ADCs Show Promise in NSCLC But Have a Long Road Ahead

Stephen V. Liu, MD

The potential role for antibody- drug conjugates (ADCs) for treating patients with non–small cell lung cancer (NSCLC) continues to evolve as new data challenge investigators to reexamine their approaches.

Fam-trastuzumab deruxtecan-nxki (Enhertu), an ADC already generating excitement in breast and gastric cancers, showed early signs of promise in patients with NSCLC with HER2 mutations or HER2 overexpression, according to data from the DESTINY-Lung01 (NCT03505710) trial.^1,2

Additionally, ADCs have begun to make their mark against novel targets. Investigators presented data from a phase 1 trial (NCT03260491) that examined patritumab deruxtecan, which includes an anti-HER3 antibody, in patients with EGFR mutated NSCLC.³ No approved HER3-directed agents are available for NSCLC, despite its expression in EGFR-mutated disease.

Data from an early analysis of the phase 1 TROPION-PanTumor01 trial (NCT03401385) that examined the TROP2-directed ADC datopotamab deruxtecan also have been presnted4 (TABLE^1-4).

“We’re being very innovative and there’s an exciting new class of drugs that we still need to learn more about because we can’t ignore their activity [in lung cancer], and those are the ADCs,” said Stephen V. Liu, MD, during an OncLive® Lung Cancer Talk video program.

TABLE. Findings for ADCs in Metastatic NSCLC

Liu was joined by Heather A. Wakelee, MD; Benjamin Levy, MD; and Sarah Goldberg, MD, MPH, in reviewing the latest data for 3 ADCs that may carve out a path forward for these compounds in patients with metastatic lung cancer.

Liu: There are a lot of different ways to attack mutated cancers [beyond tyrosine kinase inhibitors (TKIs)].

Dr Goldberg, we saw some data at the 2020 World Conference on Lung Cancer, and also some data at the 2020 [American Society of Clinical Oncology Virtual Scientific Program], about the ADC trastuzumab deruxtecan. What are your thoughts on that drug?

Goldberg: First, I agree with you, this class of drugs, the ADCs, are really up and coming in lung cancer and I think we’ve seen some really interesting data now. The data for trastuzumab deruxtecan I think looks exciting and I think in general it was an exciting World Lung with all of these different agents.

Trastuzumab deruxtecan is an ADC, which links an anti-HER2 antibody with a topoisomerase 1 inhibitor, really trying to deliver chemotherapy to cells that express HER2.

This is an interesting study [DESTINYLung01]. It was a phase 2 trial that included 2 populations of patients: those who had HER2 overexpression, which was defined as IHC [immunohistochemistry] 2+ or 3+ expression; and those with HER2 mutations.

In the group of patients who had HER2 overexpression, it was a pretty small cohort and there were about 10 patients who were IHC 3+ and 39 patients with 2+ expres-sion by IHC. Response rates varied based on the expression and among those patients with mutations. So the response rates were approximately 20% or so for patients with overexpression of 3+ and approximately 25% for those who were 2+. The duration of response was approximately 6 months in both of those groups.

Interestingly, the disease control rate was higher—approximately 80%—for those with an IHC of 3+. There is real activity there, although lower than probably we would like to see for patients historically with a targeted therapy.

The other cohort for patients with HER2-mutant disease, I think is really an interesting population where the response rate was above 60%, almost 62%. You can also see the benefit in the patients with HER2-mutant disease even over those with HER2-expressing disease in the progression-free survival data; it was approximately 14 months, whereas for patients with HER2 overexpression it was approximately 5 months. So again, I think in either population we’re seeing activity and I think it’s really something to keep an eye on as to whether this can be a drug that we use in those populations. But it’s really the patients with HER2-mutant disease that seem to derive the most benefit.

