Sugemalimab/Chemotherapy Improves Long-Term Survival in Metastatic NSCLC

“To our knowledge, the GEMSTONE-302 study is the first randomized, double-blind, phase 3 study to show significant [PFS] and [OS] benefits of a PD-L1 inhibitor (sugemalimab) plus platinum-based chemotherapy in first-line settings for both squamous and nonsquamous NSCLC in a single trial,” according to the study authors.

Combining sugemalimab (Cejemly) with chemotherapy in the frontline setting significantly extended overall survival (OS) and progression-free survival (PFS) vs placebo/chemotherapy among those with metastatic squamous or nonsquamous non–small cell lung cancer (NSCLC), according to 4-year outcomes from the phase 3 GEMSTONE-302 study (NCT03789604) published in The Lancet Oncology.1

Data showed a median OS of 25.2 months (95% CI, 20.1-30.2) in the sugemalimab arm vs 16.9 months (95% CI, 12.8-20.7) in the placebo arm (HR, 0.68; 95% CI, 0.54-0.85). The OS rates in each respective arm were 32.1% (95% CI, 26.7%-37.6%) vs 17.3% (95% CI, 11.1%-24.7%) at 4 years.

Sugemalimab-based treatment produced a median PFS of 9.0 months (95% CI, 7.4-10.9) vs 4.9 months (95% CI, 4.8-5.2) with placebo plus chemotherapy (HR, 0.49; 95% CI, 0.39-0.60). At 4 years, the PFS rates were 12.4% (95% CI, 6.9-19.6) and not estimable in each arm.

Among patients with squamous histology, the median OS was 23.6 months (95% CI, 17.9-27.4) with the sugemalimab combination vs 12.2 months (95% CI, 9.5-19.0) with chemotherapy alone, with respective 4-year rates of 27.6% (95% CI, 19.8%-35.8%) vs 11.7% (95% CI, 3.9-24.3) in each arm (HR, 0.61; 95% CI, 0.43-0.87). Additionally, the median OS in each arm was 26.0 months (95% CI, 19.6-33.3) vs 19.8 months (95% CI, 14.8-26.3) among those with nonsquamous disease; the 4-year rates were 35.5% (95% CI, 28.3%-42.8%) vs 20.2% (95% CI, 12.1%-29.9%), respectively (HR, 0.72; 95% CI, 0.53-0.98).

Additional data showed that sugemalimab/chemotherapy prolonged OS vs placebo/chemotherapy across PD-L1 expression subgroups. These improvements occurred in those with PD-L1 expression of at least 50% (HR, 0.58; 95% CI, 0.38-0.89), a PD-L1 expression of 1% to 49% (HR, 0.68; 95% CI, 0.45-1.04), a PD-L1 expression of less than 1% (HR, 0.75; 95% CI, 0.53-1.08), and a PD-L1 expression of at least 1% (HR, 0.63; 95% CI, 0.47-0.85).

“To our knowledge, the GEMSTONE-302 study is the first randomized, double-blind, phase 3 study to show significant [PFS] and [OS] benefits of a PD-L1 inhibitor (sugemalimab) plus platinum-based chemotherapy in first-line settings for both squamous and nonsquamous NSCLC in a single trial,” lead study author Caicun Zhou, MD, PhD, a professor in the Department of Oncology at Shanghai Pulmonary Hospital and Shanghai East Hospital, and from the Tongji University School of Medicine in Shanghai, wrote with coauthors.1 “The durability of the survival benefit, combined with a manageable safety profile and the capacity to extend clinical benefit to traditionally high-risk groups…positions sugemalimab plus chemotherapy as a first-line treatment option and, to our knowledge, currently the only anti–PD-L1-chemotherapy regimen with long-term safety and survival data in treatment-naive NSCLC.”

