CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: June 24, 2024
Expiration: June 23, 2025
Introduction
In this module, Edward B. Garon, MD, MS, discusses key data on the use of TROP-2–targeting antibody–drug conjugates (ADCs) in the treatment of advanced non-small-cell lung cancer (NSCLC).
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
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TROP-2 Overexpression Associations With OS, Disease-Free Survival
In the management of lung cancer, healthcare professionals (HCPs) are very familiar with using biomarkers to guide therapy. However, biomarkers are typically considered genomic drivers of disease—the exception being PD-L1, which is a slightly different target. TROP-2 is an emerging therapeutic target in NSCLC. Although TROP-2 is not considered to be a driver of lung cancer development, TROP-2 expression has been shown in multiple studies to correlate with poorer outcomes among patients with lung cancer.1,2 Consequently,TROP-2 can be considered more of a marker of tumor, as TROP-2 levels on the tumor are much greater than on normal tissue, making it an attractive target for therapeutic agents in development.
Datopotamab Deruxtecan: TROP-2–Targeted ADC
ADCs are composed of an antibody targeted to a specific marker on cancer cells that is connected by a linker to a payload. Typically, these payloads are a type of cytotoxic chemotherapy. All of the TROP-2–targeted ADCs discussed here have a topoisomerase I inhibitor payload. For example, datopotamab deruxtecan (Dato-DXd) is one of the agents for which we currently have phase III data available. It has a drug-to-antibody ratio (DAR) of 4 and a cleavable linker.3-6
TROPION-PanTumor01 NSCLC Cohort: Datopotamab Deruxtecan
The initial evaluation of Dato-DXd was conducted during the phase I TROPION-PanTumor01 study (NCT03401385). This study included multiple histologies, including NSCLC. It included a dose-escalation group, followed by dose expansion, which occurred at 3 doses of Dato-DXd: 4 mg/kg, 6 mg/kg, and 8 mg/kg. The primary endpoints of this study included safety and tolerability, although efficacy was also assessed as a key secondary endpoint.7
TROPION-PanTumor01—Updated NSCLC Cohort: Antitumor Activity
In the NSCLC cohort, across all dose levels, the response rate was approximately 25%, and the median duration of response was approximately 10 months. Based on these results, the dose of Dato-DXd chosen for further investigation was 6 mg/kg.7
TROPION-PanTumor01: NSCLC With Actionable Genomic Alterations—Antitumor Activity
As part of the TROPION-PanTumor01 study, investigators conducted an evaluation of patients with actionable genomic alterations (AGAs). As might be anticipated in an evaluation of patients with NSCLC with AGAs, this largely included patients with EGFR mutations. Responses were seen across the dose levels among patients with EGFR mutations and across a host of different resistance mechanisms and prior treatment scenarios. This data bolstered investigators’ confidence that this could be an effective treatment option for patients with NSCLC and AGAs—and, in particular, those with EGFR mutations.8
TROPION-Lung01: Dato-DXd vs Docetaxel in Previously Treated Advanced NSCLC ± AGAs
Dato-DXd was further evaluated as part of a phase III randomized study vs docetaxel. The TROPION-Lung01 trial (NCT04656652) was presented at the European Society for Medical Oncology Congress in 2023 by Aaron Lisberg. In this study, patients with previously treated NSCLC who had not received prior docetaxel were randomized one-to-one to receive either Dato-DXd 6 mg/kg IV every 3 weeks or docetaxel at the standard dosing of 75 mg/m2 IV every 3 weeks. The primary endpoints of this study were PFS and OS. Other endpoints included response rate, duration of response, and safety.9
TROPION-Lung01: Baseline Characteristics
Baseline characteristics among patients in this study were well-balanced, although most patients—approximately 77%—had nonsquamous histology. As would be anticipated from a study of NSCLC, the majority of patients were current or former smokers. Among patients who had AGAs—nearly 1 in 5 of the patients enrolled—the majority had EGFR mutations.9
TROPION-Lung01: Outcomes in ITT Population
Of the coprimary endpoints, PFS met the threshold for a positive study. In the intention-to-treat (ITT) population, the HR of 0.75 favored Dato-DXd vs docetaxel.9 Although median PFS was not particularly different between groups—4.4 months with Dato-DXd vs 3.7 months with docetaxel—there are more substantial differences when one looks at later time points, such as 6 months and 9 months from randomization.
