Peri-operative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small cell lung cancer: final analysis of the randomized RATIONALE-315 trial.

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

SY13-03: Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges

Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy

BackgroundGuidelines for driver-negative, resectable stage IIA–IIIB non-small cell lung cancer (NSCLC) recommend surgery combined with neoadjuvant chemotherapy and perioperative immunotherapy. However, the relative efficacy and surgery-related safety comparing various immune checkpoint inhibitors (ICIs) remain unclear. This study aims to directly compare the efficacy and surgery-related safety of perioperative tislelizumab versus pembrolizumab in this setting.MethodsIn this single-institution retrospective cohort study, we enrolled patients with stage IIA–IIIB NSCLC who received neoadjuvant chemotherapy combined with either tislelizumab or pembrolizumab, followed by surgery and adjuvant immunotherapy at our center (2018–2024). Propensity score matching (PSM) was used to balance baseline characteristics. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathologic response (MPR), objective response rate (ORR), overall survival (OS), event-free survival (EFS), and surgery-related safety.ResultsIn total, 245 patients were analyzed (75 in the tislelizumab group and 170 in the pembrolizumab group). Following a 1:1 PSM adjustment, each group consisted of 72 patients. No significant differences between tislelizumab group and pembrolizumab group were observed in terms of the pCR rate (43.1% vs. 40.3%; P=0.74), MPR rate (66.8% vs. 66.8%; P>0.99) or ORR (58.3% vs. 66.7%; P=0.30). There were no statistically significant differences between the tislelizumab group and pembrolizumab group in the endpoints of overall OS [hazard ratio (HR) =1.43, 95% confidence interval (CI): 0.59–3.48, P=0.42] and EFS (HR =1.93, 95% CI: 0.96–3.85, P=0.059). There was no significant difference regarding to the surgery-related safety outcomes, including operative time (160.97 vs. 177.80 min, P=0.12), intraoperative blood loss (195.95 vs. 239.73 mL, P=0.28), postoperative chest tube duration (6.594 vs. 7.656 days, P=0.15), and postoperative hospital days (10.00 vs. 10.77 days, P=0.32).ConclusionsTislelizumab and pembrolizumab demonstrated comparable drug efficacy and surgery-related safety among patients with resectable stage IIA-IIIB NSCLC undergoing neoadjuvant chemoimmunotherapy.

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Although neoadjuvant chemoimmunotherapy has emerged as a promising approach for resectable non-small cell lung cancer (NSCLC), comparative real-world data on different PD-1 inhibitors are limited. This study compared the clinical efficacy, pathological response, survival, and safety of four PD-1 inhibitors-pembrolizumab, tislelizumab, camrelizumab, and sintilimab-in patients with Stage II-IIIa NSCLC. We retrospectively reviewed 199 patients with resectable Stage II-IIIa NSCLC treated with neoadjuvant PD-1 inhibitors plus platinum-based chemotherapy from January 2018 to December 2024. After excluding 50 non-surgical cases, 149 patients were included. Outcomes compared included pathological response (pathological complete response, pCR; major pathological response, MPR), recurrence, disease-free survival (DFS), overall survival (OS), and adverse events. pCR and MPR rates were 52.2% and 58.0% (pembrolizumab), 67.6% and 75.7% (tislelizumab), 71.4% and 71.4% (camrelizumab), and 47.2% and 61.1% (sintilimab), respectively. Differences in pCR/MPR were not statistically significant. However, OS differed significantly across groups (p < 0.05), favoring pembrolizumab and tislelizumab. No significant differences were observed in progression-free survival (PFS) or recurrence among patients with pCR. Grade ≥ 3 treatment-related adverse events occurred in 27.0%-42.9% of patients, lowest in the tislelizumab group. All treatment regimens elicited substantial pathological responses and exhibited acceptable safety profiles. Pembrolizumab and tislelizumab were associated with better OS and lower toxicity, supporting their preferential use in neoadjuvant therapy for resectable NSCLC.

Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy can improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with METex14 or METamp. In 2 treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and safety profile observed in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831), a Phase II, 2-cohort, 2-stage study, is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes in patients with METex14 or high-level METamp NSCLC. Methods: Adults with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 (cohort A) or high-level METamp (gene copy number ≥10; cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescence in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks before surgical resection, followed by 3 years of adjuvant capmatinib. In the 2-stage design, stage 1 will enroll 9 patients per cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate (local assessment). Secondary endpoints are complete pathological response rate (central and local review), ORR (local assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is December 30, 2021. Citation Format: Jay M. Lee, Mark M. Awad, Teddy Saliba, Nydia Caro, Hiya Banerjee, Karen Kelly. Neoadjuvant and adjuvant capmatinib in resectable non-small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT547.

Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy is well known to improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with either METex14 or METamp. In two treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and the safety profile observed in GEOMETRY mono-1 in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831) a Phase II, two-cohort, two-stage study is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes beyond those achieved with surgery, chemotherapy, and radiation in patients with METex14 or high-level METamp NSCLC. Methods: Adult patients with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 irrespective of MET gene copy number (GCN) (cohort A) or high-level METamp with GCN ≥10 (cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescent in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks prior to surgical resection, followed by 3 years of adjuvant capmatinib. In the two-stage design, stage 1 will enroll 9 patients in each cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate based on local investigator assessment. Secondary endpoints are complete pathological response rate (central and local investigator review), ORR (local investigator assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is September 30, 2021. Citation Format: Karen Kelly, Mark M. Awad, Teddy Saliba, Nydia Caro, Beth Inserra, Hiya Banerjee, Jay M. Lee. Neoadjuvant and Adjuvant Capmatinib in Resectable Non-Small Cell Lung Cancer With MET Exon 14 Skipping Mutation or High MET Amplification: GEOMETRY-N Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA046.

Outcomes with neoadjuvant osimertinib and/or chemotherapy in patients with EGFR-mutant resectable non-small cell lung cancers.

Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis

8049 Background: Perioperative immunotherapy has emerged as a promising strategy for the treatment of resectable non-small cell lung cancer (NSCLC). This study was designed to evaluate the efficacy and safety of a comprehensive perioperative regimen, comprising neoadjuvant tislelizumab in combination with chemotherapy, followed by surgical resection and adjuvant tislelizumab, in patients with resectable stage II-IIIB NSCLC. Methods: This open-label, single-arm, phase 2 trial was designed to enroll patients (pts) with resectable stage II-IIIB (N2) NSCLC (AJCC 8 th edition). Participants received neoadjuvant therapy consisting of intravenous tislelizumab in combination with chemotherapy administered every 3 weeks for 2 to 4 cycles prior to surgery, and 0 to 2 cycles following surgery (totaling up to 4 cycles of perioperative therapy). This was followed by adjuvant tislelizumab monotherapy administered Q3W for 1 year. The primary endpoint of the study was the major pathological response (MPR) rate. Secondary endpoints included the pathological complete response (pCR) rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), and safety. Results: Between February 2023 and June 2024, a total of 30 patients were enrolled. The median age was 64 years (range: 43-77 years), with 25 males (83.3%). Twenty-eight patients (93.3%) had squamous cell carcinoma, while 2 patients (6.7%) had adenocarcinoma. In terms of disease stage, 12 patients (40%) were at stage II, and 18 patients (60%) were at stage III. For treatment, 23 patients (76.7%) received three cycles of neoadjuvant immunotherapy, and 7 patients (23.3%) received four cycles. The objective response rate (ORR) was 53.3% and surgical resection was performed in 27 patients (90%), with a complete (R0) resection rate of 96.3% (26/27). A major pathological response (MPR) was observed in 53.3% (16/30) of patients, and the pathological complete response (pCR) rate was 33.3%(10/30). With a median follow-up of 12.1 months, the median event-free survival (EFS) and overall survival (OS) data were not yet mature. In the intention-to-treat (ITT) population, the 1-year EFS rate and OS rate were 92.3% and 96.7%, respectively. During the neoadjuvant phase, the incidence of treatment-related adverse events (TRAEs) of any grade was 70%, with grade 3-4 adverse reactions occurring in 13% of patients. Conclusions: Perioperative tislelizumab achieved notable major pathological response (MPR) and pathological complete response (pCR) rates, while also demonstrating feasible surgical resection and manageable toxicity in patients with stage II-IIIB non-small cell lung cancer (NSCLC). The current data align with the initial findings and underscore the need for continued follow-up to further validate these outcomes. Clinical trial information: ChiCTR2300068140 .

