Frontline Serplulimab Plus Chemo Provides Consistent Survival Benefit in Squamous NSCLC

The addition of the novel PD-1 inhibitor serplulimab (Hansizhuang) to carboplatin and nab-paclitaxel (Abraxane) significantly and consistently prolonged progression-free survival (PFS) and overall survival (OS) vs chemotherapy alone when used in the first-line treatment of patients with previously untreated locally advanced or metastatic squamous non–small cell lung cancer (NSCLC), according to updated data from the phase 3 ASTRUM-004 trial.¹

Results from the final analysis, which were presented at the 2023 IASLC World Conference on Lung Cancer, demonstrated that at a median follow-up of 31.1 months, the median PFS increased from 5.7 months (95% CI, 5.1-6.8) by independent radiological review committee (IRRC) and RECIST v1.1 criteria with placebo plus chemotherapy (n = 179) to 8.3 months (95% CI, 7.0-9.8) with serplulimab and chemotherapy (n = 358; stratified HR, 0.55; 95% CI, 0.43-0.69; descriptive P < .001). Patients who received serplulimab plus chemotherapy achieved a median OS of 22.7 months (95% CI, 18.6-27.4) vs 18.2 months (95% CI, 14.1-20.6) with chemotherapy alone (stratified HR, 0.73; 95% CI, 0.58-0.93; P = .010).

Notably, 97 patients crossed over to the serplulimab arm during the trial, necessitating an adjustment in the 2-stage model. Accordingly, the adjusted median OS in the placebo arm was 11.5 months (95% CI, 9.6-13.5, which translated to an adjusted hazard ratio of 0.49 (95% CI, 0.37-0.64).

“In conclusion, adding serplulimab to carboplatin/nab-paclitaxel significantly improved survival in previously untreated patients with locally advanced or metastatic squamous NSCLC,” principal investigator Caicun Zhou, MD, PhD, of Shanghai Pulmonary Hospital, China, said in an oral presentation of the data. “The aforementioned combination regimen represents a new treatment option for this patient population in the global setting.”

Squamous NSCLC constitutes approximately 25% to 30% of all NSCLC cases and is characterized by a relatively low occurrence of targetable genetic alterations. Prior research has indicated that incorporating PD-1/PD-L1 inhibitors into current chemotherapy regimens can enhance responses to first-line therapy. Despite these advances, the availability of preferred treatment options with a favorable risk-benefit ratio remains somewhat limited on a global scale.

In January 2023, China’s National Medical Products Administration approved serplulimab for use in combination with carboplatin and etoposide to treat patients with extensive-stage small cell lung cancer, expanding its prior indications in squamous NSCLC and microsatellite instability–high solid tumours.² The agent’s ability to improve survival outcomes across tumor types supported the initiation of the randomized, double-blinded, international study. The data cutoff date for the analysis presented at the meeting was January 31, 2023.

The study enrolled patients aged 18 years of age or older with stage IIIB/IIIC or IV NSCLC who had not previously received systemic anticancer treatment. Patients were required to have an ECOG performance status of 0 or 1. They could not have known EGFR mutations or ALK or ROS1 rearrangements. Those enrolled on the trial were stratified by their PD-L1 expression level (tumor proportion score [TPS] <1% vs RPA 1%≤ to <50% vs TPS ≥50%), race (Asian vs non-Asian), and disease stage (IIIB/IIIC vs IV).

Study participants were randomly assigned 2:1 to serplulimab at 4.5 mg/kg on day 1 or placebo plus carboplatin at area under the concentration-time curve of 5 or 6 on day 1 and nab-paclitaxel at 100 mg/mg2 on days 1, 8 and 15. Regimens were administered intravenously every 3 weeks. After the completion of 4 to 6 cycles of chemotherapy, placebo or serplulimab monotherapy was administered for up to 2 years. Notably, study protocol allowed eligible patients to cross over to serplulimab monotherapy after disease progression.

Investigators performed the first interim analysis of OS when approximately 99 deaths had occurred, which was concurrent with the final analysis of PFS. The second interim analysis of OS was conducted when 198 deaths were reported, and the final OS analysis was performed when 299 deaths had occurred. PFS and OS were tested sequentially at an overall 2-sided α level of 0.05. The multiplicity-adjusted 2-sided α level was 0.0002, 0.012, and 0.046 for OS at the first, second, and final analysis, respectively.

The study’s primary end point was PFS as assessed by an IRRC per RECIST v1.1 criteria. Key secondary end points included PFS, OS, objective response rate (ORR), duration of response (DOR), safety, and biomarker exploration.

