Part 5: Current Challenges and Unmet Needs in Targeted Treatment Selection

Drs Langer, Lisberg, Bazhenova, and Nagasaka conclude their discussion by considering remaining challenges in biomarker testing in NSCLC and unresolved questions about the appropriate place and future prospects of targeted treatments, including ADCs.

This roundtable discussion is sponsored by Daiichi-Sankyo.

Click here to return to the entire video series 

Read the full Transcript:

Corey Langer, MD:
The therapeutic landscape is littered with the carcasses of many drugs, including many dirty TKIs that failed to look better than docetaxel. So since it is the standard in second line, with the movement of immunotherapy to frontline, virtually every company is either doing a biomarker-enriched or a general study. But how do you think we should move it into the frontline?

Aaron Lisberg, MD:

I think that for the TROP2 ADC, there's going to be that data where basically it's being combined with the frontline approaches we would use. So the high PDL1 expresser (tumor proportion score [TPS] greater than or equal to 50%) is getting pembro, and the 1-49’s (TPS 1%-49%) either getting pembro or in combination with chemo. And I think, again, we'll let the data kind of guide us. And if there is synergistic efficacy and if the toxicity is not prohibitive, then again, I think  we owe it to our patients and to the process of trying to improve therapies across the lung cancer spectrum to evaluate these agents in the frontline setting and see if they can be additive in many ways. I mean, there was a lot of skepticism.

Aaron Lisberg, MD:

My experience more recently would be with the chemo immunotherapy story, right? And there was a lot of concern that combining chemo immunotherapy in the frontline setting, the chemotherapy could kill the immune cells, etcetera, etcetera, and there were a lot of theoretical concerns, but the data looked good. And that's why I think we just need to run the studies. And if it's tolerable and the efficacy's better, then I think it will be adopted. And I think it'll make a difference for our patients.

Corey Langer, MD:

Still a bit trepidatious, personally, in combining, say, a KEYNOTE-189 approach with the ADCs, but as you point out, the data will guide us. Misako, your thoughts?

Misako Nagasaka, MD:

Sure. I think that's the whole reason why we're doing clinical trials. So I completely agree with Aaron. I do feel that in the HER2 mutated space trastuzumab deruxtecan is going to be approved hopefully sometime soon. But outside of that, I think there's a wild field out there where we have no idea what the biomarkers are and if it even means anything. Aaron, you mentioned examples of HER3 IHCs as well as TROP2 expression, but we actually saw the same thing with HER2 overexpression as well. As you know, DESTINY-Lung01 had a separate cohort for HER2 overexpressed patients, and among 2+ versus 3+, the 2+ patients had a response rate of 25%, whereas the 3+ had a response rate of 20%.

Misako Nagasaka, MD:

So I really don't know what to do with these things and it would be really, really, really nice if we can have a more biomarker-driven analysis to help guide us to really see who would benefit the most and who we can avoid extra toxicities on. I wrote a systematic review with one of my  previous fellows, it should be coming out, it’s a systematic review on T-DXd use in all solid tumors and the incidences of ILD happening. And lung cancer by far has the highest incidence of ILD, it was 26%, and in breast cancer studies like 10%, 12%. But as far as we know, there's really no clear-cut answer to why that is. Does lung cancer patients, do they have a more diseased lung at baseline? Maybe they had lobectomy previously, or chemoradiation, radiation injury, I don't know, but these are things that I think about and I hope that in the next several years, we would have a better understanding.

Lyudmila Bazhenova, MD:

Yeah. I'm not as, you know, I'm always for biomarkers, biomarkers are great, but I really don't think - I don't have big hopes that in this setting, we will be able to find the biomarker that will tell us which patients will benefit from ADCs, just because of what Aaron described as a bystander effect, right? So you might not need to have an antigen expression to actually have benefit, especially if your antigen expression at the baseline is high, such as low TROP2 and sometimes even AXL maybe not as high as CEACAM. So I'm pessimistic that we will be able to find the biomarker. The pneumonitis puzzles me a lot because if you look at the three Daiichi compounds, they all have deruxtecan derivative as the payload and in the same patients with lung cancer. If you look at trastuzumab deruxtecan, patritumab deruxtecan and datopotamab deruxtecan, they have the same payload that's all used in lung cancer. And the incidence of pneumonitis is 26 for the HER2, it's about 7 for the HER3, and it's about 6 for the DAPA - same patient, same payload, but completely different pneumonitis rate and I don't know why.