TROPION-Lung01: PFS by Histology
A striking feature of the TROPION-Lung01 study was the difference in PFS by histology, particularly among patients who had nonsquamous NSCLC, where the benefit was much more pronounced. Among this subgroup, the median PFS was 5.6 months with Dato-DXd vs 3.7 months with docetaxel (HR: 0.63). Of interest, among patients with squamous disease, there was a suggestion of potential harm from the Dato-DXd (HR: 1.38), with the PFS curves suggesting that docetaxel was associated with a longer PFS vs Dato-DXd. Among these patients, median PFS was 2.8 months with Dato-DXd vs 3.9 months with docetaxel.9
TROPION-Lung01: Interim OS in ITT Population
At the time of this analysis, there was not a statistically significant difference in OS, the other coprimary endpoint.9
TROPION-Lung01: Safety
Of note, the safety profiles differed between Dato-DXd and docetaxel. It is difficult to compare Dato-DXd with docetaxel because their toxicities are quite different. When looking at the numeric rates of adverse events (AEs), the toxicities appear somewhat similar between the 2 agents, but I would say that the actual toxicity profile between them is quite different. Cytopenias tend to dominate in the toxicity analysis for docetaxel, whereas gastrointestinal AEs and stomatitis, for example, tend to occur most commonly in patients receiving Dato-DXd. Of note, one toxicity of concern with all of the deruxtecan-based molecules, including trastuzumab deruxtecan (commonly used among patients with breast cancer), is interstitial lung disease (ILD)/pneumonitis. Although the rates of serious ILD/pneumonitis were low with Dato-DXd, there were still fatal cases.9
TROPION-Lung01: AEs of Special Interest
Looking more closely at the AEs of special interest, 7 fatal ILD events were associated with Dato-DXd, although the treating investigators determined that the cause of death in 4 cases was progressive disease.
Of note, infusion-related events were rare. Ocular events, which can be difficult for patients, were also observed, with the most common being dry eyes at 6.1%.9
Phase II TROPION-Lung05: Dato-DXd in Previously Treated Advanced NSCLC With AGAs
Next, the phase II TROPION-Lung05 study evaluated Dato-DXd specifically in patients with AGAs. Again, EGFR mutations were the most common AGA observed, although in this population several patients also had ALK gene rearrangements, as well as other abnormalities. The response rate was greatest among patients with an EGFR mutation—exceeding 40%—but the objective response rate also was encouraging in patients with ALK gene rearrangements, with nearly one quarter of the patients demonstrating evidence of a response.10
TROPION-Lung05: Intracranial Efficacy of Dato-DXd in Previously Treated Advanced NSCLC With or Without AGAs
One unique aspect of this study was the evaluation of efficacy in patients with brain metastases. There was some activity of Dato-DXd noted in patients with brain metastases, and patients with baseline brain metastases exhibited similar PFS to patients who did not.11 This is part of recently evolving literature in which patients with brain metastases, particularly those with EGFR mutations, demonstrate evidence of improved outcomes, even when chemotherapy is utilized—or large molecules such as amivantamab.
Sacituzumab Govitecan: TROP-2–Targeted ADC
One additional agent that has been extensively evaluated is sacituzumab govitecan, which is also an ADC directed against TROP-2. It contains an SN38 payload, another topoisomerase I inhibitor. Sacituzumab govitecan has a DAR of 8:1 vs 4:1 for Dato-DXd. This agent is currently approved in triple-negative and hormone receptor–positive/HER2-negative breast cancer, as well as urothelial cancer.12-14
IMMU-132-01: NSCLC Cohort of Sacituzumab Govitecan in Previously Treated Epithelial Cancers
Sacituzumab govitecan was originally evaluated as part of a basket trial, IMMU-132-01, for patients with previously treated stage IV epithelial cancers, which included patients with NSCLC. This trial evaluated the safety and response rate of sacituzumab govitecan at 4 different doses: 8 mg, 10 mg, 12 mg, and 18 mg.15
IMMU-132-01: Outcomes in NSCLC Cohort
Among patients with NSCLC, the response rate was approximately 17% in this pretreated population.15,16
IMMU-132-01: All-Cause AEs in NSCLC Cohort
As part of the basket study, the toxicity profile of sacituzumab govitecan was assessed in patients with NSCLC. Of interest, the toxicity profile observed was quite different from that of Dato-DXd, with gastrointestinal issues, such as nausea and diarrhea, and cytopenias being among the primary AEs associated with sacituzumab govitecan.15
EVOKE-01: Sacituzumab Govitecan vs Docetaxel in Previously Treated Advanced NSCLC
It took a period of time before sacituzumab govitecan was further evaluated in lung cancer, but we do now have randomized data in previously treated NSCLC, as well. Following the promising results reported from IMMU-132-01, the phase III EVOKE-01 trial evaluated sacituzumab govitecan 10 mg/kg, administered on Days 1 and 8 of each 21-day cycle, vs docetaxel 75 mg/m2 every 3 weeks, for patients with stage IV NSCLC with progressive disease after treatment with chemotherapy and immune checkpoint inhibitors.