Of the 809 patients initially screened, 537 were included in both the intention-to-treat and safety-evaluable populations. The median age was 63 years across both groups (range, 35-86). The majority of patients were male (89.7% in the serplulimab arm; 93.3% in the placebo arm), had an ECOG performance status of 1 (81.8%; 85.5%), had stage IV disease (71.2%; 72.6%), and were Asian (67.0%; 66.5%). Regarding smoking status, 22.1%, 64.0% and 14% of patients in the serplulimab arm were current smokers, former smokers, or had never smoked, respectively; these percentages were 20.7%, 68.2% and 11.2%, respectively, in the placebo arm.

In the serplulimab arm, 11.2% of patients had liver metastasis and 5.6% had brain metastasis; in the placebo arm, these percentages were 9.5% and 10.1%, respectively. In the serplulimab arm, high PD-L1 expression (≥50% TPS) was seen in 29.1% of patients, intermediate PD-L1 expression (TPS 1%≤ to <50%) was reported in 33.2%, and low PD-L1 expression (TPS <1%) was observed in 37.7%. In the placebo arm, corresponding percentages were 29.6%, 32.4% and 38.0%, respectively.

Serplulimab plus chemotherapy elicited a confirmed ORR of 60.1% (95% CI, 54.8%-65.2%) by IRRC and RECIST v1.1 criteria, which was comprised of a 3.4% complete response (CR) rate and a 56.7% partial response (PR) rate. The stable disease (SD) rate was 23.7%. Moreover, 7.3% of patients experienced progressive disease (PD) and 8.9% were not evaluable for response. In the placebo arm, the ORR was 40.8% (95% CI, 33.5%-48.4%), which included a 0.6% CR rate and 40.2% PR rate. Here, 34.6% of patients achieved SD and 12.8% experienced PD; 11.7% were not response evaluable. The median confirmed DOR was also prolonged with the serplulimab combination, increasing from 5.5 months (95% CI, 5.3-7.1) with chemotherapy alone to 11.1 months (95% CI, 8.3-15.4; HR, 0.45; 95% CI, 0.32-0.65).

A total of 43 patients in the serplulimab arm are still receiving treatment; 16 patients completed treatment and 299 discontinued treatment. In the placebo arm, 9 patients were still on treatment at data cutoff, 4 completed treatment and 166 discontinued, with the placebo regimen. Reasons for treatment discontinuation in the serplulimab arm included PD (n = 161), adverse effects (n = 49), patient decision (n = 35), death (n = 20), withdrawn consent (n = 17), physician decision (n = 6), poor treatment compliance (n = 5), loss to follow-up (n = 3), or another reason (n = 3).

Safety analysis revealed that serplulimab plus carboplatin and nab-paclitaxel had a manageable safety profile, and no new signals were observed. Any-grade treatment-emergent AEs (TEAEs) occurred in 98.9% of patients in the serplulimab arm and 98.3% of those in the placebo arm. Of these patients, 85.2% and 79.3% experienced TEAEs that were grade 3 or higher. Serious TEAEs were seen in 52.0% of those in the serplulimab arm and 42.5% of those in the placebo arm. AEs led to treatment discontinuation in 22.3% of patients in the serplulimab arm and 15.1% of those in the placebo arm. AEs led to death in 13.7% and 10.6% of patients, respectively. AEs of special interest included immune-related AEs (29.6%; 17.3%) and infusion-related reactions (1.1%; 0.0%).

Treatment-related AEs (TRAEs) occurred in 96.4% of patients in the serplulimab arm and 95.0% of those in the placebo arm. In the serplulimab arm, 33.2% experienced serious AEs and 1.1% had TRAEs that led to death; these percentages were 27.4% and 2.8%, respectively, in the placebo arm.

Of the AEs identified as directly related to serplulimab or placebo (73.2%; 62.6%), 35.5% and 31.8% were grade 3 or higher, 10.3% and 5.0% led to discontinuation, and 1.1% in each arm led to death.

The most commonly observed AEs in 10% or more patients across both groups included anemia, decreased neutrophil count, decreased white blood cell count, decreased platelet count, decreased appetite, increased alanine aminotransferase level, increased aspartate aminotransferase levels, nausea, rash, hypothyroidism, neutropenia and thrombocytopenia.

References

1. Zhou C, Hu Y, Arkania E, et al. ASTRUM-004: A phase 3 study of serplulimab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer. J Thorac Oncol. 2023;18(11):S63-S64. doi:10.1016/j.jtho.2023.09.058
2. Henlius’ novel anti-PD-1 mAb HANSIZHUANG (serplulimab) approved for the treatment of ES-SCLC. News release. Shanghai Henlius Biotech, Inc. January 17, 2023. Accessed December 4, 2023. https://www.henlius.com/en/NewsDetails-4283-26.html#:~:text=In%20the%20field%20of%20lung,first%2Dline%20treatment%20of%20SCLC.