Adding serplulimab to chemotherapy improves the overall survival in the first line treatment of patients with advanced squamous non-small cell lung cancer

Previously, results of the phase III ASTRUM-004 study showed that the addition of serplulimab (anti-PD1) to first line carboplatin/nab-paclitaxel significantly delays the disease progression in patients with locally advanced or metastatic squamous non-small cell lung cancer (NSCLC). Updated results of this study demonstrate that this delayed disease progression also translates into a significant benefit in overall survival (OS). Furthermore, longer follow-up of this study did not reveal any new, or unexpected safety signals.

Background

Squamous NSCLC accounts for 25–30% of all NSCLC cases and is characterized by a low frequency of targetable gene alterations. Previously, clinical trials have demonstrated that adding a PD-1/PD-L1 inhibitor to chemotherapy improves outcomes in the first-line setting. In line with these earlier findings, the phase III ASTRUM-004 trial evaluated the efficacy and safety of adding the anti-PD1 antibody serplulimab to chemotherapy with carboplatin/nab-paclitaxel, as first-line treatment for patients with locally advanced or metastatic squamous NSCLC.

Study design

ASTRUM-004 is a randomized, double-blind, international multicenter phase III study, in which patients with histologically or cytologically confirmed stage IIIB/IIIC or IV squamous NSCLC who did not receive prior systemic therapy were randomized (2:1) to receive intravenous serplulimab (4.5 mg/kg) or placebo (up to 35 cycles) in combination with chemotherapy (carboplatin and nab- paclitaxel, 4-6 cycles) in 3-week cycles. Randomization in this trial was stratified by PD-L1 expression level (tumor proportion score [TPS] ≥50% vs. 1%≤ TPS <50% vs. TPS <1%), race (Asian vs. non-Asian), and disease stage (stage IIIB/IIIC vs. IV). The primary study objective of ASTRUM-004 consists of the independent radiological review committee (IRRC)-assessed PFS, with secondary endpoints including OS, objective response rate (ORR), duration of response (DoR), safety and biomarker explorations. The 2023 World Conference on Lung Cancer featured the results from the pre-specified final OS analysis of this trial.

Results

As of January 31, 2023, a total of 537 patients were randomized to the serplulimab-chemotherapy (N=358) or placebo-chemotherapy group (N=179). The median age of patients in the study was 63.0 years, and almost 9 out of 10 patients was male. Furthermore, two thirds of patients had an Asian origin and about 70% had stage IV disease at study enrollment. After a median follow-up of 31.1 months, the previously reported PFS benefit of serplulimab-chemotherapy vs. placebo- chemotherapy was maintained, with a median of 8.3 and 5.7 months, respectively (HR[95%CI]: 0.55[0.43-0.69]). Importantly, the HR for PFS consistently favored the serplulimab-chemotherapy group across the prespecified subgroups, irrespective of age, sex, race, disease stage, PD-L1 expression, smoking history and the presence of liver or brain metastases. The benefit in PFS also translated into a significant benefit in OS with a median of 22.7 and 18.2 months for the serplulimab and placebo groups, respectively (HR[95%CI]: 0.73[0.58-0.93]; p=0.010). The ORR was reported at 60.1% for patients receiving serplulimab as compared to 40.8% in the placebo arm. Responses to serplulimab-chemotherapy were also more durable with a median DoR of 11.1 months as compared to 5.5 months with chemotherapy alone (HR[95%CI]: 0.45[0.32-0.65]).

Overall, 127 (35.5%) and 57 (31.8%) of patients in the respective group reported grade ≥3 adverse events related to serplulimab or placebo. These adverse events most commonly consisted of a neutrophil count decreased (14.8% vs. 14.5%), anemia (12.0% vs. 10.6%), and a decreased white blood cell count (10.1% vs. 11.2%). Immune-related adverse events were reported by 106 (29.6%) and 31 (17.3%) patients, respectively, and most frequently consisted of hypothyroidism (6.4% vs. 0.6%), rash (5.0% vs. 1.1%), and immune-mediated lung disease (4.2% vs. 0.6%).

Conclusions

With 31.1 months of follow-up, serplulimab plus carboplatin/nab-paclitaxel showed consistent benefits in PFS, OS, ORR, and DoR over placebo plus carboplatin/nab-paclitaxel in untreated patients with locally advanced or metastatic squamous NSCLC. Furthermore, serplulimab plus carboplatin/nab-paclitaxel came with a manageable safety profile, without any new or unexpected safety signals. As such, the combination of serplulimab and carboplatin/nab-paclitaxel represents a potential new treatment option for this patient population in the global setting.

Reference

Zhou C, et al. A Phase 3 Study of Serplulimab Plus Chemotherapy as First-Line Treatment for Squamous Non-small-Cell Lung Cancer (ASTRUM-004). Presented at WCLC 2023; Abstract OA09.05