e20071 Background: In recent years, multiple neoadjuvant treatment options have emerged for driver gene–positive, resectable Non-Small Cell Lung Cancer (NSCLC). However, the long-term prognosis of different treatment modalities and the specific populations that benefit most remain unclear. This study retrospectively compares multiple neoadjuvant and adjuvant strategies for driver gene–positive NSCLC, aiming to provide a reference for clinical decision-making. Methods: The medical records of patients with driver-gene-positive NSCLC who received neoadjuvant therapy and upfront surgery (US) with adjuvant targeted therapy (ATT) at Shandong Cancer Hospital and Institute from January 2021 to December 2023 were retrospectively reviewed. Patients were grouped into neoadjuvant targeted therapy (NTT), neoadjuvant chemoimmunotherapy (NCIT), neoadjuvant chemotherapy (NCT), and US+ATT. event-free survival (EFS) and overall survival (OS) were compared across the groups, and the subgroup analysis including pathological response and PD-L1 expression levels. Kaplan-Meier curves and log-rank tests were used to assess prognostic differences. Results: A total of 243 patients were included, and the median follow-up times for the NTT (n=39), NCIT (n=67), NCT (n=45), and US+ATT (n=92) groups were 23.05, 24.4, 24.9, and 23.7 months, respectively. NCIT significantly prolonged EFS compared with NCT (p=0.004). Focusing on patients with EGFR mutations, NTT combined with ATT showed no significant EFS or OS difference from NTT alone (p=0.124), but demonstrated a trend toward better EFS compared with US+ATT (after 1:1 propensity-score matching) (p=0.062). Compared with NCIT, NTT±ATT show no survival benefits; however, NCIT significantly improved EFS (p=0.001) over NCT without ATT with no OS benefit (p=0.234), and no major prognosis differences were observed between NCIT and NCT+ATT. Furthermore, among patients receiving NCIT, those who achieved a major pathological response (MPR) demonstrated significantly improved EFS (p=0.001) and OS (p=0.018). In the EGFR-mutant subgroup treated with NCIT, MPR status showed no significant impact on either EFS (p=0.128) or OS (p=0.221). Similarly, MPR status did not significantly influence survival outcomes in patients receiving NTT. Additionally, PD-L1 expression was not associated with survival outcomes. Conclusions: In patients with resectable, driver gene–positive NSCLC, NTT+ATT, NCT+ATT, and NCIT all demonstrate feasibility. Pathological response following NCIT was correlated with prognosis, suggesting it may serve as an important indicator for prognostic prediction. In the future, large-scale studies are warranted to further elucidate the long-term efficacy of different treatment strategies and to identify the patient populations most likely to benefit.

<b>Background:</b> Evidence of osimertinib as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are currently lacking. This real-world study aimed to assess the safety and feasibility of neoadjuvant osimertinib therapy followed by surgery for resectable NSCLC. <b>Methods:</b> Patients with clinical stage Ib-IIIb resectable NSCLC with EGFR mutation who received osimertinib as neoadjuvant therapy followed by surgery were included. Demographic features, assessment of response, surgery-related details and complications, toxicity profiles, and prognostic outcomes were extracted. <b>Results:</b> A total of 13 patients were included. The median age was 57 years and eight (61.5%) patients were female. The objective response rate was 69.2% (9/13) and complete resection rate was 100%. The rates of pathologic and lymph node downstaging were 100% (13/13) and 66.7% (6/9), respectively. There were no perioperative deaths and only three&nbsp;(23.1%) patients had postoperative complications.&nbsp;Seven&nbsp;(53.8%) and 13 (100%) patients experienced grade 1 treatment-related adverse reactions and laboratory abnormalities, respectively. No patients experienced drug withdrawal or surgical delays due to the adverse events. No patients showed grade 2 or worse toxicity profiles. One patient was lost to follow-up. The other 12 were alive and free of disease recurrence with a follow-up time of 10.2 months. <b>Conclusions:</b> Neoadjuvant osimertinib therapy was safe and feasible for resectable EGFR-mutated NSCLC.&nbsp;Future large prospective studies are warranted to confirm whether osimertinib as neoadjuvant therapy outperforms standard tyrosine kinase&nbsp;inhibitors or chemoimmunotherapy for resectable&nbsp;EGFR-mutated NSCLC.

