HER2-mutant Non-small Cell Lung Cancer Podcast: Knowledge Is Power (Episode 1)

00:00:00: You are listening to an AIDIS Journal podcast.

00:00:21: Hello and welcome today's podcast, Knowledge is Power.

00:00:25: Heard the mutant non-small cell lung cancer?

00:00:28: I'm Vivek Subhaya, medical oncologist and chief of early phase drug development from the Sarah Cannon Research Institute in Nashville Tennessee.

00:00:35: Welcome everyone!

00:00:37: Today we have Dr Martin Dretrich and Dr Zunand Lee.

00:00:41: Dr Dretich and Dr.

00:00:42: Lee can you please introduce yourselves?

00:00:47: This is Shining Li.

00:00:48: I'm an associate professor at MD Anderson in the department of thoracic medical oncology and also deputy section chief, but... ...I am really glad to participate today's

00:01:06: episode of Knowledge Is Power.

00:01:06: Hello!

00:01:06: Dr Martin Dietrich, I'm a Medical Oncologist at U.S.

00:01:09: Oncology Network with Cancer Cancer Center Provide in Orlando Florida.

00:01:13: Thank you so much.

00:01:14: it was a pleasure and privilege having both.

00:01:17: Today, we are going to have a herd-to-mutant non-small cell lung cancer overview.

00:01:23: Knowledge is power!

00:01:24: In the first episode of our podcast series We introduced the emerging landscape of her to mutant non small cell and cancer Highlighting its place within the broader context of non smaller lung cancer.

00:01:35: We explained what makes her two mutant non smaller than cancer unique from it's Epidemiology and biology to molecular mechanisms driving cancer growth.

00:01:46: We discussed the evolution of precision medicine in non-small cell lung cancer, and how advances in molecular profiling have enabled the development.

00:01:58: The episode also covers the latest treatment strategies including antibody drug conjugates and tyrosine kinase inhibitors.

00:02:12: This podcast aims to enhance understanding of her-to mutant non small cell lung cancer and the evolving therapeutic landscape that is reshaping management strategies for this aggressive and deadly disease.

00:02:29: All right, so you know.

00:02:32: after this brief introduction I'd like to open up.

00:02:36: You know the floor For discussing about.

00:02:38: You know what is non smaller than cancer.

00:02:41: again can doctor?

00:02:43: Lee, can you give us a brief overview of lung cancer the cancer related deaths and why her to float as all yours?

00:02:52: Thank You Dr.

00:02:53: Sabaya.

00:02:55: So long cancer is The most common cause Of death related To cancer worldwide And also in the US.

00:03:04: Really Is beyond prostate beyond breast and the colorectal and GI modalities.

00:03:10: now is a leading cause of killer for all cancer patients.

00:03:15: Non-small cell lung cancer is the most common type of lung cancer.

00:03:20: Over eighty five percent of long cancer belong to non small cell lung cancers.

00:03:25: In US, it's estimated around two hundred thousand new cases diagnosed per year and globally over a million cases diagnosed.

00:03:38: We have to say that non-small cell lung cancer in the treatment landscape has made a lot of progress.

00:03:44: In the last decade or so, especially into area one is we start to understand what are the oncogene drivers and they started will have precision oncology targets that we can actually target.

00:04:01: those drivers therefore render patient.

00:04:05: So that's on the targeted front.

00:04:08: We also have introduced immunotherapy checkpoint blockade, That area also transformed our management landscape making sometimes even the lung cancer become a chronic disease.

00:04:24: Focusing today we will be talking about her tube which is an oncogene driver so belong to group that we're talking about really moving position oncology forward.

00:04:38: HERTU is a normal gene in our body, belongs to the ERBB family.

00:04:46: but uh...in two thousand four about twenty years ago there are publications identifying if the gene goes wrong for example having mutation or insertion or amplification, that genetic event can lead to oncogenesis making the cell grow like no stop.

00:05:05: Therefore her two signaling aberration becomes a oncogenic pathway that is worth for us to think about.

00:05:14: targeting in twenty-twenty five as we're here today with start will have targeted therapies for this group of lung cancer.

00:05:23: Wow, thank you so much for that overview of non-smart cell lung cancer.

00:05:27: Again I would say in the last decade we've had over ten different oncogene drivers being targeted in lung cancer and lung cancers clearly become the postage child for precision oncology.

00:05:41: again a Martin focusing on her too can talk to us about how they drive cancer growth?

