Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1 | Nature

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Subjects

- Drug development

- Immunoediting

- Melanoma

- Translational research

Abstract

Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer1. Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1 mg kg−1) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3 mg kg−1) or intravenous ipilimumab (3 mg kg−1). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (Treg) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural Treg cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fcγ receptor (FcγR) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated Treg cell and FcγR+ M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

Main

Over the past decade, outcomes for metastatic melanoma have markedly improved, reaching 52% melanoma-specific overall survival at 10 years, driven largely by intravenous immunotherapies targeting the T cell co-inhibitory checkpoints CTLA4 and PD12. Following the approval of ipilimumab (anti-CTLA4 immunoglobulin G1 (IgG1)) in 20113 and nivolumab (anti-PD1 IgG4) in 20144,5, combined nivolumab and ipilimumab therapy was approved in 2015 and incorporated into first line treatment guidelines6. Although this combination achieves higher response rates and survival than monotherapy1, it is associated with severe (common terminology criteria for adverse events (CTCAE) grade ≥3) treatment-related adverse events in approximately 60% of patients, some of which are irreversible and 1–4% of which are fatal in real-world settings7,8, limiting its use to about half of eligible patients in routine clinical practice9. Approved anti-PD1 monoclonal antibodies act as checkpoint blockers through their non-depleting IgG4 isotype. Once PD1 receptor saturation is achieved (approximately 0.3 mg kg−1), dose escalation does not improve efficacy or meaningfully increase toxicity10,11. By contrast, ipilimumab is an unmodified IgG1 antibody that is capable of engaging Fcγ receptor (FcγR) proteins and inducing antibody-dependent cellular cytotoxicity and phagocytosis12, resulting in dose-dependent increases in both efficacy and toxicity13.

Preclinical studies indicate that intratumoural delivery of low doses of anti-CTLA4 at high local concentrations can reduce systemic exposure while preserving dose-dependent antitumour activity14,15,16,17. A phase 1 study in patients with stage III–IV melanoma (n = 12) evaluating intratumoural ipilimumab combined with intratumoural interleukin-2 showed promising activity without dose-limiting toxicity, with objective responses in 67% of injected lesions and abscopal responses in 40% of evaluable patients18.

Based on these data, we hypothesized that administering a tenfold lower total dose of ipilimumab (0.3 mg kg−1) directly into tumours at the highest commercially available concentration (5 mg ml−1) could enhance antitumour efficacy while limiting systemic toxicity. To address this hypothesis, we initiated a multicentre randomized phase 1b trial evaluating the safety, efficacy and associated biomarkers of intratumoural ipilimumab combined with intravenous nivolumab in patients with previously untreated advanced melanoma.

The NIVIPIT trial (ClinicalTrials.gov: NCT02857569) evaluated intravenous nivolumab (1 mg kg−1) combined with either intravenous ipilimumab at 3 mg kg−1 (IV arm) or intratumoural ipilimumab at 0.3 mg kg−1 (IT arm), administered every 3 weeks for 4 doses, followed by nivolumab 3 mg kg−1 every 2 weeks for up to 12 months (Extended Data Fig. 1a). A pharmacokinetic, pharmacodynamic and biomarker programme including prospective analyses of fresh tumour biopsies and blood samples was incorporated into the protocol (Extended Data Fig. 1b).

Sixty-one patients were enrolled across 4 clinical sites and random