A five-part VJ Session with thoracic oncology experts Daniel Tan, Melissa Johnson & Dean Fennell, who discuss the key highlights and data presented at the IASLC World Conference on Lung Cancer (WCLC) held in January 2021.

Welcome to The Lung Cancer Sessions by the Video Journal of Oncology (VJOncology).

Daniel Tan (National Cancer Centre Singapore, Singapore) is joined by Melissa Johnson (Sarah Cannon Research Institute, TN) and Dean Fennell (University Hospitals of Leicester NHS Trust, UK), who offer their perspectives on the most exciting announcements at the IASLC World Conference on Lung Cancer (WCLC) held in January 2021 and what research they think could change practice in the future.

The expert panel discuss the latest trial data on targeted therapies in lung cancer and mesothelioma, including KRAS G12C inhibitors, antibody-drug conjugates and anti-TIGIT antibodies. They also consider the use of biomarkers for evaluating immunotherapy response, the potential of neoadjuvant strategies, the importance of lung cancer screening and more!

KRAS G12C inhibitors & ADCs

“I think a very natural question is, how does this move into the frontline space? I think we do see that KRAS G12C, of course, is a new antigen that we know of, and so these patients do respond well to PD-1 inhibitors…I think a natural question is, could we find a chemotherapy-free option with immunotherapy and a direct KRAS G12C inhibitor in the frontline setting and exactly who are those patients? I think some of the co-mutation data may lead us to the right patient population.”

     – Melissa Johnson

Mesothelioma advances

“I suspect the main use of immunotherapy is going to be in the population of patients who’ve already been treated, and we do know many patients can go on to have re-challenge with chemotherapy over the course of a year or two years, and this will clearly be an option for them…We may well see Phase III data emerging with chemo-immunotherapy combination, which perhaps would show very favorable data in the epithelioid subgroup, giving us further choices in that frontline setting. ”

     – Dean Fennell

Checkpoint inhibition & biomarkers

“I think, despite all these interventions, there are still limitations in terms of how we’re going to better understand the micro-environment, how we’re going to understand the immune contexture in terms of allowing the appropriate cells to traffic in.”

     – Daniel Tan

 

Neoadjuvant strategies

“I was struck as I listened to the LCMC3 presentation that this data certainly adds support and adds momentum to the excitement of neoadjuvant immunotherapy. It’s been a little bit of protracted story because it’s hard to … it’s a little bit harder to find and treat these patients before they have their surgery, but I think it absolutely supports the use of neoadjuvant immunotherapy.”

     – Melissa Johnson

Adjuvants & lung cancer screening

“We can’t necessarily make those assumptions, that these non-smoking diagnosed tumors or cancers are necessarily going to behave or have the same biology as the screen detector cancers coming out of NLST or NELSON…I think that’s still a big question mark as to whether you would necessarily see the same mortality benefit, and I guess that’s really where we are now in terms of how we move forward with this.”

     – Daniel Tan

Full Transcript
Daniel Tan:
So, I'll kickstart this discussion. So, my name is Daniel Tan. I am one of the co-chairs in the recent WCLC 2020, that was actually held just in the end of January 2021. And with me today, I've got two of my colleagues, Dr Melissa Johnson and Dr Dean Fennell and I'll just let them introduce themselves in terms of where they work.

Melissa Johnson:
Hi everybody, I'm Melissa Johnson. I'm the Director of the Lung Cancer Research Program at Sarah Cannon in Nashville, Tennessee. I'll just take this opportunity to congratulate Daniel on a fantastic program. The platform was awesome and I just am struck by how we've made such progress from ASCO 2020, where I played a role, but we didn't have any live discussions, to ESMO 2020, where there was more discussion, but the PDFs were a little bit more difficult to get and you have just figured out how to do it all, and so I congratulate you on a fantastic meeting.

Daniel Tan:
Thanks for that, Melissa. It's too kind, and Dean?

