Advancements in Targeted Therapy for Metastatic NSCLC


Shared insight into the transformative impact of targeted therapies in lung cancer treatment, from adjuvant therapy breakthroughs to emerging trials, emphasizing the critical role of comprehensive molecular testing.


Melina E. Marmarelis, MD: Speaking about financial challenges, these targeted therapies are moving into all different types of spaces. I’m curious, with recent data in adjuvant therapy and all these new targeted therapies coming out, how do you see this field of targeted therapy changing?

Charu Aggarwal, MD, MPH: There is just so much incredible change coming in the future. We have talked a lot about metastatic, nonsquamous, non–small cell lung cancer [NSCLC]. We’ve talked about both immediately actionable first-line agents and a couple of agents that are actionable in the second line. But imagine all of the patients in early stage that may harbor these mutations may be eligible for targeted therapies. We already have an FDA approval for osimertinib for EGFR classical mutations, patients with early-stage resected lung cancer. We have not only seen a disease-free survival benefit, but really for the first time in lung cancer, we witnessed an overall survival benefit that was presented at the ASCO [American Society of Clinical Oncology] annual meeting.

I mean, with a hazard ratio of 0.4 [and a range of] 0.2 to 0.5, depending on which subset of the population you’re looking at, it’s incredible. And it behooves us to ensure that we perform molecular testing across all stages and ensure that we deliver adjuvant therapies as indicated. But on the heels of the presentation at ASCO, just at the ESMO [European Society of Medical Oncology] annual meeting in October, we heard data from ALINA [NCT03456076], which is a large trial of adjuvant alectinib among patients with ALK-positive resected NSCLC. What’s curious about this trial is that they actually omitted chemotherapy, so they did not administer adjuvant chemotherapy and went straight to 2 years of adjuvant alectinib and found that compared to the control group, there was a fact that we saw the proof of concept in EGFR mutant lung cancer, but seeing these curves really reinforces the fact that we need to test for molecular alterations. I think moving beyond your adjuvant targeted therapy, some new trials are revealing to us that perhaps we can move some of our second-line agents potentially into the first line.

So, for example, for EGFR exon 20 insertion mutation, a very unique heterogeneous group of mutations, we tend to reserve targeted therapies such as amivantamab, which is approved for second-line use. But now, with data presented at ESMO in the form of PAPILLON, which was a randomized phase 3 clinical trial of the use of amivantamab with chemotherapy in the first-line setting, showing an improvement in PFS [progression-free survival]. I think, again, [it is] important for us to think about moving some of these agents. We heard data on KRAS G12C inhibitors along with immunotherapy in the first-line setting. So we can envision a future where many of these agents actually become threshed into our first-line paradigm. We heard data on HER2 DXd [deruxtecan]. This is an antibody-drug conjugate [ADC] looking at HER2-mutant lung cancer with significant improvement in response rates across the second line, but also clinical trial teasers that are evaluating this drug in the first line, either with chemotherapy or without. And finally, we are seeing an explosion of antibody-drug conjugates.

We are seeing that these drugs can actually penetrate the CNS [central nervous system]. We are seeing the intracranial efficacy of drugs such as HER3 DXd. And now with immediate approvals, potentially of Trop2 ADCs, I think we’ll just have so many different options. And I think the field is just growing at a pace that we almost can’t keep up.

Melina E. Marmarelis, MD: And ADCs almost bridge these 2 worlds. They’re semitargeted, and also, some chemotherapy. Our buckets are mixing a little bit here. So it’s definitely exciting. Also, I think [it] highlights the importance of molecular testing, both in the metastatic and the early stage, as we’re certainly going to see more drugs move into the early stage to target these alterations in the adjuvant setting.

Charu Aggarwal, MD, MPH: Absolutely. As we close, what clinical pearls would you share with oncologists in the community as well as in academia for both testing and treating patients with lung cancer today?

Melina E. Marmarelis, MD: Well, that is a very big question, but I think the main message is certainly the importance of molecular testing and looking carefully at the type of molecular testing that is done—in particular, does it have DNA next-generation sequencing and an RNA component?—and also really pushing for concurrent testing. I’m certainly a believer in concurrent tissue and liquid testing, and that gives patients the best chance of being eligible for one of these targeted therapies that’ showing survival benefits. I think fighting for that and pushing for complete molecular testing will really lead you to the best outcomes for patients.

Charu Aggarwal, MD, MPH: Very well said. Thank you, Melina, for this very informative discussion, and thank you to our audience. We hope you found this OncLive Insights: My Treatment Approach program both useful and informative for your clinical practice and management of patients with metastatic, non-squamous, NSCLC. Thank you for joining us. Until next time.

Transcript edited for clarity.

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