In recent years, we have observed the pivotal role of immunotherapy in improving survival for patients with non-small cell lung cancer (NSCLC). However, the effectiveness of immunotherapy in the perioperative (neoadjuvant + adjuvant) treatment of resectable NSCLC remains uncertain. We conducted a comprehensive analysis of its antitumor efficacy and adverse effects (AEs) by pooling data from the KEYNOTE-671, NADIM II, and AEGEAN clinical trials. For eligible studies, we searched seven databases. The randomized controlled trials (RCTs) pertaining to the comparative analysis of combination neoadjuvant platinum-based chemotherapy plus perioperative immunotherapy (PIO) versus perioperative placebo (PP) were included. Primary endpoints were overall survival (OS) and event-free survival (EFS). Secondary endpoints encompassed drug responses, AEs, and surgical outcomes. Three RCTs (KEYNOTE-671, NADIM II, and AEGEAN) were included in the final analysis. PIO group (neoadjuvant platinum-based chemotherapy plus perioperative immunotherapy) exhibited superior efficacy in OS (hazard ratio [HR]: 0.63 [0.49-0.81]), EFS (HR: 0.61 [0.52, 0.72]), objective response rate (risk ratio [RR]: 2.21 [1.91, 2.54]), pathological complete response (RR: 4.36 [3.04, 6.25]), major pathological response (RR: 2.79 [2.25, 3.46]), R0 resection rate (RR: 1.13 [1.00, 1.26]) and rate of adjuvant treatment (RR: 1.08 [1.01, 1.15]) compared with PP group (neoadjuvant platinum-based chemotherapy plus perioperative placebo). In the subgroup analysis, EFS tended to favor the PIO group in almost all subgroups. BMI (>25), T stage (IV), N stage (N1-N2) and pathological response (with pathological complete response) were favorable factors in the PIO group. In the safety assessment, the PIO group exhibited higher rates of serious AEs (28.96% vs. 23.51%) and AEs leading to treatment discontinuation (12.84% vs. 5.81%). Meanwhile, although total adverse events, grade 3-5 adverse events, and fatal adverse events tended to favor the PP group, the differences were not statistically significant. PIO appears to be superior to PP for resectable stage II-III NSCLC, demonstrating enhanced survival and pathological responses. However, its elevated adverse event (AE) rate warrants careful consideration. https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42023487475.

Recent clinical studies have demonstrated that immunotherapy-based neoadjuvant therapy have promising effectiveness for patients with resectable non-small cell lung cancer (NSCLC) in terms of pathologic response. Therefore, we performed this study to investigate whether immunotherapy-based neoadjuvant therapy is effective and safe for patients with resectable NSCLC. This open-label observational two-arm clinical study was performed at Shanghai Chest Hospital in China with patients who had resectable NSCLC and received two to three cycles of immunotherapy-based neoadjuvant therapy or neoadjuvant chemotherapy alone, followed by surgical resection. The primary endpoint was a major pathologic response (MPR). The secondary endpoints include a complete pathological response (pCR), a radiologic response to neoadjuvant therapy (TRR), event-free survival (EFS), and overall survival (OS). A total of 51 patients was included in this clinical study, of which 31 patients received immunotherapy-based neoadjuvant therapy and 20 patients received neoadjuvant chemotherapy alone. The percentage of patients achieving a major pathologic response was 41.9% with immunotherapy-based neoadjuvant therapy and 15.0% (95% CI, 0.008 to 0.468; P = 0.043) with neoadjuvant chemotherapy alone. The percentage of patients with pathologic complete response was 19.4% in the immunotherapy-based group and 5% (95% CI, -0.069 to 0.318; P = 0.223) in the chemotherapy group. The radiographic response rate was 71% after immunotherapy-based neoadjuvant therapy and 60% (95% CI, -0.143 to 0.359; P = 0.417) after neoadjuvant chemotherapy. At a median follow-up of 28 months, the median EFS and OS endpoints were not reached. Neoadjuvant immunotherapy offers a considerable advantage over chemotherapy alone for resectable NSCLC in terms of the major pathologic response. Moreover, it did not enhance the risk of adverse events or hinder surgical resection.