Something that is also really important about this drug is that it is somewhat toxic. Grade 3 treatment-related AEs [adverse events] occurred in more than half of the patients. Approximately 20% of patients required dose discontinuation because of AEs and about a third required dose reductions.

Many AEs were chemotherapy-like toxici-ties, such as cytopenia, fatigue, and nausea. But one thing that we should probably all keep in mind when we’re using this class of drugs is the potential for ILD [intersti-tial lung disease]. That occurred in 16% of patients. Grade 5 ILD, so ILD that eventually resulted in death, was reported for 3 patients, so it’s something to keep an eye on. I think this is still potentially a drug that we may see moving forward, but it does have its share of toxicity for the patients.

Liu: To me, trastuzumab deruxtecan is a blockbuster in HER2-mutant disease. You’ve got a response rate of 60% in heavily pretreated patients with a PFS [progression-free survival] of 14 months. Now, that’s the upper limit of the 95% confidence interval, so that’ll probably follow a bit and we’ll see how much it falls. But it looks great in the HER2-mutant population and it looks OK in those with HER2 overexpression.

Dr Levy, if we were sitting here a year ago, and I asked you what is going to be the better predictor for an ADC overexpression or muta-tion, what would you have said?

Levy: I would have said overexpression, given what we know about these drugs. And I think we’re still learning how these drugs work, but it makes sense. I’m a simple guy, the more protein you have on the cell, it would seem more likely to be able to be targeted by a drug going after that protein. And it’s weird, right? [We are seeing] 3 times the response rate in the patients with HER2-mutant disease vs those with HER2 overexpression. I know these weren’t direct comparisons here or randomization but looking at these 2 separate cohorts [the data are] very different. And I think we’re just trying to learn.

I would have never thought that HER2 mutations were the predictive biomarker for this drug. And I think we’re still wrestling with ADCs, how they work, who they’re for. Not just for HER2 but for others that we’ll talk about. But I would have thought overexpression would have been really what would be at play here.

Wakelee: We know differently now, but if you had asked me in the past, it makes sense—you’re hitting the target and the target isn’t the intercellular target that we think about with the TKIs, it’s the protein target. And so it is hard to explain.

Liu: Dr Goldberg mentioned toxicities here. I agree with the way you put it that they seem like chemotherapy toxicities, but the efficacy is so much greater than chemotherapy and bridges the gap between those, which I think speaks to its design.

ADCs have so much potential, we’re seeing them all over the place. There was another ADC, which Dr Wakelee, I know you treat a large EGFR-mutant patient population, so you were tuned in for this other ADC that was targeting HER3, right?

Wakelee: [When considering] EGFR, which is also HER1, and then HER2 and HER3, a very closely related family, it certainly makes sense to be going after that in patients whose tumors have alterations in the EGFR pathway. [NCT03260491] included patients who had previously had chemotherapy, previously had an EGFR TKI, and so lots of prior therapies.

Despite this, the confirmed response rate was approximately 25% with patritumab deruxtecan. Is that strikingly better than second-line chemotherapy? It is a little bit better, but it is also not 50%. That is one of the criticisms we hear, that these ADCs are just fancy chemotherapy. Dr Goldberg talked about the toxicity with the trastuzumab deruxtecan. And with patritumab deruxtecan you’ve still got the deruxtecan and so you’ve got the same toxicity.

There is a pneumonitis risk, which is a little bit lower than what was presented in [DESTINY-Lung01], but you also have thrombocytopenia, neutropenia, so chemotherapy-like toxicities, rather than the EGFR toxicities that we’re used to thinking about.

You’ve also got a duration of response that’s approximately 7 months; it’s not quite as fabulous as we’ve seen in some of the more targeted therapies, but I think it’s still encouraging. It’s a different way of thinking about treating the disease. HER3 is kind of the silent partner with HER2 and HER1 and it hasn’t been something we’ve targeted previously, yet it’s always there when we’re dealing with EGFR or HER2.

