preface
The current standard of care for localized small cell lung cancer (LD-SCLC) is prophylactic cranial irradiation (PCI) after concurrent chemoradiotherapy, with a 5-year overall survival (OS) rate of only 25% to 33%. The STIMULI trial is a 1:1 randomized Phase II trial designed to demonstrate the advantages of LS-SCLC chemoradiotherapy and post-PCI double-immune consolidation therapy over observation alone. Recently, the findings were published in annals of Oncology.
Research background
SCLC accounts for about 15% of all lung cancer types and is a more aggressive subtype of lung cancer. Its malignancy is high, the disease progresses rapidly, distant metastases occur early, about 70% to 75% of patients are diagnosed with extensive stage (ED), and only 25% to 30% of patients are LD. Survival outcomes were poorer for LD-SCLC, with a median OS of only 16-24 months and a 5-year OS rate of only 25%-33%. Immune checkpoint inhibitors (ICIs) have been shown to have clinical benefit in patients with SCLC. Studies have shown that in ED-SCLC, the programmed death receptor-ligand 1 (PD-L1) inhibitor atenizumab or duvalliumab combined with etoposide and platinum chemotherapy improves survival in treated patients.
The CheckMate-032 study is a randomized, open-label Phase I/II clinical trial evaluating the treatment of treated advanced solid tumors with either navulilizumab monotherapy or ipicimumab. In a cohort of 147 patients with ED-SCLC treated advanced solid tumors, an objective response rate (ORR) of navulijumab versus ipicumab was observed at 21.9%, a disease control rate of 16.7%, and a median OS of 4.7 months, compared with 11.6%, 17%, and 5.7 months of navulijulzumab monotherapy, respectively. These results drive the CheckMate-451 and Phase II STIMULI studies (NCT02046733) to explore the role of double-immune consolidation therapy in ED-SCLC and LD-SCLC, respectively. The results of the STIMULI study are as follows.
Endometrial cancer
The study included adult patients with stage I-IIIB LD-SCLC with an ECOG score of 0 or 1. Patients who have previously received anti-tumor system therapy (excluding single-cycle chemotherapy) and chest radiotherapy are excluded. After patient enrollment, the following conditions are met to enter the randomized group: (i) four-cycle chemotherapy, (ii) at least 85% of the planned target volume (PTV), chest radiotherapy and PCI, and (iii) no disease progression (according to radiological tumor assessment).
Enrolled patients received standard platinum chemotherapy (four cycles, cisplatin 25 mg/m2, intravenously [i.v.], days 1 to 3 or 75 mg/m2, day 1, or carboplatin, AUC 5-6, according to Calvert formula, day 1 i.v.), combined with etoposide, 100 mg/m2i.v., days 1 to 3, once every 3 weeks. Synchronized chest radiotherapy (45 Gy twice a day, 30 days, 1.5 Gy each time, or 56 Gy once a day, 28 days, 2 Gy each) can be performed after the end of the first or second cycle of chemotherapy. PCI (25Gy, divided into 10 sessions) is performed between days 8 and 15 of the fourth cycle of chemotherapy.
After the completion of chemoradiotherapy and PCI, patients who did not progress to the disease were randomly included in the trial group or observation group according to a 1:1 ratio. The therapeutic dose of navulijumab was 1 mg/kg, i.v., once every 3 weeks; the therapeutic dose of ipiclizumab was 3 mg/kg, i.v., once every 3 weeks; after 4 cycles of dual-drug treatment in the experimental group, the upper limit of treatment was 12 cycles with navuliyumab (240 mg, i.v., once every 2 weeks) (Figure 1).
Figure 1. Experiment design and flowchart
Research results
From December 2015 to April 2019, a total of 222 patients were enrolled. Among them, 153 patients with LD-SCLC who did not progress after the completion of chemoradiotherapy and PCI (78 in the experimental group and 75 in the observation group) were randomized, and their median age was 62 years, 60.1% of men, 34.0%/65.4% of current/former smokers, and 66.0% of ECOG score 1.
