In patients with resectable non–small cell lung cancer (NSCLC), perioperative treatment with the checkpoint inhibitor tislelizumab plus platinum-doublet chemotherapy led to a statistically significant benefit in event-free survival and a favorable trend for overall survival, investigators for the phase III RATIONALE-315 reported at the February 2024 European Society for Medical Oncology (ESMO) Virtual Plenary (Abstract VP1-2024).
“Major pathologic and complete pathologic responses were also significantly improved with neoadjuvant tislelizumab plus platinum-doublet chemotherapy,” said first study author Dongsheng Yue, MD, of Tianjin Medical University Cancer institute and Hospital, Tianjin, China, who also presented earlier results from RATIONALE-315 at the ESMO Congress 2023 (Abstract LBA58).
“Taken together, the statistically and clinically significant event-free survival, major pathologic response and pathologic complete response benefits, alongside manageable safety, support the use of perioperative tislelizumab plus neoadjuvant platinum-doublet chemotherapy for patients with resectable stage II to IIIA NSCLC,” Dr. Yue said.
About RATIONALE-315
RATIONALE-315 enrolled 453 patients from Chinese centers with resectable stage II to IIIA NSCLC of squamous or nonsquamous histology, with no known EGFR mutations or ALK gene translocations, and who had any PD-L1 expression status. Patients were randomly assigned to receive neoadjuvant tislelizumab (3–4 cycles at 200 mg) plus platinum-based chemotherapy or chemotherapy alone. After surgery, the experimental group received up to eight cycles of adjuvant tislelizumab at 400 mg while the control arm received placebo. The primary endpoints of the study were major pathologic complete response and event-free survival by blinded independent review.
All but one patient in the study received their neoadjuvant treatment assignment, with about 93% completing it. After that, 84% of patients in the experimental arm and 76% of those in the control arm underwent definitive surgery. The assigned adjuvant therapy was received by 74% and 65% of patients, respectively.
Multiple Endpoints Met
As previously reported, following neoadjuvant therapy and resection, the rate of major pathologic response (defined as ≤ 10% residual tumor) was 56.2% in the tislelizumab arm vs 15.0% in the chemotherapy-alone arm (P < .0001)—an improvement of 41.4% with the addition of the checkpoint inhibitor. Rates of pathologic complete response (no residual tumor) were 40.7% and 5.7% (P < .0001), respectively, translating to a 35.0% improvement with tislelizumab.
KEY POINTS
- The checkpoint inhibitor tislelizumab was evaluated as neoadjuvant and adjuvant therapy in patients with resectable NSCLC in the phase III RATIONALE-315 trial, which was conducted in China.
- Tislelizumab led to increases of 41% in major pathologic response rate and 35% in pathologic complete response rate.
- At a median follow-up of 22 months, median event-free survival was not reached in either arm; at 24 months, 68.3% of patients in the tislelizumab arm were free of events compared to 51.8% of the placebo arm.
- Tislelizumab adds to a growing number of immunotherapeutic agents that, when given perioperatively, improve upon chemotherapy alone in early-stage NSCLC.
Now, at a median follow-up of 22 months, median event-free survival in the intent-to-treat analysis by blinded independent review was not reached in either arm; at 24 months, 68.3% of patients in the tislelizumab arm were free of events compared to 51.8% of the placebo arm (hazard ratio [HR] = 0.56, P = .0003), Dr. Yue reported, adding, “A clinically meaningful improvement per investigator review was also observed.”
The event-free survival benefit with perioperative tislelizumab over placebo was generally consistent across prespecified subgroups. By PD-L1 expression, hazard ratios were 0.71 for ≥ 50% PD-L1 expression, 0.34 for 1% to 49% expression, 0.50 for ≥ 1% expression, and 0.80 for < 1% expression. By histology, for squamous disease, the 24-month event-free survival rates were 70.2% with tislelizumab and 52.2% with placebo (HR = 0.56); for patients with nonsquamous tumors, these rates were 60.8% and 52.1%, respectively (HR = 0.64). Benefit of the regimen was confirmed for patients with stage II and stage IIIA disease.
At this interim analysis, a trend for overall survival benefit favoring tislelizumab was also observed (HR = 0.62, P = .0193, with P = .0001 being the statistical boundary), Dr. Yue reported.
No New Safety Signals
The safety profile of perioperative tislelizumab plus chemotherapy was manageable and consistent with the known risks of the individual therapies. Grade ≥ 3 treatment-related adverse events were observed in 72% of patients in the tislelizumab arm and 66% of the control arm, and led to death in four (1.7%) and two (0.9%) patients, respectively.
The most common toxicities in each arm were reduced neutrophil count, reduced white blood cell count, and alopecia. These were only slightly higher in the tislelizumab arm, with grade ≥ 3 rates of 61%, 17%, and 0.4% for the respective toxicities. Approximately 13% and 9% of the groups, respectively, discontinued treatment due to toxicity.
Disclosure: For full disclosures of the study authors, visit annalsofoncology.org.