Dean Fennell:
Thank you. I'm Dean Fennell. I'm coming to you from the UK. I'm Professor of Thoracic Medical Oncology, Director of our mesothelioma program and yeah, I can only echo what Melissa said, actually. What a fantastic conference and thank goodness for technology. We're obviously adapting as a world towards the virtual.

Daniel Tan:
Great, so I think ... again, by doing this, these WCLC highlights on behalf of this VJOncology program and I think what we hope to do is really to start to pull out some of the abstract presentations that we felt would be of interest to the community, and I thought we'd first start off the discussion around some of the latest targeted therapy agents that have read out. I think starting with Sotorasib, they're a KRAS G12C-specific inhibitor. Melissa, what do you think of that initial data with the mature Phase II data set showing 34, 35% response rates, relatively modest PFS, relative to some of, what we've come to be familial acquainted with some of the other oncogenic drivers? What's your sense of that data coming through?

Melissa Johnson:
Yeah, that was an important abstract as part of your Presidential Plenary Daniel, and I have to say that I've warmed up to the response rate of 37%. Of course, at ESMO the Phase I results, where the response rate was in the low 30s, but as we have continued to discuss this, we've seen also some data from Mirati [Therapeutics] with their direct KRAS G12C inhibitor and in all of these trials evaluating this drug, not just in lung cancer, but in colon and other cell tumors that harbor KRAS G12C, this is not the same as targeting EGFR or ALK, and so I have decide that I'm satisfied with the response rate near 40.

We know that the data is in front of, the Amgen 510 data, is in front of FDA and we would anticipate an approval in an area of unmet need in lung cancer, and moreover, the CodeBreak 200 trial, in which patients are now being treated, being randomized to Amgen 510 versus docetaxel. We would anticipate that that also would be a positive study, and so as we fast forward in 2021, I believe that we'll begin to see the approval of these agents, so this was an important study.

Daniel Tan:
I agree, and particularly in a molecular subtype that is still very common very around the world, maybe less in Asia, but certainly the commonness in Caucasian European descent, and here we have total unmet need in terms of targeted approaches, so I think that's really going to be welcome. I suppose the challenges, again, where do you see the future of this going into the first-line setting, and I think that's going to be somewhat more tricky with that level of activity that we've seen so far, given the fact that our first-line treatment options in this particular group of patients with this high preponderance of smokers, smoking patients, smoking history, where we know checkpoint inhibitors and chemotherapy do provide very durable long term outcomes, so that's really going to be a key challenge in terms of how we're going to improve upon some of the initial read-outs of single agent inhibitors.

Melissa Johnson:
True. I think a very natural question is, how does this move into the frontline space? I think we do see that KRAS G12C of course is a new antigen that we know of, and so these patients do respond well to PD-1 inhibitors. We saw in the plenary data that, irrespective of PD-L1, patients respond to the KRAS G12C agent in addition. I think a natural question is, could we find a chemotherapy-free option with immunotherapy and a direct KRAS G12C inhibitor in the frontline setting and exactly who those patients are? I think some of the co-mutation data may lead us to the right patient population.

The dilemma there, or the challenge, the opportunity, I guess, is whether the drugs, a TKI directed against KRAS and an immunotherapy drug will be tolerated together? We've seen examples in EGFR-positive patients, ALK-positive patients, where that's not true; they haven't been used with good tolerance, but you make a good point that this is a different biology; one that is driven by smokers, or we see more commonly in smokers and so maybe we would be able to use these drugs together.

Daniel Tan:
Yeah, so I think we really anticipate the read-out of some of the longer term or randomized data for those, in these KRAS G12C specific inhibitors, as well as some of the combinations that are really now being ramped up in early phase clinical trials. Maybe we could switch gears to talk about one of the emerging classes of ADCs that seems to now find a role in multiple cancer types. With HER2 ADCs as well as TROP-2 as well as HER3, and we've seen a few of these being reported in relatively, again, smallish Phase II studies.