Progression-free survival (PFS)
At the end of the data cut-off, 82 patients (53.6%) experienced disease progression (PD) or death (40 patients in the trial group [51.3%] and 42 patients in the observation group [56.0%]). The median PFS was 10.7 months (95% CI: 7.0 - unable to assess [NE]) in the trial group and 14.5 months (95% CI: 8.2-NE) in the observation group, and there was no significant difference between the two groups (HR=1.02; 95% CI: 0.66-1.58; P=0.93). At 12 months of follow-up, the PFS rate was 48.1% (95% CI: 36.1%-59.0%), and in the observation group it was 52.8% (95% CI: 40.9%-63.5%), while at 24 months, the trend was reversed, with PFS rates of 43.2% (30.9%-55.0%) and 40.3% (28.3%-51.9%) in the two groups, respectively (Figure 2).
Figure 2. PFS (Intent to Treat Analysis (ITT) Cohort)
THE
The median follow-up was 35.0 months (IQR: 25.5-48.1), and 77 patients are still being followed. The median OS in the trial group did not reach (NR) (95% CI: 24.1 months-NE), compared with 32.1 months (95% CI: 26.1-NE) in the observation group. A total of 71 deaths (46.4%) were observed (34 in the experimental group and 37 in the observation group). No significant prolongation of OS was observed in the experimental group (HR=0.95; 95%CI: 0.59-1.52; P=0.82). The OS rates for 24 months in the experimental and observation groups were 62.9% (95% CI: 50.9%-72.7%), respectively, and 66.4% (95% CI: 54.4%-75.9%), respectively.
Figure 3. OS (ITT Queue)
ORR
Of the 153 randomized patients, 20 had achieved complete remission (CR) after chemoradiotherapy (9 in the trial group and 11 in the observation group). The ORR was 38% (95% CI: 26%-50%; 26 patients), 47% (95% CI: 34%-60%; 30 patients) in the observation group, while the median duration of remission (DoR) was NR in both groups, and the 12-month DoR rates in the trial and observation groups were 73.2% (95% CI: 53.4%-86.0%) and 63.0% (95% CI: 40.5-79.0%), respectively. No significant differences in ORR were observed between the two groups.
security
Adverse events (AE) occurred in 98.7% and 86.7% of patients in the trial and observation groups (regardless of the relationship with treatment), and 96.2% of patients in the trial group developed at least one treatment-related AE. In the trial group, the incidence of grade 3 and above AE was 61.5% (51.3% were treatment-related AE) and 25.3% in the observation group. More than half (55.1%) of patients in the trial group discontinued treatment because of AEs. Treatment-related deaths occurred in 4 (5.1%) patients (1 case of intestinal obstruction, 1 case of lung infection and 2 cases of pneumonia), while 1 patient (1.3%) died in the observation group (the cause of death is unknown). The most common AEs were fatigue (38.6%) and anorexia (24.2%).
Conclusions of the study
Clinical activity is observed in post-line therapy with pambolizumab or navulijumab, with or without ipiclizumab. In contrast, as consolidation therapy or second-line therapy after first-line chemotherapy, navulilizumab with or without ipiimumab did not show more clinical benefit than established standard therapy. In patients with LD-SCLC, receiving navuliyumab-ipicumab double immunosuplositive therapy after chemoradiotherapy did not improve the patient's PFS and OS, possibly due to shorter treatment time.
bibliography:
Peters, S., Pujol, J. L., Dafni, U., Dómine, M., Popat, S., Reck, M., Andrade, J., Becker, A., Moro-Sibilot, D., Curioni-Fontecedro, A., Molinier, O., Nackaerts, K., Insa Mollá, A., Gervais, R., López Vivanco, G., Madelaine, J., Mazieres, J., Faehling, M., Griesinger, F., Majem, M., … ETOP/IFCT 4-12 STIMULI Collaborators (2022). Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial. Annals of oncology : official journal of the European Society for Medical Oncology, 33(1), 67–79. https://doi.org/10.1016/j.annonc.2021.09.011