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

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

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

Background In patients (pts) with non-metastatic NSCLC, surgery has curative potential but 30-80% who undergo resection experience recurrence. Neoadjuvant or adjuvant chemo is recommended for pts with high recurrence risk; however, benefits are modest and pathological complete response (pCR) with neoadjuvant chemo is low. Although immunotherapy targeting the PD-1 pathway has shown survival benefits in metastatic NSCLC, phase 3 trial results in resectable disease are yet to be reported. Recently, neoadjuvant NIVO, alone or in combination with chemo, has shown encouraging pCR rates in single-arm phase 2 studies. Here, we report the final analysis of one of the primary endpoints, pCR, of CheckMate 816 (NCT02998528)-a randomized, phase 3, open-label study evaluating NIVO + chemo vs chemo as neoadjuvant tx for resectable NSCLC. Methods Adults with clinical stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed), resectable NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to either NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles, followed by surgery. Stratification was by disease stage (IB/II vs IIIA), PD-L1 (≥ 1% or < 1%), and sex. pCR by blinded independent pathological review (BIPR) and event-free survival by blinded independent central review (BICR) are the primary endpoints. pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; pts who did not undergo surgery were counted as non-responders. Overall survival, major pathological response (MPR; ≤ 10% viable tumor in both lung and lymph nodes) per BIPR, and time to death or distant metastases are secondary endpoints. Key exploratory endpoints are objective response rate (ORR) per BICR and potential predictive biomarkers including PD-L1 and tumor mutational burden (TMB). Results Baseline characteristics were balanced between arms (n = 179 each). Neoadjuvant NIVO + chemo significantly increased pCR rates vs chemo in the intent-to-treat population (ITT) (24.0% vs 2.2%; odds ratio 13.94 [99% CI 3.49-55.75]; P < 0.0001). Improvement in pCR with NIVO + chemo vs chemo was consistent across key subgroups including disease stage (IB/II [26.2% vs 4.8%]; ≥ IIIA [23.0% vs 0.9%]), PD-L1 (< 1% [16.7% vs 2.6%]; ≥ 1% [32.6% vs 2.2%]), and TMB (low [22.4% vs 1.9%]; high [30.8% vs 2.7%]). NIVO + chemo also improved MPR rates vs chemo in the ITT (36.9% vs 8.9%), as well as ORR (53.6% vs 37.4%) and radiographic down-staging rates (30.7% vs 23.5%). Definitive surgery occurred for 83.2% of pts treated with NIVO + chemo and 75.4% with chemo; surgery was cancelled rarely due to AEs (2 pts/arm) and due to disease progression in 12 and 17 pts, respectively. Grade 3-4 tx-related AEs and grade 3-4 surgery-related AEs were reported in 33.5% vs 36.9% and 11.4% vs 14.8% of pts in the NIVO + chemo vs chemo arms, respectively. Conclusions CheckMate 816 met its first primary endpoint with a statistically significant improvement in pCR with neoadjuvant NIVO + chemo vs chemo alone per independent review. The safety profile of NIVO + chemo was consistent with the known profile of this combination regimen, and the addition of NIVO did not decrease the ability to perform surgery. CheckMate 816 is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus chemo in resectable NSCLC. Citation Format: Patrick M. Forde, Jonathan Spicer, Shun Lu, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Enriqueta Felip, Stephen Broderick, Julie Brahmer, Scott J. Swanson, Keith Kerr, Changli Wang, Gene B. Saylors, Fumihiro Tanaka, Hiroyuki Ito, Ke-Neng Chen, Cecile Dorange, Junliang Cai, Joseph Fiore, Nicholas Girard. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT003.

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

BackgroundBackground: Early stage non-small cell lung cancer (NSCLC) possessed highly local and distant recurrence rates after surgery. Recent studies showed neoadjuvant therapy can improve pathological response and postoperative survival.1–3 Using...

One size does not fit all: Nuances in postoperative N2 non–small cell lung cancer management

Invited Commentary

Background: A subset of patients experience objective clinical benefit after neoadjuvant PD-1 blockade in resectable lung cancer. The combining checkpoint blockade and chemotherapy as neoadjuvant chemoimmunotherapy therapeutic regimen might be more effective but has not been tested in resectable non-small cell lung cancer (NSCLC). Methods: This is an investigator-initiated trial for patients with resectable IIIA and IIIB non-NSCLC. The primary objective was pathological complete response (pCR). Also, the overall survival (OS) and progression-free survival (PFS) were analyzed. The correlation between the pathology response and some clinical factors was studied to identify some predictors, including PD-L1 expression. Also, artificial intelligence was utilized to incorporate multiple factors and develop a high-performance prediction model. Multiple machine learning models were built and the roles of different indicators were assessed, while the predictability of treatment outcomes was validated. Findings: Neoadjuvant PD-1 blockade plus chemotherapy was associated with few immediate adverse events. The NCIO did not delay planned surgery and led to a complete pathological response in 56% patients and a major pathological response in 80% patients. No significant correlation between the pathological response and PD-L1 expression. However, significant difference was observed between the Invade and no Invade status, with 83.3% pCR and 100% MPR rate vs. 38.5% pCR and 61.5% MPR rate (P=0.007). After model training and optimization, as well as 5-fold cross-validation, SVM and KNN were confirmed with higher prediction accuracy (both 88%). Interpretation: Neoadjuvant PD-1 blockade plus chemotherapy was associated with few side effects, and induced a complete pathological response in 56% patients. The status of the trachea was associated with pathological response. The machine learning method captures the internal correlation between the detection index and pathological response to construct a predictable model. Funding Statement: This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Declaration of Interests: None exist. Ethics Approval Statement: This study was approved by the institutional review boards at the Tianjin Medical University Cancer Institute and Hospital.

Major pathologic response is more common in survival analyses than pathological complete response. Whether major pathologic response can predict survival of patients with resectable stage IIIA non-small cell lung cancer and whether neoadjuvant chemotherapy or immunochemotherapy affect the prognosis of patients remains questionable. Patients with resectable stage IIIA non-small cell lung cancer receiving neoadjuvant chemotherapy (≥2 cycles) with/without immunotherapy were enrolled and divided into two groups according to pathological response. Comparison between the two groups was through chi-square test. Univariate Cox regression analysis and log-rank test were made to identify predictive factors of overall survival and disease-free survival. Kaplan-Meier survival curves were constructed to evaluate the prognostic impact of these factors. Totally, 38 patients were enrolled. Significant difference was observed in overall survival (P = 0.005) and disease-free survival (P = 0.007) between patients with/without major pathologic response. For patients failing to reach major pathologic response, those who underwent ≥2 cycles of neoadjuvant therapy exhibited improved outcomes in overall survival (P = 0.021) and disease-free survival (P = 0.046). Notably, within this subgroup, patients receiving ≥ 2 cycles of neoadjuvant immunochemotherapy showed a trend towards better overall survival (P = 0.076) and disease-free survival (P = 0.062). Major pathologic response can predict survival of patients with resectable stage IIIA non-small cell lung cancer. For patients potentially not achieving major pathologic response after two cycles of neoadjuvant therapy, extended cycles of feasible neoadjuvant therapy are advisable for survival benefits.

Tertiary lymphoid structures (TLS) existence is correlated with favorable prognosis in many types of cancer including non-small cell lung cancer (NSCLC). However, TLS formation and its relationship with treatment response...

PACIFIC: Time for a surgical IIIA uprising

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival. A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed. In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival. There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non-small cell lung cancer.

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.