HER2-Mutant Non-Small Cell Lung Cancer Podcast: Finding Patients (Episode 2)

00:00:00: You are listening to an ADIS journal podcast.

00:00:21: Welcome, to our listeners for a podcast.

00:00:25: Hurt of Mutant non-small cell lung cancer podcast finding patients.

00:00:29: I am Dr Vivek Subhaya medical oncologist chief of early phase drug development at the Sarah Kenner Research Institute Nashville Tennessee.

00:00:37: It is my pleasure and honor to welcome dr Martin Dreytreck Today For this podcast.

00:00:43: doctor Derek do you want to please introduce yourself?

00:00:47: Absolutely, thank you Vivek.

00:00:49: I'm Dr Martin Dietrich a medical oncologist with the US Oncology Network at the Cancer Center of Brevard in Orlando Florida and excited to be here today.

00:00:57: Thank You so much!

00:00:57: So Today The podcast is titled The Hurt To Mutant Nonchalant Cancer Podcast Finding Patients.

00:01:04: This Is Episode Two In Our Podcast Series.

00:01:07: this focuses on the critical challenge of identified patients With Hurtto Mutant nonchalants cancer.

00:01:13: We discuss why timely and comprehensive testing for herto mutations is vital to optimizing patient outcomes, how Nexen sequencing and molecular profiling are integrated into clinical practice.

00:01:26: This episode covers the practical aspects in evolving standards of herto mutation testing including use of tumor & liquid biopsies and addresses real world barriers such as cost access and awareness.

00:01:41: we also explore potential solutions, like reflex testing and collaboration with molecular pathologists to overcome current diagnostic challenges.

00:01:51: This episode emphasizes the importance of accurate an early molecule diagnosis in ensuring patients receiving the most effective personalized therapies as a treatment.

00:02:04: landscape for how to mutant non-small cell on cancer continues.

00:02:12: Let's talk about what we spoke in our previous episode.

00:02:16: The previous episode discussed how herto mutant non-small cell lung cancer represents a distinct, aggressive and challenging subset of lung cancer that requires specialized targeted treatment.

00:02:31: Here

00:02:32: We discuss when Who?

00:02:35: And How to Test for Herto Mutations In Patients with Non-Small Cell Lung Cancer.

00:02:42: So let me pose this question to our expert here, Dr.

00:02:46: Martin Dietrich Why is testing for her two mutations essential in non-small cell lung cancer and when should it be done?

00:02:55: Well just take a step back When we test the non small cell lung answer which has really a very diverse genetic field of opportunities.

00:03:04: Hurture mutations is only part of the broader panel, so we don't specifically test for her too but really want to offer every patient with a non-small cell lung cancer diagnosis independent stage or histology an opportunity for testing.

00:03:17: Herture mutations are obviously captured in the approach to molecular profiling off disease and I think it's important to identify these early events that are critical in the development and propagation of cancer before we even start thinking about therapy selection.

00:03:35: So, we want to get this done as part of diagnosis process for non-small cell lung cancers.

00:03:39: It's really very easy to find a best evidence based approach once you have full understanding stage and molecular setup In addition obviously patient specific factors.

00:03:49: so it has to be done at their first step Next generation sequencing done by liquid and tissue biopsy up front.

00:03:58: This is part of the guidelines we've seen in many studies including those that you have participated at MD Anderson, if we can currently provide these testing approaches up front.

00:04:08: We are faster and more comprehensive in many ways beneficial to patient treatment.

00:04:13: so really want focus upfront but do understand.

00:04:17: molecular profiling is a multi-layered approach which requires DNA, RNA and protein analysis with the of alterations here need to be understood from the very beginning.

00:04:31: And they should be tested and retested up on progression, obviously the undergo genetic evolutionary processes.

00:04:37: When we see her two mutations or overexpressions, we can match patients to target therapies in addition to the standard chemotherapy approaches that we have with both tyrosine kinase inhibitors than antibody drug conjugates so identifying them most options for patients medicine.

00:04:57: Thank you so much again.

00:04:59: the message is loud and clear.

00:05:01: lung cancer is a postage site for precision oncology, Again my personal belief is that you know for every patient with non small cell lung cancer.

00:05:10: we need to do comprehensive next-gen sequencing testing at diagnosis.

00:05:15: That includes herto mutation testing With all the genes So We can't guess.

00:05:19: but we Need To Do NGS Testing For Herto Mutations Should Be Carried Out An Initial Diagnosis Of Lung Cancer particularly since herto mutations have demonstrated strong response to targeted therapies such as directs and kinase inhibitors, and antibody drug conjugate.

00:05:35: This means that patients can get effective treatments earlier in the course of their

00:05:40: disease.".

00:05:41: Thank you so much!

