Lizza Hendriks:
Hello, welcome from WCLC 2022 in Vienna. I’m Lizza Hendriks. I’m a pulmonologist from Maastricht, Netherlands. And I’m joined by Tiziana Vavala, medical oncologist from Italy.

Lizza Hendriks:
It’s only the second day of the WCLC, but we have already heard some quite interesting topics we’re going to discuss. So we want to discuss the NADIM data, the update, several KRAS G12C data, and also the concept of oligometastatic disease. Thank you for listening.

Lizza Hendriks:
So, Tiziana, the NADIM trial, can you tell me what’s interesting?

Tiziana Vavala:
These days, it was a great day to discuss, but what do we want about neoadjuvant treatment? Particularly for those patients who do not respond to treatment in a neoadjuvant setting, because today we know that more than 15% of patients do not respond to neoadjuvant treatment. And the idea to have an immunosignature about their progression could be useful for us, for two reasons. Particularly, how to choose adjuvant treatment those kind of patients, if they don’t go to surgical resections. Or how can we use RT on mediastinum, particularly for those patients who can have a surgical resection. Considering that Lung ART trial suggest, do a non-extensive use of RT on mediastinum. So this has been an interesting session, I think.

Lizza Hendriks:
I think it’s also a challenge. So we know that those with the pathological complete response on neoadjuvant chemo immuno do very well. Those with a major pathological response, a little bit less, but some do very well. And usually those without a response do progress quite rapidly. But it would be very helpful to indeed have the signature, that can stratify these patients, and also identify the resistance mechanisms so that you can develop new treatments. And I think NADIM was a small sample size. I think only 36 patients analyzed, but at least some immune findings were there, suggesting how to look further. So for example, AKT seems very promising to target.

Tiziana Vavala:
And particularly we have to think also that… Also for non-responders patients, PFS is longer, is good. So we need to think also how to improve also in non-responders patients, this kind of treatment, after a local treatment.

Lizza Hendriks:
Fully agree. And indeed, avoid toxicity. So you were already talking about Lung ART. I think local relapses, they really decreased, but high risk of cardiotoxicity. We know radiotherapy acts synergistically with immunotherapy. So it could be with new radiotherapy techniques that these patients would get benefits without a toxicity. So it’s something really to explore, and hopefully to be informed with signatures that can select patients.

Tiziana Vavala:
Yes. It’s just a new kind of way to see well known things. Because new techniques about radiotherapy can lead us to improve results about immunotherapy in these kind of patients. We have to wait and research.

Lizza Hendriks:
True. In the end we need randomized clinical trials probably. But I think it’s very hypothesis generating to hear these data.

Tiziana Vavala:
Yeah. Yeah.

Lizza Hendriks:
Okay. And I think we also had interesting data about KRAS G12C. So in Europe, one approved small molecule, sotorasib. Based on Phase II data, FDA add that as a breakthrough designation. I think response rates quite similar to sotorasib. Toxicity profile a little bit different. But in the end we need to improve. We don’t see the response rates we see, for example, with EGFR and OTPI. And we also don’t see the medium PFS, the duration of response. So I think probably we need either new small molecules or combination treatments. And what were your takeaways from that session?

Tiziana Vavala:
I think that KRAS biomarker… Lizza, I don’t know if you have the same thinking about this, is a incredible biomarker. Because it’s completely different from EGFR, ALK. I think it’s really challenging research about this kind of biomarker. Because we have a small molecule that works, but with other response, as you said, not so great. But we can decide to associate this small molecule with new molecule SHP as one of this, or with immunotherapy. And so different things such as responses, but also great toxicities that lead to different kind of approach such as not concurrent, but leading approaches with immunotherapy or reductions of doses because of increasing toxicity. We are learning about this biomarker still.

Lizza Hendriks:
And I think if we look back at what we know from EGFR and ALK TKI combined with immunotherapy in general, it was quite toxic. So interstitial lung disease, hepatitis. Also, there are some real world sotorasib data. If you give it after immunotherapy, the incidence of hepatitis is quite high. So I was quite interested in the data, the Phase I data with sotorasib and either pembrolizumab or atezolizumab, and they try different combinations, different doses lead in. And I think my takeaway was that it’s still difficult to combine. I think the hepatitis was still quite a problem.

Lizza Hendriks:
It seems that the most feasible approach is a low dose sotorasib lead in and then immunotherapy, but still then it’s challenging and it’s Phase I. So I would really like to see more data about toxicity, but also responses and duration of response. Because around two third of patients got previous immunotherapy, and around 40% had the last line of previous treatment was immunotherapy. So you’re not quite sure if you look at responses, PFS, these type of things, what was the role of the combination, or what was the role of the immunotherapy monotherapy and treatment if patients are to rechallenge? So I think pre-clinically very interesting. For clinical practice still quite challenging for me, the immunotherapy.

Tiziana Vavala:
And for me, the idea is that we really don’t know if this toxicity could be maybe a drug-related toxicity, if adagrasib which is going to be the next drug in KRAS-mutated patients could have well tolerated profiles. So we have to wait and about… And search about particularly these Phase I trials.

Lizza Hendriks:
Yeah. I think also the SHIP II data were interesting, so sotorasib combined with a new SHIP II inhibitor. But I think it’s still Phase I. So the toxicity profile is less favorable than with monotherapy. I think the response rates were at least higher than with monotherapy, but I think you don’t really know whether this would be the way to go forward for all patients. Whether you would have a biomarker selection and whether in the end it’s Phase I, if the response rates will be the same in bigger trials with more patients. But I think it’s an interesting combination again.

Tiziana Vavala:
Yeah. And then we have to think to sequencing these kind of patients. Because we have to decide if one drug associations or immunotherapy before or after, or new drugs could be the best choice for our patients. I still don’t know this.

