which is the first of three small cell lung cancer abstracts. This is a phase one study of AMG757 in patients with pre-treated small cell lung cancer. So AMG757 is a biopacific T-cell engager antibody targeting both CD3 in the T-cells, as well as the DLLL3, which is a delta ligand in the three, that is expressed in small cell lung cancer. Right, so this is a phase one study, the inclusion criteria. Includes that of a patient with confirmed small cell lung cancer, had that prior treatment. Patients with untreated or symptomatic brain mets were excluded. And you can see here in the patient demographics, that the majority of patients, three quarters of patients had at least one or two lines of prior therapy. AMG 757 has a response seen in this heavily pre-treated group of patients. The confirmed partial response was 14 percent at all doses. And the disease control rate was 37 percent. The median duration response was 6.2 months. In terms of toxicities, consistent with its mode of action, the cytokine release syndrome was the commonest toxicity seen. And in terms of all great toxicities, around about 44 percent of patients had cytokine release syndrome. Other toxicities, all grades, included fever, fatigue, again, consistent with its class of side effects. In terms of grade three toxicities, only one patient, or two percent of patients, had cytokine release syndrome of at least grade three. And one patient had a grade three. The results of the treatment-related AEs resulted in patients, one patient, or two percent, had the discontinued treatment. One patient had a grade five pneumonitis. And that was considered a dose-limited toxicity. The conclusion from the office of this phase one study showed that AMG 757 is an extended biopacific T cell engager, had a favorable safety profile, and a durable response of around about six months. Grade three-related side effects were seen in 23 percent of patients. The main side effects were mainly mild, grade one or two, cytokine release syndrome. Only one patient had to stop treatment due to treatment-related toxicities. The dose optimization for single-agent AMG 757 is still ongoing. The next study is a phase one-two study coming out of Spain. And this is looking at the role of a combination of nectadine in combination with iron and Tcan in patients with relapsed small cell lung cancer. So this is a phase one study with multiple cohorts. And at the World Lung Conference, the office presented the cohort A, in which patients were dosed at a little bit of nectadine, two milligrams per square day one, and iron and Tcan, day one and eight, every three weeks. And they're reporting on the results of the 21 patients with small cell lung cancer. These are the baseline characteristics. And the majority of patients were extensive stage. And there are lots of pro-prognosis factors, including high MDH and a bulky disease, including liver metastases. Furthermore, a quarter of patients have brain metastases, and they were heavily pretreated. 38% of patients have at least two lines of treatment. And in terms of best response to prior platinum, 19% of patients' best response was a progression of disease. So this is a highly pretreated patient population. And in fact, many patients were not platinum sensitive. So what are the results? In terms of the side effects, the major toxicities, it was included fatigue in 24% of patients, and diarrhea in 28%. And malnutrition was seen in 62% of patients. They have a grade three utropenia. There were three quarters of patients had at least a grade three toxicity. And 28% required a dose delay. 52% of patients required a dose reduction. In terms of efficacy, the overall response rate was 62%. When we looked at the platinum-free interval in patients who had platinum-sensitive disease, as defined by the last dose of platinum was more than 90 days or three months, the response rate was quite high at around about 69%. And those who were deemed to be platinum-resistant, which the platinum-free interval was less than 90 days, the response rate was really impressive at around about 50%. In summary, the combination of libanectinin and adrenal tea can after first-line therapy showed quite a good response rate. Activity was seen in patients with chemo-resistant disease defined by a chemotherapy-free interval less than 90 days, also in a heavily pre-treat setting, in a third-line setting, as well as patients with brain metastases. Side effects were mainly milder suppression, fatigue, and diarrhea. The office concluded that further development of this combination is warranted in patients with small cell lung cancer. The next small cell lung cancer study is from the NCI, and this is an interesting study looking at exome sequencing in patients with small cell lung cancer. And this is a very unusual approach because most of us believe that in small cell lung cancer, it's a smoking-driven cancer, and the chances of getting a germline or hereditary