I think many viewers may not be 100% familiar with ADCs as they're still very much in development, maybe Melissa could you share some of that experience that you might have with these ADCs and which one in particular you're excited about?

Melissa Johnson:
Sure. I agree with you that antibody-drug conjugates that have been an area of interest in many other cancers prior to 2021 really had a center stage at your meeting. In particular, just to step back, antibody-drug conjugates are monoclonal antibodies attached to a linker and a payload, and the payload is chemotherapy, and in particular, there were three antibody-drug conjugates that I think of from your meeting; the HER2, T-DXd, trastuzumab deruxtecan, the TROP-2 directed antibody-drug conjugate. Let me look at my notes for how to say its name; Datopotamab, and that's DS-1062, and then U3-1402 is a HER3 antibody-drug conjugate being developed in particular for patients with acquired resistance to osimertinib.

I think it's just important to say that in the common platform that those three drugs share, made by Daiichi Sankyo, is the exatecan payload, but they all work a little differently depending on where they bind. Some of the interesting data that was presented at your meeting was in the trastuzumab deruxtecan experience. Of course, we heard about that at ASCO; response rate of 62% for patients with HER2 mutations. The new data at this meeting was another cohort in that same trial, evaluating patients with HER2 over-expression, protein expression, and interestingly, the response rate in that group was 25%, but irrespective of the amount of HER2 IHC, suggesting that at least in lung cancer, the mutation is more relevant, is the more relevant oncogene driver, as opposed to the protein over-expression which we see, for example, being relevant for breast cancer.

I loved that you included that. There was data at ASCO with T-DXd in colorectal cancer patients and gastric cancer patients, and of course this drug is already approved with the brand name Enhertu for breast cancer patients with levels of protein over-expression being a relevant biomarker for those three groups, so this is, I think, an example of a drug that has convincing activity across tumor types, and it's been a while since we've had one that has such broad activity.

Daniel Tan:
And I think in this instance, I think one of the major challenges is really going to be how we're going to refine some of the selection criteria from a biomarker point-of-view, and really selecting. I think the initial experience with HER2 is speaking to that and despite having such an established assay that is used fairly extensively in breast cancer, for example, and not just saying that ... we're not just going to have one, it's going to be multiple other targets that will need to potentially be able to develop a screening strategy to really refine patient selection in those [inaudible] patients.

Melissa Johnson:
I think that's a really good point and I think if I heard one constructive criticism of the data across the meeting, not just with the HER2 ADC, but also the TROP-2 and the HER3 antibody-drug conjugate, it was that: "Show us that your biomarker defines the right patient population", and so I think that will be the focus of additional therapy, or additional trials.

Daniel Tan:
Just before we leave off this topic on ADCs, it's interesting as well that we do see dose-dependent toxicities emerging, but not necessarily dose-dependent activity or efficacy necessarily, and I think it also speaks to that we don't fully understand the mediators of response in this and while we have the payload being delivered to the tumors, there are a whole range of other reasons, including how the chemotherapy, the cytotoxic drug, is taken up by the cancer cell that can actually influence response.

I'm going to take this opportunity now to bring Dean into the discussion because I think 2020 was a bumper year for progress in mesothelioma and we've seen certainly some really exciting data coming out from the initial presidential symposium in August and then more recently as well with Dean presenting his data on the CONFIRM trial, so Dean maybe you could share your thoughts how this has impacted the clinical practice thus far.

Dean Fennell:
Yeah. You're right, it's been a transformative year with positive Phase threes too, which is unique for us, I think, in this field, having read out. So just looking back, the very first approval, of course, of chemotherapy was back in 2004: the FDA approval of pemetrexed and cisplatin, and although we've had positive trials since that time, it really wasn't until the last conference that we saw the CheckMate-743 data reading out with ipilimumab-nivolumab versus chemotherapy as positive Phase III, so hazard ration of 0.74, a very respectable, significant read on an early read of the data, and the controversy there, I guess if there is one, is around the sub-grouping.

