Sands, Jacob

8057 Background: The NCI Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) study tested resected stage II-IIIB(N2) NSCLC for targetable EGFR and ALK alterations and PD-L1 expression to screen patients for biomarker-driven adjuvant therapy trials (NCT02194738). Local lab results were requested when available for comparison to central lab results. Methods: We identified patients with both central and local PD-L1 results in the ALCHEMIST adjuvant immunotherapy study screening population. Discrepancies in tumor proportion score (TPS) between central and local PD-L1 were defined using prespecified cut-points (granular: <1%, 1-<5%, 5-<10%, 10-<20%, 20-<30%, 30-<40%, 40-<50%, 50-60%, 60-<70%, 70-<80%, 80-<90%, 90-<100%; clinical: <1%, 1-<50%, 50-100%). Large discrepancies were defined as ≥ 50 percentage point differences; for these cases, local PD-L1 and hematoxylin & eosin-stained slides were requested. These and all central slides were digitally scanned at 40X. Three expert pathologists reviewed the scanned slides in a blinded fashion. Differences between patient or tumor characteristics were assessed by Chi-square and Wilcoxon rank sum tests. Percent agreement was computed within and between the reviewers. Results: Central and local PD-L1 results were available for 497 patients. 177 cases (36%) had discrepancies that placed patients in different clinical TPS categories (<1%, 1-<50%, 50-100%). Among these, 43 cases had large TPS discrepancies; 14 had available local testing slides. 46 of the 320 cases without discrepancy were randomly selected as controls. No patient or tumor characteristics were associated with discrepancy, including tumor location, histology, grade or cancer stage (p > 0.05). Pairwise comparisons of TPS according to three pathologists re-reading the same scanned PD-L1 slides showed similar levels of disagreement in clinical TPS category whether there was initial discrepancy between central and local results (24%, 34%, and 23%; mean 27%) or not (33%, 30%, and 20%; mean 28%). Among the 14 cases with large initial discrepancies and local slides available, there was agreement in clinical TPS category when the anonymized central and local scanned slides were re-read by the pathologists in 54%, 38%, and 43% of cases, despite 100% non-agreement in initial reads. There were higher rates of agreement when the tested slides both originated from the same (100%) versus different (35%) blocks, when the same (48%) versus different (40%) PD-L1 antibodies were used, and when the cases were of non-squamous (52%) versus squamous (14%) cell carcinoma. Conclusions: There are substantial differences in PD-L1 TPS read by pathologists that can result in placement of patients in different categories commonly used for clinical management. These differences have clear implications in clinical trials and routine patient care.

8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

8000 Background: The NCI’s ALCHEMIST program has screened thousands of patients with resected lung adenocarcinoma for mutations in EGFR and ALK. EA5142 studied the efficacy of adjuvant nivolumab after standard of care adjuvant therapy in patients with resected lung adenocarcinoma without sensitizing EGFR and ALK alterations and squamous cell carcinoma. Methods: Patients enrolled in the ALCHEMIST screening trial (A151216) with resected NSCLC tumors at least 4 cm and/or lymph node positive (N1/2) (for lung adenocarcinoma, without sensitizing EGFR and ALK alterations), were centrally tested for tumor cell PD-L1 expression using the DAKO 28-8 clone. After completion of all planned adjuvant therapy (chemotherapy and/or post-operative radiation) patients were randomized 1:1 to adjuvant nivolumab 480 mg IV every 4 weeks for up to 1 year or best supportive care. Patients were stratified by tumor histology, stage (AJCC 7 th edition IB/IIA vs IIB/IIIA), prior adjuvant treatment, and PD-L1 status (<1% vs ≥1%). The primary study endpoints were disease free survival (DFS) in all patients and in patients with high tumor PD-L1 expression (≥50%). Overall survival was powered to be tested hierarchically, if DFS was positive. Results: Between July 2016 and October 2019, 935 patients were randomized across 378 sites. The treatment arms were balanced for age (median 66 years), sex (52% male), smoking status (10% never smoked), histology (29% squamous), stage and PD-L1 expression (29% PD-L1 high). With a median follow-up of 72.6 months, nivolumab did not improve DFS in the intention to treat population (median DFS 71.3 months vs. 68.8 months in observation arm), hazard ratio (HR) 0.97 (95% CI 0.81-1.17, p=0.78) or the PD-L1 ≥50% subset (median DFS 89.8 months vs. 78.5 months in observation arm), HR 0.86 (95% CI 0.59-1.25, p=0.43). In multivariate analysis, adjusting for age, gender, and smoking history, the DFS HR was 0.99 (95% CI 0.82-1.19, p=0.89) in all randomized patients and 0.82 (95% CI 0.56-1.2, p=0.31) in the PD-L1 ≥50% subset. As the primary recurrence endpoint included any lung cancer, including new primaries, a sensitivity analysis was performed excluding new primary lung cancers, DFS HR 0.97 (95% CI 0.80-1.18, p=0.76) in all patients and HR 0.88 (95% CI 0.60-1.30, p=0.52 in the ≥50% subset. The median duration of treatment with adjuvant nivolumab was 9.4 months (range 0-12.7 months). The most common reasons for nivolumab discontinuation were adverse event (29%), patient withdrawal (11%), and disease progression while on treatment (10%). Treatment related grade 3-5 toxicities were reported in 25% of patients: Grade 3: 23%, Grade 4: 2%, Grade 5: <1%. Conclusions: In patients with resected NSCLC (≥4cm or LN+, EGFR/ALK -) adjuvant nivolumab did not improve DFS, irrespective of tumor PD-L1 expression. Clinical trial information: NCT02595944 .