prescription is actually quite an interesting hypothesis. So the bottom line is that the investigators found that in fact 44% of small cell lung cancer patients had a potential germline mutation, and of this, around about 12% of patients had germline mutation in the ACMG genes, and two-thirds of those genes that were detected that were germline were actually involved in DNA repair. About one-third of cases had loss of hydroxygocity in BRCA2, MLH1, and SMARCA4. In conclusion, the germline type genotypes that was detected using whole exome sequencing was actually associated with a family history of cancer as well as a sensitivity to platinum. So we can see here on the survival curves on your right that patients who had the pathogenic germline mutation are seen. The recurrence-free survival with the treatment of platinum was longer than patients without pathogenic germline mutations. However, there was no difference in the overall survival. We're moving on to uncommon EGFR mutations and HER2 mutations using proziotinib. So this is an updated result, and there were two cohorts of patients, over 100 patients for the exome 20 mutations, and around about 90 patients for HER2 exome 20 mutations. Many of these patients, as you can see here, were heavily pretreated with the treatments as shown here. In terms of the efficacy, the responses in patients with second-line EGFR exome 20 mutations, response rate is around about 15%. With HER2 exome 20 mutations, response rate is around about 21% to 38%. Responses were seen regardless of the type of chemotherapy or immunotherapy as we've seen previously. 28% of patients who have brain metastasis, responses were seen in this subset of patients with HER2-positive exome 20 mutations. In conclusion, the overall response rate for the HER2-positive cohort in the second-line setting was 27%, was higher. Interestingly, patients were heavily pretreated with the HER2 cohort. The disease control rate in both EGFR exome 20 and HER2 exome 20 mutations was around about 70%. Activity was seen in the CNS for both patients with EGFR exome 20 insertions as well as HER2 exome 20 insertions. Toxicity profile, which I did not show, was similar to the second-generation EGFR TKIs, would be GI toxicities and skin toxicities. This is the MetExome 14. This is an update of the vision study of Teportinib, which has been approved in Japan for MetExome 14 skipping mutations. Just move on to the next slide. So the response, the median age, just to highlight this, that is atypical of that with oncogene driver lung cancer. These 10 patients tend to be older and also tend to actually have a positive smoking history. So it's actually important to also do tests for biomarkers in the patients who are older with a positive smoking history. The responses is around about 45% regardless of the prior treatment status, whether the treatment naive or had prior treatment. In terms of prior treatment, again, responses are very consistent with responses seen in patients who received prior chemotherapy or have had prior immunotherapy, either in combination or as single agents. The median progression-free survival was quite consistent around about nine to 11 months, depending on the treatment status. Moving on to fusion oncogene drivers. This is letrotreptinib. This is a study, a phase one study, combined with data from the BASCA trial called the Navigate Study, presented by my co-presenter, Daniel Tan, for this entrec fusion. They tend to be younger, and you can see the list of fusions here. Half the patients have brain metastasis. Primary endpoint was response rate. The best response was seen here. We ran about 70 or 77% independent radiological review of patients who had a response rate. Treatment response was shown here between two to 39 months, and patients, 64% of patients, still had treatment ongoing. And trial one study is a study using letrotreptinib, and this is Dr. Cho's presentation. He presented data on the RAS1 TKI naive patient, which is the first cohort. So with this updated data from the RAS1 treatment naive patients, the overall response rate was 93% in the phase two cohort, and when it was combined with the prior phase one cohort, the response rate was very similar. So that comes to a conclusion of my study, my presentation. Thank you very much. Fantastic. Thanks very much, Ross, for going through the last day, and that wraps up all three days. I guess now we are opening the discussion to questions and answers if there are any from the audience. But maybe I can just get the ball rolling and, you know, with Professor Wu, the president of this meeting, we've seen some data with, you know, neoadjuvant checkpoint inhibitors being presented. And of course, you've been, you know, instrumental in driving the field forward with many, several trials in this space as well with TKI as well as chemotherapy. How do you see this, you know, the neoadjuvant effort moving forward? Do you think that