A vast majority of the signal seems to be in the non-[epithelioid?] subgroup of patients, and the FDA, of course, have approved this now across the board. We'll see what the health economics reads out like for different regions of the world, and that's where we come then to the second line, because with the CONFIRM, we've not seen any superiority really for any single drug in the phase three part of the study. We read out with a hazard ratio of 0.72, again an early read of the data, with about 230 events from 294 required events, and this was a study really in a population that had received at least one, and the majority actually two courses of chemotherapy.

So based on the survival, the improved secondary endpoint of progression-free survival, we would say this certainly represents a now validated option for patients, because how you reconcile these two immunotherapy treatments in the first and second line, and one argument might be that patients certainly have a slightly better outcome within the first seven months with chemotherapy if they're ... as seen in the CheckMate-743, and given the equivalence, certainly in the subgroup analysis, some may consider going forward in the future to try and sequence with second-line immunotherapy.

I suspect the main use of immunotherapy is going to be in the population of patients who've already been treated, and we do know many patients can go on to have re-challenge with immunotherapy...with chemotherapy rather, over the course of a year or two years, and this will clearly be an option for them. I think in the future [inaudible] is definitely towards frontline immunotherapy, it has to be; we've seen that in lung cancer and with chemotherapy that is now currently ongoing. We may well see Phase III data emerging with chemo-immunotherapy combination, which perhaps would show very favorable data in the epithelioid subgroup, giving us further choices in that frontline setting.

Daniel Tan:
Maybe a question to you with regards to your thoughts around that difference in epithelioid and non-epithelioid histology with regards to frontline. Beyond that, do you ... is there a biological basis for that difference that you are seeing?

Dean Fennell:
Yeah, for a long time, certainly based on some of the pre-clinical and translational PD-L1 expression studies, it was suggested that the sarcomatoid might be a more sensitive subgroup for immunotherapy. I think [the Phase III?] shows very clearly actually, that these two subtypes don't appear to be different [in combination immunotherapy?]. Rather the positive [inaudible] strong signal that we see in the non-epithelioid is a consequence of the core benefit from chemotherapy. It has a duration of about 0.4, which is due to the low, short PFS associated with the chemotherapy, so the histology is something that we've always known, which is that it's prognostic, negatively prognostic relatively, for the non-epithelioid, and when we look at the placebo control in the relapse setting, we did see no difference, essentially, in survival for, well, we saw a survival advantage for the epithelioid in relapse.

That difference was narrowed significantly in the non-epithelioid, but then we have to remember that it was an under-powered overall survival in this presentation, and that we're waiting for more events, I think, in the non-epithelioid to see exactly how they do, but just to answer your question and summarize; I think that immunotherapy works equally well in these two subgroups where chemotherapy doesn't.

Daniel Tan:
Interesting. I think, really congratulate you for running that investigator-initiated study, coordinated out of an academic unit. Where do you see future combinations, and I guess that question as well to Melissa; what are you excited about in terms of future of treatment options for mesothelioma?

Dean Fennell:
For me, just briefly, I think with our growing understanding of the genomic landscape, Nic Waddell actually, from Australia, gave a nice overview of the genomic landscape in this conference. We now have very frequently-occurring tumor suppressor targets which may be actionable. We presented some, we actually published some data which we sent to the ASCO last year on PARP inhibition in BAP1 mutant patients. The study met its primary endpoints as an investigator-initiated Phase II, and we got data we'll be presenting on targeting CDKN2A and I suspect the opportunities to target things like the Hippo pathway as we develop new approaches, so yeah, I know we're 10 years behind lung, but it'd nice to see some [inaudible] approaches which demonstrate specific [inaudible] for the relapse setting because the population is so heterogeneous.

Daniel Tan:
And Melissa? I guess you have something to say to that with the advances, specifically in cell therapy or other kind of ADCs?