00:05:41: So let's talk to Martin about how are herto mutations detected?

00:05:48: Can I

00:05:56: think there are a number of technical aspects to the detection up front and i think one other nice ways that we've understood next generation sequencing is really not looking for specific aspect.

00:06:10: the HER-II alterations, we know that there's a number of different classes of HER-III alterations that are oncogenic and likely actionable.

00:06:20: The most important ones obviously the intercellar kinase domain mutations themselves.

00:06:24: they increase affinity to ATP and induce configurational changes that activate their process.

00:06:30: but we really need technology that covers transmembrane in extracellular kinase domains mutations as well.

00:06:36: so this is an addition too with information from all genes if you can test one assay.

00:06:41: the next generation sequencing is really these standard of care and really supplanted single gene testing for patients here, for analysis.

00:06:50: We need from the very get-go identify the best sample sites.

00:06:55: I think Imaging up front is very helpful to get sites of biopsies that are reliably accessible.

00:07:03: We want to get as much tissue as possible, there's never going be a shortage.

00:07:06: both for standard-of-care practice and clinical trial the availability of sufficient sample is critical And then we obviously wanna handle this sample with diligence To ensure if you have histological diagnosis it still important But less and less so without the information that we get from molecular profiling.

00:07:26: So getting DNA in RNA sufficient samples is really critical, We can get a DNA from the bloodstream.

00:07:33: I think there's some approaches.

00:07:34: they will also try to select some RNA form The Bloodstream as very short lived low quantity kind of extractions or DNA From the Bloodstream.

00:07:42: it's Very helpful but the DNA snippets that we detect from cancer are different DNA fragments that we can get from a tissue biopsy.

00:07:51: It actually lends itself very well for small mutations like in HER-II, so liquid biopse probably are very similar to EGFR and the detection of liquid biopsy here.

00:08:03: I think for fusions or higher molecular alterations it may be more challenging And i think its not liquid versus tissue promise of being less invasive, maybe less side effects for the patient.

00:08:17: It'll capture different sides of disease that are probably more homogenous in beginning treatment and obviously faster turnaround time is not just a theoretical feature but it also leads to an accelerated time to starting a treatment.

00:08:30: So this complements each other very well, so it used to be tissues versus liquid.

00:08:36: I think at this point we are really seeing that they're complementing accessible way of getting liquid biopsies.

00:08:48: And we do want to get two more biopsys, I think this is not going to be replaced anytime soon but liquid biopsy really belong and the guidelines now include the liquid biobsies in a concurrent fashion as a diagnostic testing option to enhance the diagnostic accuracy and therapeutic decision-making.

00:09:04: i think that's a clear practice pattern...I wouldn't make the stage dependent anymore.

00:09:09: precision medicine has reached um the metastatic space surgery after radiation, so it can be done reflexively on every patient without ever over-testing a patient.

00:09:20: I think information here is power and we should exploit both technologies liquid NGS and tissue NGS plus the immunostechemistry as way to fully characterize their cancer really have very detailed discussion with our patients about what options match their tumor biology in best ways.

00:09:36: Thank you so much well said!

00:09:37: The message is loud and clear here.

00:09:40: Nexen sequencing is recommended for all patients newly diagnosed with advanced non-smartal lung cancer to inform optimal therapy.

00:09:49: The goal standard for Nexen sequencing, is tumor biopsy providing high quality reliable DNA samples directly from the tumor.

00:09:57: Liquid Biopsy is emerging as a crucial complementary tool for nexon sequencing.

00:10:03: so although tumor biopsies are still preferred method of initial diagnosis and comprehensive molecular profiling many clinics are integrating liquid biopsy into initial testing concurrently in parallel with tumor biopsies to enhance diagnostic accuracy and therapeutic decision-making.

00:10:23: So, let me ask the next question where we were talking about uh...the Next Generation Sequencing.

00:10:30: so Martin how do you think next gen sequencing is utilized in clinical practice?

00:10:37: This is to discuss of next generation sequencing.

00:10:43: Well, I think in all fairness when i look at the evolution of next-generation sequencing it was very clear that precision medicine with its twenty year track record has had a delayed implementation.

00:10:54: I think there are many factors to explain.

00:10:56: initially we have problems getting coverage through insurances access and sometimes they were lack understanding importance for precision medicines but did have the advent of immunotherapy captured many subtypes non-small cell cancer quite helpful.

00:11:10: so our testing patterns weren't really sufficient.

00:11:13: We saw in many real-world evaluations a biomarker testing pattern in the US of about fifty percent or patients that were diagnosed with non-small cell lung cancer between twenty eighteen and twenty twenty, I think there are Yeah, initiatives to enhance testing and really make this a hard stop in the guidelines both an NCCN and ASCO.

