ESMO 2016 Press Release: Neoadjuvant Immunotherapy Prior to Surgery is Safe and Feasible in Early Lung Cancer

LUGANO-COPENHAGEN – Neoadjuvant immunotherapy with the PD-1 inhibitor nivolumab is safe and feasible prior to surgery for early lung cancer, researchers reported at the ESMO 2016 Congress in Copenhagen.1

“Until now nivolumab and the other anti-PD-1 and anti-PD-L1 drug studies have only been reported in metastatic or advanced lung cancer,” said lead author Dr Patrick Forde, Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins, Baltimore, US. “This was the first study of neoadjuvant PD-1 blockade in early stage lung cancer.”

The primary objective of the study was to see whether it was safe and feasible to administer neoadjuvant nivolumab to patients with early stage non-small-cell lung cancer (NSCLC) prior to resection of the tumour. Treatment was considered feasible if it did not delay surgery.

Exploratory aims included extensive correlative analyses of the pretreatment biopsy and post-treatment resected tumour including PD-L1 staining, multiplex immunohistochemistry and T cell receptor sequencing. An additional exploratory analysis looked at the degree of pathological regression. This was analysed by a lung cancer pathologist using a method previously reported for use in measuring response to neoadjuvant chemotherapy in NSCLC. Major pathological regression (90% or more) was defined as a resected specimen with less than 10% remaining viable tumour cells.

The study included 20 patients who had a tumour biopsy taken. They then received two doses of nivolumab at four and two weeks prior to surgical resection of the tumour.
The results in the first 16 patients were presented today. The investigators found that there were no significant safety concerns and no delays to surgery with nivolumab.
Six of 15 patients (40%) had major pathological regression of their tumour following nivolumab. All of those tumours had dense infiltration of immune cells and either a complete pathologic response or isolated remaining tumour cells. An additional five patients had some regression of their tumour noted and evidence of immune infiltration. Multiplex IHC demonstrated infiltration of cytotoxic T cells into the tumours and also detection of new T cell clones in the tumour that did not appear to be present in the pre-treatment biopsy.

Forde said: “We found that neoadjuvant administration of nivolumab is safe and feasible in stage I-IIIA NSCLC and also a preliminary signal that anti-PD-1 immunotherapy may have activity in early stage lung cancer. Following these initial results we are expanding the study. One cohort will receive a third dose of nivolumab preoperatively and the other will receive the combination of nivolumab and ipilimumab preoperatively. This expanded study will continue to be conducted in collaboration with investigators at Johns Hopkins University and Memorial Sloan-Kettering Cancer Centre. Others, such as the Lung Cancer Mutation Consortium in the United States, are also conducting larger studies of neoadjuvant immune checkpoint inhibition in NSCLC.”

Commenting on the study, Professor Pieter Postmus, chair of Thoracic Oncology at the University of Liverpool, UK, said: “There is a potential for bias when comparing a small biopsy, which might not represent the whole tumour, with the resected tumour. This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”

“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumour cells in tumour biopsies taken before and four to eight weeks after immunotherapy,” continued Postmus. “If in this way regression - as defined in the preoperative study - correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies."

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Notes to Editors

References

  1. Abstract LBA41_PR - ‘Neoadjuvant anti-PD1, nivolumab, in early resectable non-small-cell lung cancer‘ will be presented by Dr Patrick Forde during the Proffered Paper Session, Non-metastatic NSCLC and other thoracic malignancies on Friday, 7 October, 14:00 to 15:30 (CEST) in Room Madrid.

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Abstract for LBA41_PR
Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer
P.M. Forde1, K.N. Smith1, J.E. Chaft2, M. Hellmann2, T. Merghoub2, J.D. Wolchok2, S.C. Yang3, R.J. Battafarano3, E. Gabrielson4, C.S. Georgiades5, F. Verde5, G.L. Rosner6, J. Naidoo1, T.R. Cottrell4, J.M. Taube4, V. Anagnostou1, V.E. Velculescu1, S.L. Topalian3, D.M. Pardoll1, J.R. Brahmer1
1Department of Oncology, Johns Hopkins University, Baltimore, MD, USA, 2Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3Department of Surgery, Johns Hopkins University, Baltimore, MD, USA, 4Department of Pathology, Johns Hopkins University, Baltimore, MD, USA, 5Department of Radiology, Johns Hopkins University, Baltimore, MD, USA, 6Division of Biostatistics, Johns Hopkins University, Baltimore, MD, USA
Background: Nivolumab is a PD-1 inhibitor that has demonstrated durable responses and improved survival in patients (pts) with previously treated, metastatic non-small-cell lung cancer (NSCLC). This is the first report of neoadjuvant PD-1 blockade in pts with early stage NSCLC.