Melissa Johnson:
I do think ... I agree with Dean that it’s not always good to be first. Sometimes it's good to be last, and so I think we're benefiting, the field of mesothelioma is benefiting from some of the mistakes and assumptions we made in non-small cell lung cancer five or seven years ago. I'm excited about CAR-T cell therapy in mesothelioma patients. There was multiple discussions that featured, Prasad Adusumilli's work with mesothelin-directed CAR at Memorial. There's also a French group that has had similar successes with intrapleural administration. I think that's a really important aspect of both of the works, and maybe why CAR-T cell therapy will gain traction in mesothelioma relative to non-small cell or small cell for example, that is more systemic.

One of the challenges of CAR therapy is getting the CAR-T cell to the tumor, and so that's easier if you're putting it right up next to the cancer within the plural space. We have a mesothelin-directed CAR made by TCR Squared at Sarah Cannon and we've been very impressed with the ability of patients and the interest in patients to travel. It almost reminds me of an EGFR or an ALK patient population; they are younger, they're informed about their cancer and they're looking for the very best therapies. We have a lot of ways to take care of patients who are coming from out of town, and so that is a nice synergy for them, so I'm excited to see that field continue to develop.

Daniel Tan:
Fantastic, and to your point; I guess every ... I think, despite all these interventions, there are still limitations in terms of how we're going to better understand the micro-environment, how we're going to understand the immune contexture in terms of allowing the appropriate cells to traffic in, and this notion of this immune ... different immune set points of different tumors is nicely exemplified by the emerging data with combination checkpoint inhibitors in that PD-L1 more than 50% cohort, for which, again, we've seen in the last ASCO and then this time again updated data for TIGIT antibody in the PD-L1 more than 50% group, and of course in the Presidential Symposium, we saw the first presentation of the CTLA-4 in combination with PD-1 versus pembrolizumab showing no significant benefit but increased toxicities in that population.

Again, speaking to Dean's point that very good control arms. I think, big difference here, you have a control arm that is appropriate and that performs very well and certainly it's interesting that we begin to see some of the combinations working in very specific PD-L1 [inaudible] within lung cancer. Melissa, what are your thoughts around that data? Again, you've been involved with the TIGIT antibody development as well.

Melissa Johnson:
I agree. I am excited that we may be taking another step in how we understand these therapies, because we know that patients with different levels of PD-L1 clinically look and respond very differently to chemotherapy with IO alone. I think the pembro-ipi versus pembro data that showed no difference was surprising to me, and I think the discussant made a really good point that it was a PD-L1-high patient population, and perhaps that's not the patient population where the anti-CTLA-4 component is relevant or necessary, so I thought that was maybe a good take-home point from a negative trial.

The TIGIT data is interesting and a little biased, but I will say that I'm a little skeptical too; we'll see. The CITYSCAPE data showed that for patients that the addition of tiragolumab, an anti-TIGIT antibody, to atezolizumab in a newly diagnosed advanced patient population. There was a small improvement in response rate and PFS in intent to treat patient population, but that increased in a PD-L1 high group of patients. The biomarker analysis that was reported at this meeting suggested that actually whether you use the Dako 22C3 assay to define your PD-L1 cut point, or if you use Ventana's SP263, the same was true; the PD-L1 high patient population had improved responses in PFS, and so now we await the SKYSCRAPER Phase III, in which patients are all PD-L1 high.

We're participating in this trial. I noted this week that the trial is now beginning to look at Dako as well as Ventana to measure PD-L1 and so we'll see what implications that has, but it would be great to have more doublet options without chemo for our patients.

Daniel Tan:
For sure, and Dean I guess the PD-L1 has caused some angst in the lung cancer world, it doesn't seem to be that predictive in the mesothelioma subgroup analysis. What's your take on that?