It made a lot of sense to go after HER3 and I think that the data are encouraging. We are going to need to see a bit more and I think we’re probably going to need to see some randomized comparisons to chemotherapy options that we would otherwise be using, such as docetaxel or docetaxel plus ramucirumab [Cyramza]. Those sorts of comparisons might be needed.

Or it might be that this is another treatment option. The more options that we have, the more lines of therapy, the more we’re helping our patients live as long as possible.

Liu: Well put. I think that one of the big advantages of patritumab deruxtecan over docetaxel is that it is simply not docetaxel [which can be a tough drug]. That is a huge, huge advantage for patritumab deruxtecan. This is clearly an area of need. Osimertinib [Tagrisso] has been around for a while and we’ve adapted that. After osimertinib, the bottom kind of falls out. This is really a need in your practice, Dr Goldberg?

Goldberg: Oh, absolutely. I completely agree. I think we were so excited when we see a patient with an EGFR mutation, because we have a great drug, osimertinib. But then what? I think this is a big need.

We often will give patients chemotherapy after [osimertinib], which is fine, but I think if we had other options, I think we would all be excited to use them. And, I agree with what Dr Wakelee said, I think the response rate is kind of on par with a lot of other chemotherapies, but there still could be a role. Many of these patients are younger and otherwise healthy and they can oftentimes tolerate multiple lines of therapy and more options are better.

One thing that would be nice to see with activity [attributed to] HER3 expression with this drug is that maybe it’s a biomarker within the EGFR-mutant population. Those are things that will hopefully enrich patients that are likely to benefit, and then we’ll see, hopefully, higher response rates if we get the biomarker fine-tuned.

Liu: We also learned that ADCs are not just for driver-positive cancers.

Levy: That’s right. We’ve got another ADC, datopotamab deruxtecan, which targets Trop2, a glycoprotein that is highly expressed on a variety of solid tumor malignancies, including NSCLC. It makes sense to explore this drug in patients with NSCLC and we had the first-in-human study results presented at [2020 World Lung]. Approximately 159 patients were treated in this phase 1 study with single-agent datopotamab deruxtecan and there was a 4-, 6- and 8-mg cohort for a total of 159 patients.

Approximately half of the patients in each of the cohorts had 3 or more lines of prior therapy; they didn’t have to have Trop2 expression to be on the study.

We saw a response rate of approximately 20% to 25%, depending on the cohort that was evaluated. If you look at some of the spider plots, some of these responses were durable and meaningful. And then, in terms of toxicity, there were some of toxicities similar to what we’ve seen before; more GI [gastrointestinal] toxicities than we’ve seen with others including nausea, stomatitis, fatigue, vomiting, decreased appetite, and constipation. Interestingly, we didn’t see a lot of neutropenia, which we’ve seen with the other Trop2 ADCs.

As we learn more and more how to use these drugs, it will be important to understand how to manage the ILD associated with them.

Liu: I think another thing we need to do is we have to decouple ADCs with the thought that you need overexpression. Because clearly you don’t. I think that the 4 of us are reasonably logical and although it’s logical that you would need [overexpression] there, you don’t. We’ll let [other investigators] explain why, but we just need to decouple that with ADCs, because they’re not going anywhere. These are clearly active drugs.

References

1. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non–small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504
2. Nakagawa K, Nagasaka M, Felip E, et al. Trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: interim results of DESTINY-Lung01. J Thorac Oncol. 2021;16(suppl 3):S109-S110. doi:10.1016/j.jtho.2021.01.285
3. Yu H, Baik C, Gold K, et al. Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. J Thorac Oncol. 2021;16(suppl 3):S107. doi:10.1016/j.jtho.2021.01.281
4. Spira A, Lisberg A, Sands J, et al. Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: updated results of TROPION-PanTumor01 phase 1 study. J Thorac Oncol. 2021;16(suppl 3):S106-S107. doi:10.1016/j.jtho.2021.01.280