00:11:37: We really can't match our guideline recommendations without next generation sequencing.

00:11:41: we have seen the introduction of liquid biopsy in twenty-twenty three for her two mutations as part of the broad molecular profiling.

00:11:49: parents who probably had them before but it wasn't really relevant because major treatment, so the HER-II mutation testing has gotten significantly better.

00:11:59: I think that numbers are showing there's not optimal.

00:12:02: we really need to get as close to a hundred percent possible and i would say for practical purposes uh... one hundred percent liquid biopsy testing is available.

00:12:11: every patient may not have tissue on every patient in sufficient quantity but this should be routinely included.

00:12:17: four treatment now then they have hurt who you really needed.

00:12:20: understand that at the heart of mutation detection is the first step.

00:12:24: Translating this and contextualizing into the disease space, using it for best implementation of her two-directed therapy is sort of next frontier to ensure that education reaches all our colleagues.

00:12:37: That they know herd humitation testing now much more relevant than a few years ago with non-small cell lung cancer.

00:12:45: Thank you so much again.

00:12:46: how we need to do comprehensive sequencing at diagnosis for every patient with non small cell lung genomics is the diagnosis.

00:12:57: Then her too.

00:12:57: mutation testing was added to the NCCN recommendations in twenty-twenty three as a part of the broad molecular profiling, so her to mutation testing not often routinely performed and clinical practice partly due to historic lack of heterodirected therapy.

00:13:13: now we have heterodirecter therapies for this deadly disease.

00:13:18: So let's talk about how do you mutation right?

00:13:22: What are the current challenges with herter mutation testing in non-small cell and cancer?

00:13:30: Well, I think a lot of it is awareness.

00:13:32: The diagnostic guidelines have included her to testing in the guidelines now but there's still lack of awareness about how good options are for targeting her too and we discussed this on our first podcast that had discussion around antibody drug conjugates introduced by her two mutation subtypes.

00:13:54: also the arrival of tyrosine kinase inhibitors in non-small cell lung cancer matching the disease biology quite well and are actually very helpful.

00:14:04: We do have a concern about cost, next generation sequencing is an expense that can be perceived as expensive.

00:14:10: I think insurance coverage has gotten better but there's still some assays.

00:14:14: they cover more than fifty genes for example.

00:14:16: often times deemed to be experimental it may not be covered.

00:14:20: so this barrier in testing and lack of awareness on how the test here can be utilized because later development some of the original registrational trials we have did not include them specifically, or exclude them specifically like you see for EGFR and Alex.

00:14:37: So it is sort contextual development of data that we need to appreciate here, but it is now standard-of-care.

00:14:45: It's the biological central feature of disease when we see our herd two mutation and really determines disease biology.

00:14:52: It helps us lean on the EGFR experience as a lot of biological clinical overlap.

00:14:58: so detecting these mutations is critical.

00:15:03: There are challenges with herd mutation testing, so can you comment on how oncologists working in community settings might integrate or access such testing if not routinely available?

00:15:15: It

00:15:18: really depends on the individual practice setting.

00:15:20: I think we have help from the electronic or medical records in our network, We have an automatic prompt to order these tests if not already done by a reflex pattern?

00:15:30: I think where at time and precision medicine when we can take this back To our pathology colleagues and talk about the ubiquitous need for testing and really stress The idea of after identification of a non-small cell lung cancer diagnosis And two reflex test four next generation sequence.

00:15:47: I think this is now most appropriate in cases where systemic therapy is considered.

00:15:52: Really very few exceptions to that rule, and the early disease space maybe when we don't consider systemic therapy.

00:16:00: but i do think it's important And I think thats how data connects with guidelines.

00:16:05: if you develop a pattern of testing Where we utilize external help reference laboratories Also there are utilization of external help through molecular tumor boards of therapies, that we can develop testing patterns and treatment patterns in the community setting.

00:16:22: That really allow us to provide the best standard of care in any geography.

00:16:26: I think those resources are now available And we should really exploit them!

00:16:31: The obstacles have gotten smaller for use.

00:16:34: It's got more complicated but i think it has a positive side effect on having more options.

00:16:40: Thank you so much again!

00:16:41: I see that way with NDS panels and companion diagnostics are increasingly supported through accelerated pathways.

00:16:49: However, as you said reimbursement remains uneven especially outside major academic centers.

00:16:55: so we really need policy advocacy and pilot programs here And again.

00:17:01: there were several programs that enable community oncologists for expert interpretation.

00:17:08: The good news is beyond the niche boutique academic centers across a community, I think that commercial labs and commercial sequencing companies offer scalable solutions for integrating next generation sequencing into clinical workforce.

