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

Abstract

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.

Keywords: Anti-CTLA-4; Immunotherapy; Interferon; Ipilimumab; Melanoma.

Fig. 1

Peripheral blood mononuclear cells (PBMC) T-Cell Clonality in patients with no evidence of disease relapse after surgery (durable NED) versus patients with disease progression with or without subsequent death (PD/CTB). Measurements were made in PBMC at baseline (before the initiation of systemic therapy), then at 6 weeks and 3 months

Fig. 2

Tumor T-Cell fraction in patients with pathologic complete response (pCR) versus residual tumor at the time of definitive surgery (approximately 6–8 weeks from baseline). Measurements were made in primary melanoma tumor biopsies (Primary), pre-treatment metastatic melanoma biopsies (Pre Tx Met) and post-treatment metastatic melanoma biopsies (Post Tx Met; approximately 6–8 weeks from baseline)

Fig. 3

Tumor infiltrating lymphocyte (TIL) clonality in primary melanoma tumor biopsies (Primary Tumor) and post-treatment metastatic melanoma biopsies (Post Tx Met; approximately 6–8 weeks from baseline). Higher TIL clonality in primary tumor, and more so following neoadjuvant immunotherapy, was associated with improved relapse free survival (RFS)