Dean Fennell:
Yeah, one message that has come from earlier studies in retrospective cohorts was that PD-L1 was negatively prognostic, and that was borne out to a degree in CheckMate-743, where patients just seemed to do worse in both arms if they were PD-L1 positive. I think the main challenge definitely has been around the type of clone that's been used in the studies. Cell signaling has been used, for example, in the PROMISE study; very high expression rate, somewhere around 60% I think it was. We've seen consistent results with the Dako 22C3. I think Boston ran a large retrospective cohort study.

We've ran other studies, actually some clinical trials in which we've used 22C3 and we're consistently seeing somewhere in the order of about 20, 25% expression, but that's measuring almost identically to how we measure in lung cancer using the geo-proportion score and the various levels. One of the things I should say is that we did only present the greater than 1% versus less than 1% cut-off. We will have data actually with mature survival and confirm, looking at the greater than 50% to see if there is anything there, either prognostic or predictive, but you're absolutely right; we saw nothing to suggest any predictive or prognostic effects in a placebo control study.

Daniel Tan:
Is there a significant human operational burden in mesothelioma?

Dean Fennell:
Well, I think again, Nic Waddell covered a little bit of this actually; the mutation burden is very low in mesothelioma and [inaudible], the upper limit for I think one patient, was eight mutations per megabase and the average is around about two, so that can 10 mutational megabase that we see in lung, we're way, way away from that. I think Aaron Mansfield from the Mayo has published on this and we know the [inaudible] landscape because it's so different in mesothelioma, we see a lot of copy number losses, possibly chromothripsis or some unusual transformative event during the evolution of the cancer that leads to a lot of genome rearrangements, and it's probably through these rearrangements that we're seeing new antigens form, and that's not been picked up using conventional sequencing approaches and so we don't know yet what's driving immune response in mesothelioma.

We have some ... we see some fantastic respondents to the monotherapy and one possibility is that there are factors that are regulating the recruitment and activation states of cytotoxic T-cells, so that's something we want to explore obviously within CONFIRM.

Daniel Tan:
Okay, that's fascinating. Almost like oncogene-driven cancers, but maybe slightly better than oncogene-driven lung cancers in terms of response to immunotherapy.

Dean Fennell:
Very much so, yeah.

Daniel Tan:
Let's move to where we think we might be able to learn a lot from these, in terms of biomarkers for immunotherapy response and moving into that early-stage peri-operative setting. I think we saw some nice ... one of the largest trials, neoadjuvant trials, single arm, 181 patients with atezolizumab in the LCMC3 study and that showed a path CR rate of 7%, MPR rate of 31% with some increase when you enrich for the PD-L1 more than 50%. Melissa, what's your thought around this whole move towards neoadjuvant treatments, and do you think we're ready to ... where do you think this field is going to head to in terms of next steps towards standard of care, I suppose, or the willingness for physicians to start even thinking about this as the best standard of care?

Melissa Johnson:
I was struck as I listened to the LCMC3 presentation that this data certainly adds support and adds momentum to the excitement of neoadjuvant immunotherapy. It's been a little bit of protracted story because it's hard to ... it's a little bit harder to find and treat these patients before they have their surgery, but I think it absolutely supports the use of neoadjuvant immunotherapy. I was sharing with you all before we started taping that my surgeons love a dose or two of immunotherapy. It doesn't suppress the blood counts of the patient prior to the operation and they can see the favorable response in the tumor tissue.

They actually say the tumor tissue and the lymph nodes are sticky and they feel different after immunotherapy, and it's different from what they were used to with chemotherapy, so we're not quite there yet but I remain enthusiastic and I think neoadjuvant immunotherapy feels different in the clinic, to the idea or the concept of adjuvant immunotherapy to me.

Daniel Tan:
No, I agree, and I think in the Presidential Symposium we also saw some of the challenges in terms of awaiting some of the adjuvant trials to read out and the longer term, read out for that with the ITACA trial, so I think in lieu ... in light of all the rapid developments in combinations, again one key challenge is really going to be establishing good surrogate endpoints perhaps in trying to rapidly screen through all the agents and the multiple combinations that are potentially coming through into this setting, and Dean, any interest with neoadjuvant approaches in mesothelioma?