00:17:25: So work force and workflows training in next gen sequencing interpretation on access to molecular tumor boards as you said are critical for confident test utilization.

00:17:38: again this cannot be underestimated.

00:17:41: here, I think we need to have a genomically fluent workforce so that we can use and at least all these precision medicines in the future.

00:17:52: So Martin what can be done to overcome the challenges specifically with herto-mutation testing?

00:18:02: Yeah i think if the adoption of reflex testing would be critical.

00:18:12: I think this will accelerate that time to treatment, it'll make their first visits for non-small cell and cancer patients more meaningful because oftentimes we don't have molecular profiling in cannot make any significant recommendations.

00:18:26: so... The Reflex Testing is really a process initiated by the pathologist supported or requested by medical oncology.

00:18:33: So there's a multidisciplinary component immediately up on detection of a non-small cell lung cancer diagnosis.

00:18:39: And again, I would stress that this is independent of histology.

00:18:42: while we see an enrichment in certain mutations and adenocarcinomas.

00:18:46: We do see many mutations in squamous cell carcinomas to transcend from adenocarcinomas or have the unique subset for which research investigations are quite interesting?

00:18:55: And we wanna really offer patients both standardive care and research developments in the non-Small Cell Lung Cancer Subset.

00:19:03: The expedited way of obtaining this process here is important for the capture of all mutations and genomic alterations, ensure timely treatment decisions.

00:19:13: The molecular pathologists oftentimes they come from reference labs may be helpful partners in consultants interpretation.

00:19:20: these results particularly helpful.

00:19:23: healthcare providers that make cover a broad array disease spaces not have academic support network as you were mentioning.

00:19:31: those are great resources to in the community.

00:19:38: The HERTU mutation comes reflexively, I think this is now clearly integrated and that technology certainly has gets linked to more and more treatments that are emerging within the HERTU mutant non-sponsor lung cancer space.

00:19:55: It's also important to be able go back prior tumor samples if necessary, either review reports of available or add on additional biomarkers when they were tested initially.

00:20:06: so we really want have a current part.

00:20:09: obviously programmatically speaking you could get liquid biopsy see what the current state is even without requiring additional sample but always make sure All the options are available and tested for at a time that patient is receiving treatments.

00:20:21: If a patient had surgery year ago, certain mutations weren't linked yet to their respective treatment opportunities we really want address it with laboratories seeing if they have everything covered because maybe this may be best option of patients who haven't been highlighted in reports or data but hasn't been updated.

00:20:43: so these look-backs are critical.

00:20:46: have the best set of data available to make a decision treatment at each point.

00:21:16: especially exon-twenty insertions, develop and adopt her to specific immunocisteric chemistry scoring system tailored for non-smartial cancer that reduce variability in the interpretation.

00:21:28: Number three expand use of liquid biopsy for patients with limited or poor quality tissue samples.

00:21:34: circulating DNA CTDNA testing offers a noninvasive alternative.

00:21:40: this is specially useful for monitoring disease progression.

00:21:43: are even finding resistance mutations?

00:21:45: number four The most important one, educate the healthcare provider teams and train them.

00:21:54: Provide training on recognizing herto alterations in non-small cell lung cancer.

00:21:59: We also need to ensure collaboration with molecular pathologists to interpret complex or ambiguous results.

00:22:08: Rebiopsy Retrospective Testing.

00:22:13: archived tumor samples for HERTU mutations, especially when new targeted therapies become available.

00:22:18: They can identify patients who were previously untested or misclassified.

00:22:23: Number six, integrate testing into clinical workflows.

00:22:27: Embed HERTUTesting into standardized diagnostic panels for lung cancer.

00:22:31: ensure that HERTUDesels are available before treatment decisions made.

00:22:38: Finally finally again here I would make a personal plug encourage enrollment in clinical trials for non-small cell and cancer.

00:22:48: Again, that's very important because as a field we have done lot of the last decade but we had to do much more.

00:22:57: So thank you so much Dr.

00:22:58: Martin Dietrich for being here.

00:23:01: In conclusion several targeted therapies including tyrosine kinase inhibitors and antibody drug conjugates are becoming available and have shown promising results in her to mutant non small cell lung cancer.

00:23:13: Comprehensive genomic profiling at the time of lung-cancer diagnosis is essential, to identify patients with her to mutations so that they can receive treatment appropriate for them.

00:23:27: Thank you so much!

00:23:28: Thank You So Much Everyone For Listening To This Podcast.

00:23:50: You can listen to more podcasts by subscribing to ADIS Journal Podcasts with your preferred podcast provider, or by visiting the journal website.

00:24:00: For a full list of declarations including funding and author disclosure statements and copyright information please visit article page on the journal web site.

00:24:10: The link for the article page is found in the podcast description.