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TROP 2 Targeted ADCs in NSCLC
Mapping TROP-2–Targeted ADCs Into the NSCLC Treatment Landscape

Released: May 02, 2024

Expiration: May 01, 2025

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Key Takeaways
  • When sequencing antibody–drug conjugates (ADCs), both the target and the payload must be considered along with the characteristics of the tumor and whether the patient has been exposed to therapies related to the payload previously.
  • ADCs with the same target can have different efficacy and safety profiles, depending on the antibody, the payload, and the linker.
  • Key toxicities associated with TROP-2 ADCs should be anticipated and appropriately managed, including with dose reductions when necessary.

Antibody–drug conjugates (ADCs) are composed of a monoclonal antibody targeting a tumor cell antigen, a cytotoxic payload, and a linker. ADCs are uniquely suited to deliver potent cytotoxic agents directly to tumor cells, thereby enabling the use of compounds in concentrations that would otherwise cause severe toxicity. However, questions of how best to use these agents in clinical practice and how to sequence ADCs in non-small-cell lung cancer (NSCLC) remain, as do concerns regarding the potential for treatment-related adverse events (AEs).

To date, the only ADC approved for NSCLC is the HER2-directed trastuzumab deruxtecan, which is indicated for previously treated HER2-mutant NSCLC. However, novel TROP-2‒targeting ADCs, including datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan, are currently under investigation in advanced NSCLC. Unlike the HER2-targeted ADC trastuzumab deruxtecan, biomarker analysis of TROP-2 aberrations or expression is not predictive of response to TROP-2–targeting ADCs. HER3-directed ADCs have also shown promise, particularly in EGFR-mutant NSCLC after progression on EGFR-directed therapy. Despite HER3 expression being common in this setting, early studies indicate that it is not a useful predictive biomarker.

Currently, the only approved ADC for NSCLC is trastuzumab deruxtecan, targeting HER2, but potential approvals of other ADCs targeting HER3 and TROP-2 are on the horizon. Once these agents are approved, how would you go about sequencing these treatments?

Luis Paz‑Ares, MD, PhD:
The thing to remember is that tumors are not all equal, and biomarkers are not all created equal. The first step in choosing a sequence of ADCs for NSCLC is determining what genetic alterations are present in the tumor. Patients who have actionable genomic aberrations are likely to derive greater benefit from related targeted therapies than patients who do not, but the goal of sequencing these treatments is to maximize all the potential treatment options available to provide patients with extra opportunities to improve survival and overall outcomes.

Knowing the molecular background of each patient’s disease is important for treatment selection, and also for understanding how emerging therapies, including TROP-2‒targeting ADCs, may fit into a patient’s treatment plan. 

David Planchard, MD, PhD:
I totally agree. Rather than choosing between treatment A and treatment B, I like to think of sequencing as reserving additional options for treatment in later lines of therapy. Evidence shows that the more lines of treatment available to patients, the bigger the improvement in overall survival (OS). In addition to continued treatment of recurrent disease, sequencing therapies can also provide options for mitigating treatment-related toxicities.   

A major challenge with sequencing treatments is the lack of clinical trial data. Clinical trials often exclude participants with prior exposure to any ADC, so there is not much evidence for how effective certain ADCs are after exposure to other ADCs. However, there are 2 ways that we can think about sequencing ADCs: the target and the payload. That is, choosing which agent to use first will depend on what ADCs are available for a specific target as well as whether the tumor is sensitive to each ADC’s payload. The question is, should one expect an ADC to be effective in patients who have been exposed to the same payload before? Or should they always receive an ADC with a different payload? To make these decisions, I think healthcare professionals (HCPs) can take a lot of what we know about sequencing chemotherapy and apply it to sequencing ADCs as well.

Luis Paz‑Ares, MD, PhD:
To delve further into that idea, studies so far have been quite focused on developing ADCs for specific biomarkers or tumor antigens, but there is not much research, as yet, on biomarkers that could help predict payload sensitivity. Historically, the choice of chemotherapy for patients with NSCLC varied for squamous compared to nonsquamous carcinomas. For example, cisplatin/gemcitabine or IO + carboplatin/paclitaxel is recommended for squamous carcinomas while cisplatin/pemetrexed ± IO is recommended for nonsquamous carcinomas. With that in mind, I foresee that in the future there may be multiple ADCs that target the same antigen, but with different payloads depending on the tumor’s sensitivity to the different chemotherapy payloads.

Helena Yu, MD:
I think we know very little about the mechanisms of resistance to ADCs, but I think it is clear from case reports that patients can develop resistance to the payload as well as the antibody when receiving an ADC.

I think the EVOKE-01 and the TROPION-Lung01 trials of sacituzumab govitecan and Dato-DXd, respectively, illustrate important points about the nuances between different ADCs with the same target. EVOKE‑01 was somewhat similar to TROPION‑Lung01 in the sense that both compared an ADC to docetaxel in patients with advanced NSCLC who were previously treated with platinum-based chemotherapy and immune checkpoint inhibitor therapy, including squamous and nonsquamous carcinomas. In both studies, patients with actionable gene alterations were allowed, but no active central nervous system metastases and no leptomeningeal disease were allowed. In EVOKE-01, patients were randomized to sacituzumab govitecan or docetaxel, while participants in TROPION-Lung01 were randomized to Dato-DXd or docetaxel. In January 2024, a press release stated that the EVOKE-01 study did not meet its primary endpoint of OS but did show a numerical improvement in patients with both nonsquamous and squamous disease, as well as in patients nonresponsive to their last prior therapy. Although cross-trial comparisons cannot be made, it is important to keep in mind that TROPION‑Lung01 has also not shown a clear difference in OS (a coprimary endpoint of this trial), though these data are still immature. However, Dato-DXd was associated with improved progression-free survival (PFS) in patients with nonsquamous histology and worsened PFS in patients with squamous histology. So, I am interested to see the subgroup analysis by histology of the EVOKE-01 trial when it is presented, likely later this year. 