Dean Fennell:
Yeah, I mean, there are [inaudible] in the neoadjuvant space looking at immunotherapy. There was a comment I was going to make actually around the rationale for whether you go adjuvant or neoadjuvant, and I think some of the pre-clinical data does speak to neoadjuvant having advantage in that when you treat these tumors, you have a T-cell memory, T-cell complement, which might lead to a protracted tumor suppressive activity beyond resection. Whereas, of course, if you resect all the tumor, you're removing a lot of that T-cell memory, resident T-cell memory and you may lack some of that additional efficacy in the immunotherapy post-surgery, so it's really interesting to hear Melissa's experience clinically with the neoadjuvants.

The science may underpin a justification for what we're seeing in real life, and that could have a bearing on what we end up doing actually, in the longer term. In mesothelioma, very early to say. Surgery is still quite controversial, and we've just completed recruitment of the last patient into a randomized Phase III of surgery called MARS2. It's under Eric Lim, who I know had an award at this recent conference. We need to understand what surgery is really contributing to the management survival of patients with mesothelioma to really get a view into the longer distance, actually, as to where we'll go with things like neoadjuvant and other treatments.

Daniel Tan:
Mm-hmm (affirmative). Of course, I think the impact on the longer-term outcomes conceivably may be quite different when we look across the different modalities of therapy, so some of the assumptions that we made with targeted agents don't necessarily extrapolate into this, in using immunotherapy for reasons Dean has already nicely discussed, just by virtue of the mechanism of action. I think I agree that the LCMC3 was also very reassuring in that if you look across the surgical experience, it didn't necessarily, in this larger cohort, it didn't really lead to that many treatment delays or delays in surgery and certainly proved to be feasible.

Just before we touch on one of the last topics of screening, there was this much anticipated adjuvant, osimertinib or the ADURA study with the read out of adjuvant chemotherapy. In a way it wasn't ... it didn't come too much as a surprise when read out, that we saw a substantial amount of the benefit was really driven by just by virtue of giving osimertinib, and in fact adjuvant chemotherapy had a very minor minimal impact it seemed, when you look at the subset who received it. I don't know, Melissa, what's your thought around that data that read out this time?

Melissa Johnson:
Yeah, I agree with you Daniel and I have found; since the FDA approval of osimertinib for patients in the adjuvant setting, as I try to explain it, I get ... I have struggled to explain why you should get chemo and then osimertinib, and so it's convenient that the larger magnitude of benefit or the larger proportion, I should say, of benefit was in the targeted therapy. In the ADURA trial of course, patients received chemotherapy as was the investigator preference and the patient preference likely, and so I think that's a ... it's a little wrinkle, a little twist in the initial ADURA trial that was a plenary at ASCO, and I think we are all still trying to reconcile the trial with the practical reality that if you have this drug, for a patient who has an EGFR mutation and the patient is sitting across from you in the examining room, it's really hard to say, "No, you should get chemotherapy."

So clearly that's a controversial topic and I mean no disrespect to all of our colleagues that work so hard to establish the benefit of platinum-based chemotherapy for patients with adjuvant ... in the adjuvant setting, but I do wonder if this is also the tipping point towards a more targeted approach in the adjuvant setting.

Daniel Tan:
I guess, how much are you looking forward to maybe some of the longer term read outs of this trial? That's clearly one of the things that is still favoring chemotherapy, if you ... for whatever you say, there's still that, at least, long term survival benefit, whereas, I guess, with the adjuvant TKI now we don't have ... we're not quite there with that data.

Melissa Johnson:
It's true, I think it does remind of the adjuvant Herceptin story in breast cancer though, where they had the same ... and I say they ... they had the same discussion, and argument even, when the initial results came out and look how we use that Herceptin in the adjuvant setting now and other HER2 directed therapies, so I am cautiously optimistic that we'll see a survival benefit in this setting as well, given the hazard ratio in the data presented.