Corey Langer, MD:

I wonder if it's because it's more successful in the DESTINY trial and perhaps people were on it longer and therefore had an opportunity to develop both late toxicities, although it certainly generally happens earlier. Aaron, any insights into the toxicity or is it still somewhat willy-nilly?

Aaron Lisberg, MD:

Yeah. I don't think we know. I mean, obviously there's a possibility that it could be target engagement, and maybe more lung tissue expresses HER2 or something like that, but these are all questions that we need to explore, and they're all important questions for us and our patients.

Corey Langer, MD:

So it's time to wrap up. You 3 have been phenomenal. All extemporaneous description of a mountain of data which, let's face it, has all been generated really in the last 3 to 6 years. I started out in this field in the late ’80s believe it or not, before carbo was approved.

Key Takeaways

Corey Langer, MD:

So the strides we've made have really been exponential, I think certainly in the last 10 years and particularly in the last 5. What key takeaway messages from each of you?

Aaron Lisberg, MD:

Take-home points, just kind of going through the discussion as we talked about, biomarker testing is critical. I think, clearly in every patient with adenocarcinoma that has advanced metastatic disease. And I would argue that the panel has, for the most part, agreed - certainly in squamous cell patients that are non-smokers and emerging also in patients with squamous that are smokers - we need to be getting testing in all our patients; that there is a clear benefit to getting both tissue and liquid in parallel at time of diagnosis if possible, iterative testing at time of progression is important and liquid is a great tool for that. Our list of targets continues to increase. I think we have a lot of great drugs the majority of which we can use in the frontline setting, but there are some nuances so I think it is important to just stay on top of that.

Aaron Lisberg, MD:

And then in terms of the ADC and the last section we just discussed, I personally am very enthusiastic. I think that these drugs have real possibility of entering the field of defeating docetaxel finally in the second-line setting. And I'm excited to see what they could potentially also do in the frontline setting. And I think ultimately, like we've been talking about the data will guide us, and I think that the future is bright.

Corey Langer, MD:

So relegate docetaxel to third- or fourth-line, where it deservedly belongs.

Aaron Lisberg, MD:

I would like to.

Lyudmila Bazhenova, MD:

Building on what Aaron said, one more point to add: when you do the molecular testing, understand what you found and know that, for example, NTRK point mutation is not the same as NTRK fusion, and there also, ROS1 point mutation is not the same as ROS1 fusion, and understanding the differences between EGFR exon 20 insertion versus EGFR classical mutation. So it's important to test out patients, but it's also important to know what you're looking at and if you are not sure the mutation that you discovered, if you're not sure what you do, there are always people you can contact, the molecular pathologists that you reference company, they're always very available to us. So just make sure you know what you're looking at before you make treatment decisions.

Misako Nagasaka, MD:

I think my take-home message would be that if you don't know, you can't treat. So testing really is key. And I really agree with Corey, I hope that one day it becomes standard all over that we do upfront liquid and tissue.

Corey Langer, MD:

So, I agree with all three of you. The strides we're making have been incredibly impressive. Without question, ADCs are the next big wave, but how to discipline the toxicities, I think, is going to be a big challenge. I'm still concerned about some of the studies with the lack of marker or specificity that we're going to be back in the realm of just incremental improvements, maybe two-month improvement or three-month improvement in survival if we observe survival, not the phenomenal improvements we saw with immunotherapy or, for that matter, with targeted therapy. Getting back to marker testing, as I said earlier my goal, at least for the rest of my career, is to make sure that liquid and tissue are paired at diagnosis preferably as early as possible, that we accelerate the timetable, that reflex testing becomes standard, and that we need to also continue our education of our colleagues outside of medical oncology, particularly interventional pulmonary and interventional radiology, to make sure we get adequate specimens because, as Misako has pointed out, if you don't know, you can't treat, and if the tissue specimens are inadequate, you're really foundering, you’re confronting the necessity of perhaps a repeat biopsy, particularly if liquid is unrevealing.

Corey Langer, MD:

So, maximize the tissue, maximize the yield from the tissue, and do it as quickly as possible so we can get our answers as quickly as possible. So this has been a wonderful experience and I look forward to doing something like this again.