In many ways, this trial is similar to the TROPION-Lung01 study of Dato-DXd vs docetaxel. The scope of the study was very similar, except for the primary endpoint. Although OS and PFS were the coprimary endpoints of theTROPION-Lung01 study9, OS was the sole primary endpoint in the EVOKE-01 trial. Secondary endpoints included PFS, response rates, safety, and quality of life.17,18
EVOKE-01: PFS in ITT
Of interest, there was not a huge difference with respect to PFS between sacituzumab govitecan and docetaxel, although this was not the primary efficacy outcome of this study.17,18
EVOKE-01: OS in ITT (Primary Endpoint)
For the primary efficacy analysis of OS, this study did not meet its primary endpoint. The HR of 0.84 trended toward benefit with the ADC, with a median OS of 11.1 months observed with sacituzumab govitecan vs 9.8 months with docetaxel, but this was not statistically significant.17,18
EVOKE-01: OS by Histology in Patients Nonresponsive to Last Anti–PD-1/PD-L1–Containing Regimen
Of note, the difference in histology seen with Dato-DXd was not observed with sacituzumab govitecan. In fact, patients with squamous and nonsquamous histology receiving sacituzumab govitecan appear to have similar median OS—11.8 and 10.7, respectively—and the HR, if anything, is more impressive for the patients who have squamous cell NSCLC.17
EVOKE-01: OS in Key Subgroups
One key point of discussion regarding this data at ASCO 2024 was that among patients who did not respond to their last regimen, which included a PD-1 or PD-L1 inhibitor, there was a more impressive improvement in median OS—11.8 months with sacituzumab govitecan vs 8.3 months with docetaxel (HR: 0.75; 95% CI: 0.58-0.97).17,18
Sacituzumab Tirumotecan (MK-2870; SKB264): TROP-2–Targeted ADC
The final TROP-2–directed ADC that I will discuss is sacituzumab tirumotecan. This ADC actually has the same antibody as sacituzumab govitecan but a different payload, which, again, is a topoisomerase I inhibitor. This ADC has a DAR of approximately 7:1.19-21
Phase I/II MK-2870-001 Trial: NSCLC Cohort
There are early-phase data evaluating sacituzumab tirumotecan from the phase I/II MK-2870-001 trial. Among patients with NSCLC, the data showed an overall objective response rate of 38.5%. Of note, approximately one half of participants in this study had EGFR mutations. Among that group of patients, the response rate was higher, 60.0%, compared with 26.3% in patients who were EGFR wild-type. The toxicities associated with this agent include cytopenias and stomatitis.21
MK-2870-004: Sacituzumab Tirumotecan vs CT in Previously Treated Advanced NSCLC With AGA
This agent also is being evaluated in a randomized phase III trial (NCT06074588), but in this case, it is being evaluated in patients with AGAs who have received prior tyrosine kinase inhibitor therapy, as well as platinum-based chemotherapy. Here, sacituzumab tirumotecan is compared with chemotherapy. Participants will receive 4 mg/kg of sacituzumab tirumotecan on Days 1, 15, and 29 of a 6-week cycle vs investigators' choice of docetaxel or pemetrexed. The primary endpoints of this study are PFS and OS, specifically in the EGFR-mutated cohort. Secondary endpoints include response rate in patients with EGFR mutations and efficacy evaluations in all patients.22
Summary
Currently, we have phase III data with the TROP-2–targeted ADCs Dato-DXd and sacituzumab govitecan. The outcomes with these therapies in patients with advanced NSCLC with or without AGAs have been variable. Ongoing trials, particularly those combining these agents with immunotherapy and other drugs, may better inform HCPs regarding the benefits of these therapies and the optimal patient population.
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