00:05:51: Yeah, so there is a number of features.

00:05:53: nothing that you've already touched a little bit on this her two.

00:05:55: It's very complex and member of the her to or or BB family.

00:06:02: This is obviously first introduced, I think this was our first segue into precision oncology via the epidermal growth factor receptor.

00:06:09: Our first actionable gene and much more common mutation in these receptors really have key roles in regulating cell growth survival and differentiation by activating a whole number of downstream signaling pathways that are important here.

00:06:30: achieve a state of ligand independence.

00:06:32: So some of the auto regulatory mechanisms are going away, we see downstream activation Hereto overexpression probably not as important.

00:06:41: in osmosis lung cancer was first identified.

00:06:44: It drives cancer growth and many disease spaces, first in breast cancer but we see it in many others as well.

00:06:51: We see an increase in dimerization And we see here both HOMO and heterodimerization within the ERP-BV family An activation of downstream autophosphorylation, leading to a continuous signaling of the pathway that then leads to uncontrolled oncogenic growth.

00:07:08: There are three main principles of HER-II activating mechanisms and I think the mutations are most relevant.

00:07:14: we're seeing in non small cell lung cancer.

00:07:17: In this case, the HER-III mutations are different from the mutations we see in EGFR.

00:07:22: We have distribution which is very rare at EGFR but as you can see here exon-twenty insertion mutations, we can see gene amplifications or epigenetic events that lead to protein overexpression.

00:07:37: And each of them are very biologically distinct and need different treatment approaches for cancer.

00:07:43: they may not overlap in the way they execute their signaling but it's important.

00:07:53: The overexpression, and I think this is a question of how we define it.

00:07:59: We currently have an HER-II overexpression label for three plus biminoster.

00:08:02: chemistry can vary greatly between the different subtypes.

00:08:06: as you see incidence here somewhere between seven and twenty-three percent um...the amplifications may have some overlap between them.

00:08:14: so we see a broader spread here as well between two to twenty-two percent uh...of non-small cell lung cancers And further her to mutations that we see here mainly again their HER-ii X on insertion mutations.

00:08:26: We also see extracellular domain mutations, as well as transmembrane domain mutations are present in around two to four percent of non-small cell lung cancers and here obviously enriched in the adenocarcinoma subset.

00:08:40: Wow!

00:08:40: How much we have learned about her too?

00:08:43: In the last few decades.

00:08:45: again for broad listeners listening today's in essence right there ways in which HER-II can be activated, not just in non-small cell lung cancer but many cancers.

00:08:56: One is the gene mutation number two is gene amplification and three protein overexpression.

00:09:02: Gene mutation and gene amplifications are detected by what we call as comprehensive next generation sequencing whereas the protein over expression is detected for clinical trials of this specific test called immunohistochemistry.

00:09:19: And again, as Martin clearly outlined it is you know for lung cancer and many other cancers the immunohistochemistry.

00:09:26: It has to be scored IHC three plus.

00:09:30: so Again a lot we learned in the last two decades about her too.

00:09:36: So talking About Her Too Honing In on Dr.

00:09:41: Zunin Tapping To Her Knowledge & Insight.

00:09:46: How do you think herd to mutant nonce monster lung cancer differ from other types of lung cancer?

00:09:50: Oh, yeah.

00:09:51: Thank You Vivek.

00:09:53: So her too just like Martin was explaining earlier Her two is a family member of ERBB.

00:10:01: family Is basically ERBB-II.

00:10:05: The more familiar target ERBB one is EGFR.

00:10:11: We already know EGFR mutation occurs in NOSMO cell lung cancer around, depending on the region anywhere between fifteen to fifty percent of long-ardinal carcinomas.

00:10:23: So her two mutations actually have a lot of similarity compared to EGFR.

00:10:30: From patient characteristics we've seen her two mutations occur more common in ardent carcinoma occur more common in female patients who never smoke cigarettes, and occur in patients or little younger than the US population of initial diagnosis of non-small cell lung cancer.

00:10:53: The initial diagnosis age sometime is between fifty five to sixty.

00:10:59: so I have to say that this a very devastating disease as you can tell person who never smokes cigarette, thinking their risk is very minimal.

00:11:10: However this disease can just all of a sudden happen.

00:11:15: related to that her two mutation non-small cell lung cancer also have usually an aggressive disease course.

00:11:24: at the time of initial diagnosis.

