Neoadjuvant Nivolumab in Early-Stage, Resectable Non-Small Cell Lung Cancers Abstract 8508 Chaft JE, Forde PM, Smith KN, Anagnostou V, Cottrell TR, Taube JM, Rekhtman N, Merghoub T, Jones DR, Hellmann MD, Yang SC, Broderick S, Rusch V, Velculescu VE, Topalian SL, Pardoll DM, Brahmer JR
There have been no advances in systemic therapy to treat resectable lung cancers since 2004 Nivolumab induces deep and durable responses in a subset of patients with lung cancer Neoadjuvant nivolumab treatment Rationale for Neoadjuvant Nivolumab May induce immunity against micrometastases Allows pathologic response assessment Provides tissue for correlative studies
Neoadjuvant Nivolumab Schema Newly diagnosed resectable stage I (>2cm)/II/IIIA NSCLC Nivolumab 3mg/kg IV (Day -14 & Day -28) Surgical resection (Day 0) Standard of care postoperative treatment Tumor Biopsy PBMC & plasma collection Tumor & Lymph Node Assessment TILS PBMC & plasma collection
Primary: Safety & feasibility Drug-related adverse events (90 days post-nivolumab or 30 days post-op, whichever is longer) Feasibility of resection without extended delays (>37 days from preplanned date of surgery) Sample size: 6 patient safety run-in, then up to total of 20 resected patients Exploratory endpoints Pathologic response Study Endpoints Recurrence free and overall survival Immunologic correlates of clinical outcomes
Patients 21 treated with preoperative intent 22 enrolled 20 resected 1 unresectable (tracheal invasion) 1 withdrawn (diagnosis change to SCLC) Characteristics N = 21 Age yrs, median (range) 67 (55-84) Male/Female 10/11 Adenocarcinoma Pleomorphic carcinoma Squamous Clinical Stage (AJCC 7 th ed) IA/IB IIA IIB IIIA Smoking status Never Former/Current 14 1 6 4 5 5 7 3 18
Primary Endpoints Feasibility: Safety: Nivolumab did not delay or interfere with surgery in any patients One death in the postoperative safety period was unrelated to study drug (sequelae of traumatic fall) Drug-related adverse events N = 22 (All treated) Any grade N(%) Grade 3-4 N(%) Fever 1* (5) 0 Thyroid dysfunction 1 (5) 0 GI Anorexia/dysgeusia Vomiting/diarrhea LFT abnormality 2 (9) 1 (5) 1 (5) Pneumonia 0 1* (5) Infusion reaction 1 (5) 0 CNS (delirium) 1 (5) 0 *Nivo dose #2 was withheld in 1 patient due to fever and pneumonia, surgery was not delayed 0 0 0
Radiographic Responses to 2 Doses of Nivolumab Pleomorphic, Pathologic CR Squamous, Pathologic CR 4 weeks Prenivo Postnivo RECIST* N (%) PR 2 (10%) Stable disease 18 (85%) PD 1 (5%) *Measurements per RECIST v1.1 but not confirmed as surgery followed 1 st assessment
Pathologic Responses to Neoadjuvant Nivolumab Percent Pathologic Regression 20 10 0-10 -20-30 -40-50 -60-70 -80-90 -100 Pre-treatment PD-L1 Unknown Negative Positive * Major pathologic response (MPR) was seen in 9/21 cases [43% (95% CI 24-63%)] Pre-treatment PD-L1 positivity [ 1% membranous staining (Dako 28-8)] did not correlate with MPR *MPR is defined as 10% viable tumor cells 1,2 1. Pataer A, et al. J Thorac Oncol. 2012;7(5):825-832. 2. Hellmann MD, et al. Lancet Oncol. 2014;15(1):e42-50.
Clinical Follow-Up Median post-op follow-up is 12 mos (range 2-20) None of the patients with MPR have recurred 2 of 20 resected patients have recurrent lung cancer 1 solitary brain metastasis, treated now NED x 1year 1 systemic recurrence 1 year post-op 2 deaths Patient who was not resected died of disease 1 death not related to drug or disease
Multiplexed Immunofluorescence Shows Post-Treatment Influx of CD8+ T Cells Pre-treatment Key PD-L1 PD-1 CD8 FOXP3 CD68 Tumor DAPI Post-treatment
Background for Correlative Studies Tumor & normal DNA Whole exome sequencing Mapping to reference genome Somatic sequence alterations Predicting neoantigens Antigen processing Epitope abundance MHC binding Mutation Associated Neoantigen (MANA)
Mutation Burden and Neoantigen Density Are Associated With Pathologic Response to Neoadjuvant Nivolumab (N = 11) SEQUENCE ALTERATIONS MANAs HISTOLOGY PD-L1 STATUS # Sequence Alterations # Sequence Alterations Residual Tumor (%) Residual Tumor (%) R = - 0.869 P =.001 R = - 0.869 P =.001 # MANAs # MANAs Residual Tumor (%) Residual Tumor (%) R = - 0.861 P =.001 R = - 0.861 P =.001 Squamous Nonsquamous PD-L1 1% PD-L1<1% PD-L1 expression assessed using the Dako PD-L1 IHC 28-8 pharmdx.
TCRseq: Deep Sequencing of CDR3 Regions to Analyze the Entire TCR Repertoire and, Thus, T-cell Clonality ~50 V segments D J Rearrangement at the DNA level Constant N-Region Diversity CDR3 region generates all the TCR diversity
T Cells Specific for Dominant Mutation-Associated Neoantigen (MANA) Expand in Peripheral Blood Upon Neoadjuvant Treatment With Nivolumab TCR Vβ CDR3 sequences: Activation of 3 T cell clones specific for MANA#7 that are found in tumor MANA#7-specific T cell clones found in tumor and LN Frequency of MANA#7 specific T cell clones in peripheral blood over time Clonal frequency 1.6% of total TIL Clonal frequency Initiate nivolumab Surgery Individual MANA peptides tested Day relative to surgery
Nivolumab prior to lung cancer resection did not delay surgery in any of the treated patients No unexpected safety signals were seen 43% of tumors demonstrated a major pathologic response Correlative studies in a subset of tumors: Conclusions Associated mutation and MANA burden with pathologic response Identified MANA-specific TCRs in blood and tumor Observed temporal increases in MANA-specific TCRs in the peripheral blood after nivolumab treatment, a potential biomarker of nivolumab response