Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Joshua E. Reuss, Valsamo Anagnostou, Tricia R. Cottrell, Kellie N. Smith, Franco Verde, Marianna Zahurak, Mara Lanis, Joseph C. Murray, Hok Yee Chan, Caroline McCarthy, Daphne Wang, James R. White, Stephen Yang, Richard Battafarano, Stephen Broderick, Errol Bush, Malcolm Brock, Jinny Ha, David Jones, Taha MerghoubJanis Taube, Victor E. Velculescu, Gary Rosner, Peter Illei, Drew M. Pardoll, Suzanne Topalian, Jarushka Naidoo, Ben Levy, Matthew D. Hellmann, Julie R. Brahmer, Jamie E. Chaft, Patrick M. Forde

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13 Scopus citations


Background We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Methods Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. Results While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. Conclusions Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Original languageEnglish (US)
Article numbere001282
JournalJournal for immunotherapy of cancer
Issue number2
StatePublished - Sep 13 2020


  • clinical trials as topic
  • immunotherapy
  • lung neoplasms
  • tumor biomarkers
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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