that's increasingly done in your practice? And maybe Ross, you can comment as well, what your thoughts are in terms of, you know, what's required for us to transition into this or to start incorporating neoadjuvant approaches? Yeah, thank you, Daniel. So, this is the excellent question. So, I think, so far, for all the neoadjuvant treatment, we create the target, some molecule or the IO for the patient without the driver gene mutation. So, especially for the IO, the neoadjuvant in this space, we are only saying this treatment, neoadjuvant, is the feasibility. We find the major responsibilities, okay, and also the monotherapy or the combination therapy, all those are okay. So, I think, but the important thing is the NPR or the PCR translation for the over-survival, so far, we don't know. So, I think we need much more data on the clinical trial and then the answer this question. But in my, personally, I think we don't need the over-survival. We only need to know the DFS is okay, that's okay, because the over-survival too long time. Maybe you are one to waiting the over-survival, maybe you need a seven to ten year later. Yeah. I guess the other challenge, of course, before we get to you, Ross, is the fact that, you know, even we do neoadjuvant approaches, it's still hard to tease apart how much is going to be contributed by adjuvant if you then, you know, go with, have a hybrid system or a bit of a hybrid approach to the treatment. So, I guess there are many moving parts in that space. Ross, you have any thoughts on this? Yeah. So, yeah, and I totally agree, Elon. I mean, the first thing we had to tackle is, you know, demonstrate in the randomized manner that the neoadjuvant approach and all the data points to, hey, look, this is really, really, really efficacious and the toxicities are much more favorable. But we still had to show in a randomized manner that it's better than the adjuvant approach. So, and that trial is ongoing. We know that. So, and the main issue is do we, can we wait for the over-survival? And as Elon nicely pointed out, it's going to take a long, long time to get a positive result. And by that time, the standards of care would have changed again. Defining closer surrogates like NPR, for example, is very important. So, at least we know in the breast cancer setting using chemotherapy, there is a correlation or association with survival. So, we have to also show that too, but how can we show this? So, of course, no randomized trials have been done. So, and then we still need to have appropriate follow-up of all these biomarker-driven trials to show that NPR can give a good readout. I do have hopes. I mean, DFS is reasonable because we know in the adjuvant colorectal setting that DFS is a very strong surrogate for survival. So, whereas in lung cancer, DFS is an appropriate surrogate only for those with that chemotherapy. I mean, the trials have shown that, but not with, not even with TKIs actually, but just with the chemotherapy. So, we need randomized data and hopefully more biomarker work, but certainly this is the way to go in the future to try to take advantage of the intact immune system with the intact tumor microenvironment prior to, you know, before any treatment's been given. Well, I think that another important point is that for the new adjuvant treatment, especially for the IL, we could get them much more tissue. So, based on this tissue, after the IL treatment, and then we could do so much, so many, many translation research. We understand the mechanism. So, maybe we could give the patient the more and more precise treatment. I think this is important, very, very important. I agree. And then one more thing is that the adjuvant immunotherapy trials are actually more mature in terms of the development compared to neoadjuvant actually. So, there will be a different stance of care by the time the neoadjuvant data rolls out actually. So, there's, you know, some adjuvant trials that are enrolling right now. So, they will have a head start already. I agree with the adjuvant. Now, the adjuvant is still one of the standard care. But again, because the treatment is so quickly advanced. So, I don't know. Now, the adjuvant is still the standard care? Maybe it's something different because based on the adjuvant trial, we'll find that regardless of the adjuvant chemotherapy or not, the PR cells are okay. So, I think we need the new, the question, we need the answer, the adjuvant chemotherapy, we need or not. Hi, Dr. Ross. Dr. Ross, so I think you are very interested about the small cell lung cancer. But based on this data, I think, do you think that what is the newer future for the small cell lung cancer? What is the direction? What is immunotherapy or other? Yeah, look, I think immunotherapy, I mean, I think the difference between immunotherapy, as we're using it now, where our immune checkpoint inhibitors versus something like the biopacific antibodies, such as the BITES or