Neoadjuvant PD-1 blockade in resectable lung cancer

Patrick Forde, Jamie E. Chaft, Kellie Smith, Valsamo Anagnostou, Tricia R. Cottrell, Matthew D. Hellmann, Marianna Zahurak, Stephen Broderick, Stephen C Yang, David R. Jones, Richard J Battafarano, Moises J. Velez, Natasha Rekhtman, Zachary Olah, Franco Verde, Jarushka Naidoo, Kristen Marrone, Haidan Guo, John William Sidhom, Jiajia ZhangJustina X. Caushi, Hok Yee Chan, Robert B Scharpf, James White, Edward Gabrielson, Hao Wang, Gary Rosner, Valerie Rusch, Jedd D. Wolchok, Taha Merghoub, Janis M Taube, Victor E Velculescu, Suzanne Topalian, Julie Brahmer, Andrew Mark Pardoll

Research output: Contribution to journalArticle

Abstract

BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.

Original languageEnglish (US)
Pages (from-to)1976-1986
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number21
DOIs
StatePublished - May 24 2018

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Lung Neoplasms
Clone Cells
Neoplasms
Non-Small Cell Lung Carcinoma
T-Lymphocytes
Ligands
Tumor Burden
Mutation
Body Weight
nivolumab
Safety
Survival
Antibodies
Therapeutics
Proteins

ASJC Scopus subject areas

  • Medicine(all)

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Neoadjuvant PD-1 blockade in resectable lung cancer. / Forde, Patrick; Chaft, Jamie E.; Smith, Kellie; Anagnostou, Valsamo; Cottrell, Tricia R.; Hellmann, Matthew D.; Zahurak, Marianna; Broderick, Stephen; Yang, Stephen C; Jones, David R.; Battafarano, Richard J; Velez, Moises J.; Rekhtman, Natasha; Olah, Zachary; Verde, Franco; Naidoo, Jarushka; Marrone, Kristen; Guo, Haidan; Sidhom, John William; Zhang, Jiajia; Caushi, Justina X.; Chan, Hok Yee; Scharpf, Robert B; White, James; Gabrielson, Edward; Wang, Hao; Rosner, Gary; Rusch, Valerie; Wolchok, Jedd D.; Merghoub, Taha; Taube, Janis M; Velculescu, Victor E; Topalian, Suzanne; Brahmer, Julie; Pardoll, Andrew Mark.

In: New England Journal of Medicine, Vol. 378, No. 21, 24.05.2018, p. 1976-1986.

Research output: Contribution to journalArticle

Forde, P, Chaft, JE, Smith, K, Anagnostou, V, Cottrell, TR, Hellmann, MD, Zahurak, M, Broderick, S, Yang, SC, Jones, DR, Battafarano, RJ, Velez, MJ, Rekhtman, N, Olah, Z, Verde, F, Naidoo, J, Marrone, K, Guo, H, Sidhom, JW, Zhang, J, Caushi, JX, Chan, HY, Scharpf, RB, White, J, Gabrielson, E, Wang, H, Rosner, G, Rusch, V, Wolchok, JD, Merghoub, T, Taube, JM, Velculescu, VE, Topalian, S, Brahmer, J & Pardoll, AM 2018, 'Neoadjuvant PD-1 blockade in resectable lung cancer', New England Journal of Medicine, vol. 378, no. 21, pp. 1976-1986. https://doi.org/10.1056/NEJMoa1716078
Forde, Patrick ; Chaft, Jamie E. ; Smith, Kellie ; Anagnostou, Valsamo ; Cottrell, Tricia R. ; Hellmann, Matthew D. ; Zahurak, Marianna ; Broderick, Stephen ; Yang, Stephen C ; Jones, David R. ; Battafarano, Richard J ; Velez, Moises J. ; Rekhtman, Natasha ; Olah, Zachary ; Verde, Franco ; Naidoo, Jarushka ; Marrone, Kristen ; Guo, Haidan ; Sidhom, John William ; Zhang, Jiajia ; Caushi, Justina X. ; Chan, Hok Yee ; Scharpf, Robert B ; White, James ; Gabrielson, Edward ; Wang, Hao ; Rosner, Gary ; Rusch, Valerie ; Wolchok, Jedd D. ; Merghoub, Taha ; Taube, Janis M ; Velculescu, Victor E ; Topalian, Suzanne ; Brahmer, Julie ; Pardoll, Andrew Mark. / Neoadjuvant PD-1 blockade in resectable lung cancer. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 21. pp. 1976-1986.
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abstract = "BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45{\%}). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45{\%} of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.",
author = "Patrick Forde and Chaft, {Jamie E.} and Kellie Smith and Valsamo Anagnostou and Cottrell, {Tricia R.} and Hellmann, {Matthew D.} and Marianna Zahurak and Stephen Broderick and Yang, {Stephen C} and Jones, {David R.} and Battafarano, {Richard J} and Velez, {Moises J.} and Natasha Rekhtman and Zachary Olah and Franco Verde and Jarushka Naidoo and Kristen Marrone and Haidan Guo and Sidhom, {John William} and Jiajia Zhang and Caushi, {Justina X.} and Chan, {Hok Yee} and Scharpf, {Robert B} and James White and Edward Gabrielson and Hao Wang and Gary Rosner and Valerie Rusch and Wolchok, {Jedd D.} and Taha Merghoub and Taube, {Janis M} and Velculescu, {Victor E} and Suzanne Topalian and Julie Brahmer and Pardoll, {Andrew Mark}",
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T1 - Neoadjuvant PD-1 blockade in resectable lung cancer

AU - Forde, Patrick

AU - Chaft, Jamie E.

AU - Smith, Kellie

AU - Anagnostou, Valsamo

AU - Cottrell, Tricia R.

AU - Hellmann, Matthew D.

AU - Zahurak, Marianna

AU - Broderick, Stephen

AU - Yang, Stephen C

AU - Jones, David R.

AU - Battafarano, Richard J

AU - Velez, Moises J.

AU - Rekhtman, Natasha

AU - Olah, Zachary

AU - Verde, Franco

AU - Naidoo, Jarushka

AU - Marrone, Kristen

AU - Guo, Haidan

AU - Sidhom, John William

AU - Zhang, Jiajia

AU - Caushi, Justina X.

AU - Chan, Hok Yee

AU - Scharpf, Robert B

AU - White, James

AU - Gabrielson, Edward

AU - Wang, Hao

AU - Rosner, Gary

AU - Rusch, Valerie

AU - Wolchok, Jedd D.

AU - Merghoub, Taha

AU - Taube, Janis M

AU - Velculescu, Victor E

AU - Topalian, Suzanne

AU - Brahmer, Julie

AU - Pardoll, Andrew Mark

PY - 2018/5/24

Y1 - 2018/5/24

N2 - BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.

AB - BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.

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U2 - 10.1056/NEJMoa1716078

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SP - 1976

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