Methods: Pts with untreated, resectable, stage I-IIIA NSCLC underwent pretreatment tumor biopsy and then received two doses of nivolumab 3mg/kg administered at 4 and 2 weeks prior to surgical resection. Postoperatively, standard adjuvant chemotherapy was administered at investigator discretion. The primary endpoints were safety and feasibility of preoperative nivolumab administration. Exploratory endpoints included the degree of pathologic regression, as well as molecular and immunophenotypic changes in tumor and peripheral blood, including T cell repertoire analysis by TCR CDR3 deep sequencing, function, gene expression profiling, and tumor antigen recognition. An initial 6-patient safety run-in cohort was followed by an expansion cohort, with a planned accrual of 16 resected pts.

Results: As of 09/19/2016, 18 pts were enrolled and 16 completed surgical resection (two patients were not ultimately resected). No delays to surgery or surgical complications related to nivolumab occurred. Twelve of 15 resected patients (80%) had pathologic evidence of tumor regression, and 6 (40%) achieved major pathologic responses (MPR; <10% residual viable tumor), at the time of abstract submission final pathology was pending from the 16th resected pt. Of the 6 MPR pts, 3 had no radiographic evidence of response. Surgical specimens in all cases were characterized by substantial T cell infiltration. Among 6 MPRs, 4 tumors have been tested with PD-L1 IHC (28-8 assay) and 3 were positive. Both unique and shared T cell clones were expanded in both tumor and peripheral blood, including new infiltration of T cell clones found only in the post-treatment tumor specimen.

Conclusions: Neoadjuvant nivolumab was feasible and safe. Most pts have pathologic evidence of anti-tumor response, including MPR in 6 of 15 pts. Neoadjuvant anti-PD1 immunotherapy may have substantial anti-tumor activity in early stage NSCLC.

Clinical trial identification: identifier: NCT02259621

Legal entity responsible for the study: Johns Hopkins University School of Medicine

Funding: Stand Up to Cancer, AACR, CRI and LUNGevity BMS pharmaceuticals supplied nivolumab and funding for PD-L1 testing

Disclosure:
P.M. Forde: Research grants to my institution for clinical trials of which I am PI from BMS, Novartis, AstraZeneca, Kyowa, outside of this submitted work. Consultant/Advisory Board (uncompensated) - AstraZeneca, Celgene.
J.E. Chaft: Consulting or Advisory Role: Myriad Genetics, Biodesix, Genentech/Roche, Clovis Oncology, AstraZeneca/MedImmune Honoraria: Dava Oncology Research funding to Institution: Lilly, Genentech/Roche, BMS, AstraZeneca/Medimmune.
M. Hellmann: Consulting or Advisory Role: Third Rock Ventures, BMS, Merck, Genentech, Alexion Pharmaceuticals, Inovio Pharmaceuticals, AstraZeneca/Medimmune Research Funding: BMS
J.D. Wolchok: Consultant/Advisory Role: BMS, Merck, Medimmune, Ziopharm, Polynoma, Polaris, Jounce, Genentech Travel/Expenses: BMS Stock/Ownership: Potenza, Vesuvius Research Funding to Institution: BMS, Medimmune, GSK, Merck.
E. Gabrielson: Leadership: Taxus Cardium Pharmaceuticals Stock/Ownership: Taxus Cardium Pharmaceuticals.
J.M. Taube: Consultant/advisory board for Merck, BMS, Astra Zeneca and I receive investigator-initiated research funding from BMS.
V.E. Velculescu: Leadership/Stock/Ownership/Consultant/Advisory Role: Personal Genome Diagnostics Honoraria: Janssen Patents/Royalties: Qiagen, Exact Sciences, Inostics, Myriad Genetics, Personal Genome Diagnostics.
S.L. Topalian: Consultant/Advisory Role: Five Prime Therapeutics, GSK, Jounce Therapeutics, ImaginAb Travel Expenses: BMS, Five Prime Stock/Ownership: Five Prime Research Funding: BMS.
D.M. Pardoll: Consultant/Advisory Role: Pfizer Research Funding: Potenza Therapeutics, Compugen, BMS Patents/Royalties: BMS Travel/Expenses: AstraZeneca, BMS, Pfizer.
J.R. Brahmer: Consultant/Advisory Role: Merck KGaA, BMS, Lilly Travel Expenses: BMS, Merck Other relationship: BMS Research Funding to Institution: BMS, Merck, AstraZeneca, Celgene.
All other authors have declared no conflicts of interest.
Keywords: early lung cancer, nivolumab, Neoadjuvant, PD1