biopacific T-cell engages is that the immune checkpoint inhibitors are dependent on the intrinsic immunogenicity of the tumor for its activity, whereas biopacific antibodies can activate a T-cell response against DLL-positive tumor cells. So, we don't require intrinsic immunogenicity, which is the PD-L1, PD-1 axis. So, I think, you know, theoretically, it's more targeted and you're able to draw in the cytotoxic T-cells in a way, you know, theoretically closer, you know, it's more active in terms of mechanisms, if you're speaking. So, theoretically, it is promising, but again, this is a very small sample set. It's only, what, 30-odd patients or something, and it's only a phase one study. So, we still need, you know, further trials to see whether it is legitimate, because we've had lots of, you know, other candidates, for example, the, you know, the ADCs, for example, Roberti, for example, you know, the program was stopped. So, we still need to have, you know, further follow-up data to see whether biopacific antibodies is a better approach to the treatment of small cell lung cancer. But I think, you know, some sort of immunotherapy, we've shown in the first line setting, that the additional immunotherapy, you know, that the margin is small, but at least it's advanced, both the use of atezolizumab or tovalumab in the frontline setting. I think, you know, we have to move away from just any more chemo, but some sort of immunology type approach is the way to go. Yeah. And I think if we just take reference, even with the other presidential symposium, in that PDR1 more than 50%, where we didn't see that, you know, again, that anticipated benefit of maybe two is maybe better than one, in terms of the checkpoint inhibitor approaches, I think, in a way, it's a good reminder of, you know, there are several nuances that still need to be taken into consideration with regards to combinations and the future of how we're going to develop these agents. Was that a surprise for you, Ross and Yilong? Yeah, I mean, that was, well, I mean, there was a slight difference between CHECKMATE 227, which is, I guess, everyone will be drawn in allergy with KINO 598. The control arm is totally different. So, I mean, in 227, the control arm was chemotherapy. So, you know, you've got a different beast here with a single-agent Pembrolizumab. And Yilong showed the curves nicely, that the PFS curves and the median overall survival was the same for Pembrol IP as compared to Ipinevo, right? So, in terms of absolute values, of course, we shouldn't be doing trial comparisons, but the outcomes were very similar. But the only difference was the control arms were different. And the control arm in the KINO 598, we know it's the same as the outcomes in the combination. But in chemo, which is in CHECKMATE 227, the control arm did worse. So, hence, to me, that's how it probably explained the difference in these two trials, is that the control arm was, you know, was the more contemporary one. So, that's why, you know, my explanation for why the one positive trial and the other one was negative. I don't think, you know, it's the efficacy of the experimental arm. Yeah, I agree with the Roche's opinion. So, let me to see the CHECKMATE 227 or the Pembrol plus the Ip in this clinical trial. So, I think the Ip plus another drug, I think, in personally, I think there's no future. Yeah, no future, because maybe in the relapse or resistance setting, maybe they some the lower, but in the force line setting. So, almost all the combination with the IO, with the PEDAT1 plus the CHECKMATE 247, always not so good, but then the IO plus chemo or the IO plus others. Yeah, I mean, if we can get away with single agent, you know, because anything with combination will tend to have more toxicity. So, we can, you know, if the data suggests that, you know, single agent immune check inhibitor, it has similar outcomes to combination as shown in 598, then that's the way to go. But we do know that that combination is better than chemo. And we also know that single agent is the same as combination IO. Right. Okay. And then also know that single agent monotherapy for PEMBRO is better than chemo alone. So, I think we know where the pecking order is. Yeah. Okay, then, if there are no other questions or points to raise, I think that's all we have time for today. I'd like to thank our speakers, Professor Yilong Wu and Associate Professor Daniel Tan for joining us today. Also, thanks to Aubrey Hsu for actually arranging this webinar. Please keep an eye out for an email that will be sent for program evaluation and CME information later on today. I'd like to thank everyone for joining in and thank you for your participation. Thank you very much. Okay. Thank you. Bye-bye. See you again. Bye-bye. Thank you. See you.

ISLC 2020

World Conference on Lung Cancer

Singapore

webinar

precision medicine

novel therapies

lung cancer research

biomarker analysis

targeted therapies