The antibody-drug conjugate, sacituzumab tirumotecan (sac-TMT; MK-2870) plus pembrolizumab (Keytruda) in the first-line improved progression-free survival (PFS) vs platinum-based chemotherapy plus pembrolizumab in patients with PD-L1–negative, advanced nonsquamous non–small cell lung cancer (NSCLC) without EGFR or ALK alterations, according to interim data from the phase 3 OptiTROP-Lung06 trial (NCT06711900) presented at the
At a median follow-up of 9.7 months, the median PFS by blinded independent central review (BICR) was 15.0 months (95% CI, 9.9-not evaluable [NE]) with sac-TMT plus pembrolizumab (n = 229) compared with 5.7 months (95% CI, 5.5-7.4) with chemotherapy plus pembrolizumab (n = 226; HR, 0.49; 95% CI, 0.36-0.65; P < .0001). The 12-month PFS rates for the Sac-TMT and chemotherapy arms were 51.1% and 22.8%, respectively.
Investigator-assessed PFS also showed a similar benefit (HR, 0.52; 95% CI, 0.40-0.69). Overall survival (OS) was immature and reported descriptively only; median OS had not been reached in either arm (HR, 0.58; 95% CI, 0.38-0.88), and the 12-month OS rates were 77.6% vs 66.4% for each of the respective arms.
"Sac-TMT plus pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy plus pembrolizumab,” said lead study author Caicun Zhou, MD, PhD, of Shanghai East Hospital, Tongji University, in China. “Results from the OptiTROP-Lung06 study support sac-TMT plus pembrolizumab as a potential new first-line treatment option for PD-L1 negative advanced NSCLC without EGFR or ALK alterations.”
Notably, the combination previously extended PFS beyond that achieved with pembrolizumab monotherapy among patients with PD-L1–positive advanced NSCLC in the phase 3 OptiTROP-Lung05 trial (NCT06448312).2
The open-label, multicenter trial enrolled patients with locally advanced or metastatic nonsquamous NSCLC that lacked sensitizing EGFR or ALK alterations, had not received systemic therapy in the advanced setting, had an ECOG performance status of 0 or 1, and had PD-L1 expression on fewer than 1% of tumor cells.1
In total, 455 patients were randomly assigned to pembrolizumab at 400 mg every 6 weeks combined with either sac-TMT at 4 mg/kg every 2 weeks or with pemetrexed and cisplatin every 3 weeks for up to 4 doses, followed by pemetrexed maintenance (n = 226). Pembrolizumab could continue for up to 18 cycles of 6 weeks each. Sex, ECOG performance status, and disease stage served as stratification factors.
PFS by BICR was the trial’s primary end point, whereas OS, investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety were among the secondary end points.
At baseline, the median age was 63 years in both arms, 72.1% of patients in each arm were male, and 91.7% and 91.6% had stage IV disease in the sac-TMT and chemotherapy arms, respectively. Most patients in each arm had an ECOG performance status of 1 (sac-TMT, 82.5%; chemotherapy, 82.3%), were current or former smokers (65.5%; 62.8%), and had an adenocarcinoma histology (99.6%; 100%). Notably, most patients had stage IV disease (91.7%; 91.6%) and fewer had 3 or more distant metastatic sites (22.7%; 25.7%).
The ORR by BICR was 50.2% (95% CI, 43.6%-56.9%) with sac-TMT plus pembrolizumab vs 47.3% (95% CI, 40.7%-54.1%) with chemotherapy plus pembrolizumab. Deep responses, meaning complete or partial responses in which the summed diameters of target lesions decreased by 50% or more from baseline, were achieved by 28.8% vs 17.3% of patients, respectively. The DCRs were 90.4% (95% CI, 85.8%-93.9%) vs 88.5% (95% CI, 83.6%-92.3%).
The median DOR was 13.6 months (95% CI, 9.7-NE) with sac-TMT compared with 6.8 months (95% CI, 4.2-10.6) for the chemotherapy arm (HR, 0.47; 95% CI, 0.29-0.77). Moreover, the 12-month DOR rates were 61.7% (95% CI, 47.5%-73.1%) vs 27.2% (95% CI, 11.2%-46.0%).
PFS favored sac-TMT plus pembrolizumab across most subgroups analyzed, including patients with low TROP2 expression (HR, 0.49; 95% CI, 0.30-0.80), patients with high TROP2 expression (HR, 0.59; 95% CI, 0.37-0.92), and current or former smokers (HR, 0.36; 95% CI, 0.25-0.51).
In both arms, 99.6% of patients experienced at least 1 treatment-emergent adverse effect (TEAE). Grade 3 or higher TEAEs were reported in 47.6% of the sac-TMT arm compared with 60.6% of the chemotherapy arm, and serious TEAEs were observed in 35.8% vs 36.3%, respectively. Dose reductions due to TEAEs were needed in 4.8% vs 19.9% of patients, and TEAEs were fatal in 2.2% vs 6.2%.
Anemia was the most common TEAE in both arms (82.5%; 84.5%), followed by decreased neutrophil count (47.2%; 65.9%), and decreased appetite (40%; 45%). Notably, alopecia was experienced by 62% of patients in the pembrolizumab arm, compared with 14% in the placebo arm.
Additionally, stomatitis was reported in 51.1% of the sac-TMT arm vs 8.4% of the chemotherapy arm, and among patients receiving sac-TMT, 21.8%, 27.1%, and 2.2% had grade 1, 2, and 3 stomatitis, respectively. Ocular surface toxicity (13.5%; 2.7%) was limited to grade 1 or 2. Rates of pneumonitis, a category that included interstitial lung disease, were 10.5% vs 13.7%, with grade 3 or higher pneumonitis in 1.7% vs 3.1%.
Disclosures: Zhou reported receiving honoraria for speaking engagements from Eli Lilly, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc., Amoy Diagnostics, Allist, and Dizal; and serving as an advisor for Innovent Biologics, Hengrui, Qilu, and TopAlliance Biosciences Inc.
