Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-α2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire.

Autor: Tarhini A; UPMC Hillman Cancer Center, Pittsburgh, USA. tarhina1@ccf.org.; Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute and Case Comprehensive Cancer Center, 9500 Euclid Ave CA6-157, Cleveland, OH, 44195, USA. tarhina1@ccf.org., Lin Y; UPMC Hillman Cancer Center, Pittsburgh, USA., Lin H; UPMC Hillman Cancer Center, Pittsburgh, USA., Rahman Z; UPMC Hillman Cancer Center, Pittsburgh, USA., Vallabhaneni P; UPMC Hillman Cancer Center, Pittsburgh, USA., Mendiratta P; Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute and Case Comprehensive Cancer Center, 9500 Euclid Ave CA6-157, Cleveland, OH, 44195, USA., Pingpank JF; UPMC Hillman Cancer Center, Pittsburgh, USA., Holtzman MP; UPMC Hillman Cancer Center, Pittsburgh, USA., Yusko EC; Adaptive Biotechnologies, Seattle, USA., Rytlewski JA; Adaptive Biotechnologies, Seattle, USA., Rao UNM; UPMC Hillman Cancer Center, Pittsburgh, USA., Ferris RL; UPMC Hillman Cancer Center, Pittsburgh, USA., Kirkwood JM; UPMC Hillman Cancer Center, Pittsburgh, USA.
Jazyk: angličtina
Zdroj: Journal for immunotherapy of cancer [J Immunother Cancer] 2018 Oct 23; Vol. 6 (1), pp. 112. Date of Electronic Publication: 2018 Oct 23.
DOI: 10.1186/s40425-018-0428-5
Abstrakt: Background: Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR).
Methods: Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood.
Results: Thirty patients (age 37-76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p = 0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21-54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18-51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p = 0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival.
Conclusions: Neoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials.
Trial Registration: ClinicalTrials.gov, NCT01608594 . Registered 31 May 2012.
Databáze: MEDLINE
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