00:11:27: significant portion patient anywhere between fifteen to twenty five percent already has three metastases.

00:11:35: Therefore, I think trying to make sure that we understand each lung cancer at the initial diagnosis is quite important.

00:11:43: To identify her to mutation as a driver.

00:11:47: also looking back into Martin's earlier discussion and of course your summary The other two type of her to alteration overexpression amplification have different behavior, meaning that oftentimes it happens with her to mutation but sometimes they don't.

00:12:08: so we need to distinct those two different types and then make sure we offer the right treatment based on the right genetic alteration.

00:12:18: Thank you very much!

00:12:19: So again explain why precision medicine in lung cancer?

00:12:29: So, I think what you are truly alluding to is her to now becomes a emerge as new target.

00:12:38: We know that it drives tumor growth we actually not finally have options to treat the patients right.

00:12:45: so if its an alteration or don't have any a good precision oncology method to help the patients, it's not as important us truly identify the patient and offer the right treatment matching the oncogene.

00:13:01: So we finally enter an era that we have different treatment options.

00:13:06: so the first possibility is targeted chemo, basically targeting HER-II.

00:13:22: That has been FDA approved for HER-ii mutation activating mutation non small cell lung cancer patient after initial treatment.

00:13:32: so using this position oncology approach we have seen really good response in around the fifty to fifty five percent trust to some other direct CTKM for this patient population.

00:13:47: Thank you so much!

00:13:48: So again, antibody drug conjugates are... Again we live in an era of antibody drug conjugate and small molecule inhibitors.

00:13:56: here they're essentially atrogen harsh right?

00:14:00: They combine a monoclonal antibody with chemotherapy and deliver these important chemotherapy payloads directly into the cancer cells like a drone.

00:14:10: So Dr.

00:14:11: Martin, so again can you contrast antibody drug conjugate and tyrosine kinase inhibitors?

00:14:17: And where do we use them in her to mutated non-small cell lung cancer?

00:14:23: Oh, absolutely.

00:14:24: I think there is a sort of difference in mechanism.

00:14:27: the antibody drug conjugates are more specific and their delivery compared to standard chemotherapy.

00:14:34: In addition to that we're also using topoisomerase inhibitor payload.

00:14:39: That is a mechanism that we haven't traditionally used than non-small cell lung cancer.

00:14:43: But it's a chemotherapy that Is probably targeting a more chemotherapy sensitive subset identified by they heard two mutations.

00:14:51: It's why we see these good response rates.

00:14:53: A tyrosine kindness inhibitor contrasts to that.

00:14:56: by really specifically targeting.

00:14:58: the mutational underpinning of cancer.

00:15:02: We are blocking ATP binding competitively through highly specific small molecules that are competing with ATP in their ATP-binding pocket, and thereby deactivating the main switch of cancers.

00:15:14: so it's a very different concept than we're targeting extracellular versus intracellulary here with the ADC and the TKI respectively and thereby exploiting type in its precision.

00:15:30: Obviously, the concern is with all targeted therapies that evolutionary mechanisms apply and resistance occurs through a variety of mechanisms we yet have to understand better.

00:15:42: but I think those are two options to exploit this same target in non-small cell lung cancer when properly identified.

00:15:49: Thank you so much for explaining it to our listeners.

00:15:56: ultimate precision medicine.

00:15:58: So here patients are less likely to be exposed to ineffective treatments, saving time resources and unnecessary side effects from chemotherapy.

00:16:07: so it's good to always have more options here.

00:16:10: .So we have a monoclonal antibody with chemotherapy that is an ADC.

00:16:14: in contrast ,we also have now this tyrosine kinase inhibitor directly inhibiting the intracellular domain of Tyrosine kinases appear to be most effective and tolerable group of agents directed at her to mutated non-small cell lung cancer.

00:16:33: Again, to our listeners we had an amazing discussion here with Dr.

00:16:38: Martin Dietrich and Dr.

00:16:39: Zunat Lee.

00:16:41: so what we learned from hear her to mutant non small cell on cancer represents a clear distinct aggressive and challenging subset of non smaller than cancer that requires specialized targeted treatment.

00:16:55: We are still learning a lot about the biology of lung cancer, biology of non-small cell lung cancer.

00:17:00: Biology of her to mutant lung cancer.

00:17:03: So The growing understanding of her two mutations in lung cancer is opening doors for targeted treatments and clinical trials.

00:17:13: Thank you so much for listening to this podcast.

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