David Planchard, MD, PhD:
That’s right, I think these 2 studies illustrate that even though Dato-DXd and sacituzumab govitecan are both ADCs targeting TROP-2, sacituzumab govitecan does not seem to exhibit the same difference in efficacy between histologic types as Dato-DXd. This shows that even though these agents have the same tumor target, the differences in the payload, antibody structure, and linker between the 2 resulted in different efficacy and safety profiles. Dato-DXd is associated more with interstitial lung disease (ILD), stomatitis, and ocular AEs, while sacituzumab govitecan is associated more with neutropenia and gastrointestinal AEs, such as diarrhea. Altogether, I believe we still have much to learn about the nuances between different ADCs.

Luis Paz‑Ares, MD, PhD:
I think the same is true for mechanisms of resistance. Resistance can occur at any step in the process of ADC delivery, be it changes in expression of the target antigen, mutations resulting in elimination of the antibody binding site, impaired payload release, or resistance to the payload itself. To truly understand how resistance to ADCs arises, parallel RNA and whole-exome sequencing of sequential biopsies on patient cohorts will be required. So far, there are data of isolated cases with mutations on topoisomerase‑1, or with decreased expression of a given target. But there are robust cohorts of patients that have been sequentially biopsied and comprehensively analyzed.

David Planchard, MD, PhD:
I think that brings up an important point regarding how important it is to perform biomarker testing and conduct studies to assess what biomarkers may be determinants of efficacy for certain agents. For example, development of tusamitamab ravtansine, an ADC targeting CEACAM5, will be discontinued, despite this agent showing initial promise. I believe the phase III trial was conducted without sufficient biomarker selection in trial participants – randomized patients were required to have CEACAM5 expression of ≥2+ intensity in ≥50% of tumor cells, but either archived or fresh biopsies was allowed, thus obscuring any potential efficacy. I think review of tusamitamab ravtansine efficacy in patients with fresh tumor biopsies could have been explored to determine a specific threshold for efficacy, but this analysis was not performed and proper biomarker selection of patients was never established.

How concerned should HCPs be regarding the key toxicities with each TROP-2–directed ADC? 

Luis Paz‑Ares, MD, PhD:
When ADCs were first introduced, HCPs were very concerned about their associated toxicities, but our understanding of how to mitigate and manage them has come a long way. For most types of AEs associated with ADCs, if patients develop asymptomatic AEs or are only experiencing mild symptoms, I am quite confident with maintaining their current dose and monitoring for worsening symptoms. When patients do start to be more symptomatic, I think HCPs should approach management of toxicities carefully, with appropriate dose holds and/or modifications. For any symptomatic AE, it is important to do a full investigation into the symptoms patients are experiencing to understand the extent of the AE and how to manage it. In addition, with the risk of ILD, it is very important to me that we have a pulmonologist on our team who is an expert on managing all those cases. 

Lastly, HCPs should bear in mind that management of toxicities also depends on the type of agent. Dato-DXd is more associated with ILD, stomatitis, and ocular events while sacituzumab govitecan is more likely to induce neutropenia and gastrointestinal events.

David Planchard, MD, PhD:
As with trastuzumab deruxtecan, decreasing the dose of most ADCs will significantly reduce treatment-related toxicity. I think HCPs can feel comfortable reducing the dose to mitigate toxicities without worrying about whether reducing the dose will reduce efficacy. As HCPs used to do with chemotherapy, I think dose reductions are an important way of reducing AEs while maintaining patients on treatment. HCPs need to remember that, for the patient, quality of life is just as much a priority as staying on treatment. In all, I think if HCPs can anticipate toxicities like stomatitis and respond quickly with dose reductions, management of key toxicities will not be an issue.

Helena Yu, MD:
Anecdotally, I think that the dexamethasone mouthwash does help with management of stomatitis and mucositis associated with Dato-DXd. I agree that dose reductions are of great importance. ADCs are chemotherapy essentially, so management of key toxicities will be similar in some ways.

Luis Paz‑Ares, MD, PhD:
In my practice, one of the issues that I am having with managing mucositis is access to treatment, particularly the steroid mouthwash at local pharmacies, possibly because they are not familiar with ADC-related mucositis. Now I have that made within the hospital pharmacy, just to be sure that patients have access.

I believe that in time, HCPs will be a lot more proficient at managing ocular toxicity as well. Up to this point, it was uncommon for HCPs in oncology to refer patients to ophthalmologists for management of treatment-related toxicities. In my practice, we really had to work hard to ensure that patients receiving Dato-DXd could get their ocular toxicities addressed. For us, it is not enough to have an appointment in 5 months, these patients need an appointment with an ophthalmologist quickly and I think that is something that should be worked out among clinics.

Your Thoughts?
Based on the evidence and the key toxicities, how likely are you to recommend an ADC for your patients with NSCLC? Leave a comment to join the discussion!

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