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Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer.

Publication ,  Journal Article
Liveringhouse, CL; Latifi, K; Asous, AG; Lam, NB; Rosenberg, SA; Dilling, TJ; MacMillan, GV; Chiappori, AA; Haura, EB; Creelan, B; Gray, JE ...
Published in: Int J Radiat Oncol Biol Phys
July 15, 2023

PURPOSE: We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial. METHODS AND MATERIALS: Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests. RESULTS: The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n = 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n = 12, 63%) or patient choice (n = 2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method. CONCLUSIONS: Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

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Published In

Int J Radiat Oncol Biol Phys

DOI

EISSN

1879-355X

Publication Date

July 15, 2023

Volume

116

Issue

4

Start / End Page

837 / 848

Location

United States

Related Subject Headings

  • Prospective Studies
  • Oncology & Carcinogenesis
  • Nivolumab
  • Neoplasm Staging
  • Melanoma
  • Lung Neoplasms
  • Ipilimumab
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • Antineoplastic Combined Chemotherapy Protocols
 

Citation

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Liveringhouse, C. L., Latifi, K., Asous, A. G., Lam, N. B., Rosenberg, S. A., Dilling, T. J., … Perez, B. A. (2023). Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys, 116(4), 837–848. https://doi.org/10.1016/j.ijrobp.2023.01.006
Liveringhouse, Casey L., Kujtim Latifi, Amalin G. Asous, Nghi B. Lam, Stephen A. Rosenberg, Thomas J. Dilling, Gretchen V. MacMillan, et al. “Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer.Int J Radiat Oncol Biol Phys 116, no. 4 (July 15, 2023): 837–48. https://doi.org/10.1016/j.ijrobp.2023.01.006.
Liveringhouse CL, Latifi K, Asous AG, Lam NB, Rosenberg SA, Dilling TJ, et al. Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2023 Jul 15;116(4):837–48.
Liveringhouse, Casey L., et al. “Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer.Int J Radiat Oncol Biol Phys, vol. 116, no. 4, July 2023, pp. 837–48. Pubmed, doi:10.1016/j.ijrobp.2023.01.006.
Liveringhouse CL, Latifi K, Asous AG, Lam NB, Rosenberg SA, Dilling TJ, MacMillan GV, Chiappori AA, Haura EB, Creelan B, Gray JE, Tanvetyanon T, Shafique MR, Saltos AN, Weiner AA, Clarke J, Kelsey CR, Kim S, Caudell JJ, Rose TA, Conejo-Garcia JR, Li J, Schell MJ, Antonia SJ, Perez BA. Dose-Limiting Pulmonary Toxicity in a Phase 1/2 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2023 Jul 15;116(4):837–848.

Published In

Int J Radiat Oncol Biol Phys

DOI

EISSN

1879-355X

Publication Date

July 15, 2023

Volume

116

Issue

4

Start / End Page

837 / 848

Location

United States

Related Subject Headings

  • Prospective Studies
  • Oncology & Carcinogenesis
  • Nivolumab
  • Neoplasm Staging
  • Melanoma
  • Lung Neoplasms
  • Ipilimumab
  • Humans
  • Carcinoma, Non-Small-Cell Lung
  • Antineoplastic Combined Chemotherapy Protocols