Thoracic oncologists weigh how TROP2-directed antibody-drug conjugates fit into sequencing and combination strategies for EGFR-mutated NSCLC.
After progression on frontline osimertinib (Tagrisso)–based therapy in EGFR-mutated non–small cell lung cancer (NSCLC), the choice between the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) and amivantamab (Rybrevant)–based regimens increasingly comes down to which adverse effect (AE) profile a patient can live with.¹
“There’s equipoise between those 2 [options],” Helena A. Yu, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said during a recent OncLive® Scientific Interchange and Workshop. “I don’t think that there’s a clear winner. They’re both active.”
The panel was moderated by Elaine Shum, MD, of New York University Langone Health in New York and revolved around a case discussion of a 50-year-old never-smoker with EGFR L858R–mutated NSCLC and brain metastases whose lung disease had progressed 18 months after she started receiving osimertinib plus chemotherapy.
Sarah Waliany, MD, of Mass General Brigham in Massachusetts, said the patient’s 10-month chemotherapy-free interval made rechallenge reasonable, alongside Dato-DXd or amivantamab plus lazertinib (Lazcluze). Knowing the reason why pemetrexed (Alimta) was stopped, she added, would help determine which path to take.
The dermatologic AEs associated with amivantamab weighed heavily in the discussion.
“I haven’t had a patient who hadn’t had an issue with amivantamab,” said Amin Nassar, MD, of Yale School of Medicine in New Haven, Connecticut.
Olivia Fankuchen, MD, MSc, of Weill Cornell Medicine in New York, said she raises the option of Dato-DXd with patients who work with their hands or in kitchens, for whom skin AEs are “a real quality of life issue.”
In a pooled analysis of the EGFR-mutated subsets of patients from the phase 3 TROPION-Lung01 (NCT04656652) and phase 2 TROPION-Lung05 (NCT04484142) trials (n = 117; median of 3 prior lines of therapy [range, 1-5]), Dato-DXd produced a confirmed objective response rate of 43% (95% CI, 34%-52%), a median progression-free survival (PFS) of 5.8 months (95% CI, 5.4-8.2), and a median overall survival (OS) of 15.6 months (95% CI, 13.1-19.0).² Deborah B. Doroshow, MD, PhD, of the Tisch Cancer Institute at Mount Sinai in New York, said recent stereotactic radiosurgery makes such data hard to interpret.1
TROP2-Directed ADCs in EGFR-Mutated NSCLC
Stomatitis occurred in 60% of patients in the pooled analysis, ocular surface events were reported in in 32% of patients (grade ≥ 3, 3%), and adjudicated drug-related interstitial lung disease (ILD) was seen in 5 patients. The panelists cited ophthalmology access as the main AE mitigation bottleneck. Yu said she does not delay treatment for the eye examination unless a patient has pre-existing eye disease. Additionally, Daniel Rosas, MD, of Memorial Healthcare System in Florida, said he now routes dexamethasone mouthwash prescriptions through his hospital pharmacy after retail pharmacies struggled to fill these requests.
Doroshow described a frozen oral mouthpiece that patients wear during Dato-DXd infusion and for several days after each dose, noting, “you can’t [only use it] during the infusion because of the prolonged exposure to the cytotoxin.”
In the phase 3 OptiTROP-Lung04 trial (NCT05870319), sacituzumab tirumotecan (MK-2870/SKB264; n = 188) improved median PFS by blinded independent central review vs platinum-based chemotherapy (n = 188; HR, 0.49; 95% CI, 0.39-0.62; P < .0001), and an OS improvement was also reported with the ADC (HR, 0.60; 95% CI, 0.44-0.82; P = .001), with no drug-related ILD reported.3
In the phase 2 ORCHARD trial (NCT03944772), osimertinib plus Dato-DXd at 6 mg/kg yielded a median PFS of 11.7 months (95% CI, 8.3-21.7) and a median OS of 26.2 months (95% CI, 14.8-NC) vs 9.5 months (95% CI, 7.2-9.8) and 19.8 months (95% CI, 13.5-23.3), respectively, with Dato-DXd at 4 mg/kg.4 However, grade 3 or higher treatment-related treatment-emergent AEs occurred in 56% vs 34% of patients, respectively. Additionally, 59% of patients required Dato-DXd dose reduction at the higher dose.5
Separately, the phase 3 EVOKE-03/KEYNOTE-D46 trial (NCT05609968) of sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) missed statistical significance for a PFS benefit vs pembrolizumab alone (HR, 0.81; 95% CI, 0.66-1.00; P = .0252), underscoring that a plausible mechanism of action for an investigational agent does not ensure a positive trial.6
The faculty doubted that TROP2-directed ADCs will reach the frontline setting unless they offer a markedly better balance of efficacy and AEs than the finite chemotherapy course used in the phase 3 FLAURA2 trial (NCT04035486).¹ Doroshow described the ADC class as having “moderate activity, significant toxicity, and incremental [improvements over time].”
Nassar said that biomarkers should reflect how much of an ADC is internalized, not just how much TROP2 sits on the cell surface. Furthermore, Fionnuala Crowley, MD, of Mount Sinai, explained that renal impairment may rule out pemetrexed use and therefore presents a clear case for Dato-DXd use in these patients.
Rosas and Dylan Fortman, MD, of the University of Michigan in Ann Arbor, called for broader community clinical trial access and patient education related to ADCs.
“I would like to see more mechanistically informed study design,” Doroshow concluded.