Lizza Hendriks:
I think there were also data about new KRAS G12C inhibitors. So the GDC compound, I think again, early phase, and you cannot compare clinical trials with each other, but if you looked at the highest dose level, the majority of the patients had a response. So I think it’s quite interesting, but again, low number of patients, and we need to see more data. But I think for me, that was also quite promising.

Tiziana Vavala:
Yeah. And a good number of patients to have the possibility to decide, to study, and decide what could be better for them.

Lizza Hendriks:
I think maybe a takeaway, it wasn’t mentioned at the conference is, but I think biomarker testing really should be done by all patients. And there are quite some data, for example, from the US that only two third of patients get biomarker testing. But also for physicians in daily clinical practice, look back at your patients. So if you have a patient treated with immunotherapy two years ago, and maybe at that time, you didn’t have anything for KRAS G12C so you didn’t write it down, you didn’t note it, look back for all your patients. Check whether all biomarkers were evaluated, and whether the patient had a KRAS G12C mutation.

Tiziana Vavala:
And it is important that KRAS has to be the standard in biomarker testing, as well as EGFR, ALK, BRAF, is not so simple. We have to have all the testing biomarkers for all the patients at the right moment.

Lizza Hendriks:
And if you didn’t do it before, because it was not relevant, go back to your tissue and test, or liquidnbiopsy also possible, but really you need to test. I think also for the future, it was a little bit addressed in that session is that patients with KRAS mutations quite often have brain metastasis. [inaudible] we have some data from ESCO a couple of months ago. Response rates in the brain were around 30%. Sotova said we don’t have data yet. But as these patients quite often have brain metastasis, we need to have CNS-penetrating drugs with also long duration of disease control in the brain.

Tiziana Vavala:
But now for adagrasib we have six patients with a great control rate, 10%. 100% old patients control rate on brain, and awaiting results for sotorasib. But we have to improve also this kind of evaluation, because we need for radiotherapy also these patients in immunotherapy. So we are here.

Lizza Hendriks:
Awesome, true. So still lots of things to evaluate. And I think another topic, it was not in an abstract session, but in a plenary session. And I think it’s hot. It’s oligometastatic disease. The more you talk about it, the more difficult it becomes.

Tiziana Vavala:
Just in the same place.

Lizza Hendriks:
And I think oligometastasis… Yeah, it’s a few metastasis, but I think there are multiple definitions. If you look at clinical trials, some trials count the primary, some trials count the mediastinal lymph nodes, some trials allow patients with up to three metastatic sites, others say it’s six metastatic sites. And if you look at daily clinical practice, most patients enrolled in a clinical trial only have one or two metastases, and usually don’t have documented mediastinal disease. And I think quite some interesting concepts were discussed at the plenary. So indeed, should we count metastases? Should we look at the volume? Should we look at the type of oligometastasis? Is it synchronous? Is it induced? Is it metachronous? Does the type of location of the metastasis matter? If you have a patient with widespread metastasis and the patient responds very well to treatment, maybe that patient will do better with an induced oligometastatic state than a patient with upfront oligometastasis. So what were your takeaways from that session?

Tiziana Vavala:
I think this is a very challenge… It has been a very challenging session because it’s too simple to number metastasis. What if we think to four metastasis than three? What the difference? We have to think to the volume, but we have to think to the kind of prevention of those patients. We have to think if they are oncogene-addicted patients, we have to think to a lot of thinking in the era of immunotherapy also for oncogene-addicted patients, for different biomarkers such as KRAS, such as BRAF. These patients, these diseases are completely different. And we need to discuss for every patient the right approach. And don’t forget that we have to think to all disease, and not just the number.

Lizza Hendriks:
True. And even I think for immunotherapy, we know that some patients have very long term disease control without any local radical therapy. So these patients, you would probably harm with adding radiotherapy or surgery with a risk of the morbidity or even mortality, long term toxicity. And we don’t know yet. So I think it’s a complete new area of clinical trials. And I think one of the first steps is indeed applying all the definitions. But also to be flexible and with new resource, new data. And that’s what you’re doing.

Tiziana Vavala:
Yeah. I think this is one of the low times that we have not to start necessarily from the definition, but from the patient, this kind of disease.

Lizza Hendriks:
And that you have, I think… That you evaluate one concept in the clinical trial, and that you don’t put all the patients with different types of oligometastatic induced whatever disease into one trial, but that you really define the patient population you want to evaluate, and also focus on long term endpoints and toxicity.

Tiziana Vavala:
And then a priority manner in this kind of study is fundamental.

Lizza Hendriks:
True. And imaging. I think that wasn’t discussed a lot. It was only in the consensus definition. But if you look at the clinical trials that have been performed, I think if you look at oligometastatic disease, you should do brain MRI. You should do a dedicated PET. You should evaluate the mediastinum if necessary. If it influence your treatment, have pathological proof of metastasis because you know a PET scan can be false positive.

Tiziana Vavala:
Yeah. So can confirm that invasive is on mediastinum too in these kind of patients is fundamental.

Lizza Hendriks:
Yeah. So I think so far WCLC is very interesting. It ranges from early disease, like neoadjuvant therapy, and IDing biomarkers, to molecular analysis, new targets, which we thought they were undruggable for long. And now we have multiple new options being evaluated. And also the concept of oligometastatic disease. We approached it very easily, one definition. And I think that’s not true, and it will become as complicated as the treatment of oncogenic drivers, or immunotherapy resistance. But I think it’s promising and very interesting.

Tiziana Vavala:
Thank you. I think just another thing. The multidisciplinary approach is now more than ever fundamental. We have to go further on.

Lizza Hendriks:
Yeah. Fully agree and very good closing.