Daniel Tan:
Okay, and I guess then we move to the lung cancer screening, which is an important topic of course. I think what we saw this time was the data emerging from a screening study coming out of Taiwan 12,000 patients ... approximately 12,000 patients that were treated with single arm and the patients were ... it was a fairly high incidence of lesions being picked up. I think it was approximately 3%, thereabouts. What are your thoughts around, I guess, in the uptake of lung cancer screening in the US and how is that ... how does this data fit into some of your thoughts around screening?

Melissa Johnson:
Well, I think it opened my mind to the idea of what a high-risk patient is that doesn't have a personal smoking history and of course, the NLST data and the NELSON trial defined a patient population with a significant smoking history, so it made ... it gave me pause in the ... One of my breast cancer colleagues texted us, in the United States, the number of patients being diagnosed and maybe treated with breast cancer.

Those statistics are, and maybe it's the death rate, have surpassed that of lung cancer females, and so ... and she happened to say, "Gee, this is a shame. This isn't something to be proud of" yesterday, and I found myself thinking about the ... is it the TAYLOR study? The screening study-

Daniel Tan:
TALENT, yeah.

Melissa Johnson:
TALENT. Thank you, and it does seem as though there are factors at play that are becoming more relevant, I guess, as we go along.

Daniel Tan:
No, I agree, and I think it's really something that we've recognized for a while in terms of the preponderance in Asian female and it's certainly something that really ... I guess the question is: what's next in terms of how do ... we can't necessarily make those assumptions that these non-smoking diagnosed tumors or cancers are necessarily going to behave or have the same biology as the screen detector cancers coming out of NLST or NELSON.

Melissa Johnson:
Yes.

Daniel Tan:
I think that's still a big question mark as to whether you would necessarily see the same mortality benefit, and I guess that's really where we are now in terms of how we move forward with this. I do think that, whether you like it or not, the ... even as we speak, there are a lot of so-called health screening practices that are not necessarily ... that are doing CT scans and we know that CT scans are becoming ... they’re fairly ubiquitously done in some quarters, so I think there needs to be a framework, at least, to be able to increasingly capture some of this data and try to make sense of how we're going to move forward with a survival screening strategy.

Melissa Johnson:
Daniel, I'll just say; the other fascinating thing about that abstract was this idea of the cooking index. We were ... in my clinic, we were Googling it. My nurse practitioner was like, "Was is that?" It was a question that was addressed in the live discussion afterwards, but I think you've ... that data has uncovered a risk factor that maybe I hadn't appreciated before.

Daniel Tan:
Yeah, and I think this is also the key with some of the efforts that IASLC is trying to do is ensure that whatever screening effort that's going on around the world hopefully doesn't just happen in a silo and as much as possible to learn from the various experience and the nature of the nodules that may be screen detected. I think that ultimately will allow us, as I said, develop more rational guidelines moving forward. I think those are some of the key things, any other thoughts from WCLC, Dean and Melissa?

Melissa Johnson:
The only other thing I might add is I thought that there was some fantastic discussions around the idea of acquired resistance to immune therapy and I think the title of the session was 'Bench to Bedside' and I think that I was very encouraged by this meeting that we are moving beyond our current standard of care paradigms in real ways that will affect the longevity of our patients, and so I just over ... I can't say enough how much I enjoyed the meeting and I hope to get the opportunity to visit Singapore in real life one day.

Daniel Tan:
Yeah, absolutely right. That was the pat that was missing the most last weekend; it's having everyone in Singapore and certainly we really hope that we'll get a chance to hangout in Singapore in due course, so I think with that, let's wrap up. Thanks very much for the time and everyone stay safe. Have a good day.

Melissa Johnson:
Yeah, thank you.

Daniel Tan:
Bye.

Sign-up for our Newsletter!

Keep up to date with all the latest news with our monthly newsletter