In the double-blind GEMSTONE-302 trial, 479 patients were randomly assigned 2:1 to receive sugemalimab (n = 320) or placebo (n = 159) in combination with chemotherapy. Patients received sugemalimab at 1200 mg or matched placebo; chemotherapy consisted of carboplatin area under the concentration–time curve 5 mg/mL per minute and pemetrexed at 500 mg/m2 if they had nonsquamous disease or carboplatin plus paclitaxel at 175 mg/m2 if they had squamous disease. Treatment was administered intravenously on day 1 of 3-week cycles for a maximum of 4 cycles, with maintenance treatment persisting for a maximum of 35 cycles.

The trial’s primary end point was PFS per investigator assessment using RECIST v1.1 criteria. Secondary end points included OS, objective response rate (ORR), duration of response (DOR), safety, and pharmacokinetics.

Patients 18 to 75 years old with histologically or cytologically confirmed stage IV NSCLC per 8th International Association for the Study of Lung Cancer criteria, no prior systemic therapy for advanced or metastatic disease, and a measurable target lesion based on RECIST v1.1 guidelines were eligible for enrollment on the trial.2 Additional eligibility criteria included having an ECOG performance status of 0 or 1 and a minimum life expectancy of 12 weeks.

Baseline disease characteristics and demographics appeared to be comparable between the treatment arms. The median age was 62.0 years (IQR, 56.0-67.0) in the sugemalimab arm and 64.0 years (IQR, 56.0-68.0) in the placebo arm; most patients in each arm were male (79% vs 81%). Investigators noted brain metastases in 16% and 11% of the investigational and placebo arms, respectively.

Data showed an ORR of 63% (95% CI, 57.9%-68.7%) with the sugemalimab regimen vs 40% (95% CI, 32.6%-48.3%) with placebo plus chemotherapy. In each arm, the median DOR was 9.9 months (95% CI, 8.6-13.3) and 4.4 months (95% CI, 3.5-6.1).

The median OS among patients with brain metastases at baseline in the sugemalimab (n = 50) and placebo arms (n = 17) was 26.0 months (95% CI, 12.4-not reached [NR]) vs 9.0 months (95% CI, 5.2-20.8), respectively (HR, 0.44; 95% CI, 0.24-0.81). Among 46 patients who crossed over to sugemalimab monotherapy from the placebo arm, the median PFS was 4.0 months (95% CI, 2.1-5.8), and the median OS was 15.6 months (95% CI, 10.3-21.0).

In the sugemalimab and placebo arms, respectively, the most common grade 1/2 adverse effects (AEs) included anemia (59% vs 57%), decreased white blood cell counts (42% vs 42%), increased aspartate aminotransferase (34% vs 25%), and increased alanine aminotransferase (33% vs 30%). The most frequent serious AEs in each arm included pneumonia (3% vs 4%), anemia (3% vs 3%), and decreased platelet counts (3% vs 3%).

Fatal AEs occurred in 20 patients (6%) who received sugemalimab-based treatment, which included deaths with unspecified causes (n = 7) pneumonia (n = 3), cerebral infarction (n = 3), myelosuppression with septic shock (n = 1), septic shock alone (n =1), abdominal pain (n = 1), cardiac failure (n = 1), intracranial hemorrhage (n = 1), immune-mediated lung disease (n = 1), and respiratory failure (n = 1). Nine (6%) patients in the placebo arm experienced fatal AEs, which included deaths of unspecified causes (n = 3), pneumonia (n = 2), suicide (n = 1), diabetic ketoacidosis (n = 1), epilepsy (n = 1), and multiple organ dysfunction syndrome (n = 1).

References

1. Zhou C, Wang Z, Sun M, et al. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): 4-year outcomes from a double-blind, randomised, phase 3 trial. Lancet Oncol. Published online June 13, 2025. doi:10.1016/S1470-2045(25)00198-6
2. A study of CS1001 in subjects with stage IV non-small cell lung cancer. ClinicalTrials.gov. Updated August 9, 2024. Accessed June 18, 2025. https://tinyurl.com/356jbtt7