Brief Report: Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination with Pegilodecakin in Patients with Metastatic Non-Small-Cell Lung Cancer (CYPRESS-1 and CYPRESS-2)

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J Thorac Oncol


INTRODUCTION: Checkpoint inhibitors (CPI) have been approved to treat metastatic NSCLC. Pegilodecakin+CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS-1 and CYPRESS-2.

METHODS: CYPRESS-1 (N=101) and CYPRESS-2 (N=52) included ECOG 0-1, 1L/2L metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS-1) or nivolumab (CYPRESS-2); experimental arms received pegilodecakin+CPI. Patients had PD-L1 tumor proportion score (TPS) ≥50% (CYPRESS-1) or 0-49% (CYPRESS-2). Primary endpoint was ORR per investigator. Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included immune activation biomarkers.

RESULTS: Median follow-up for CYPRESS-1 and CYPRESS-2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin+pembrolizumab versus pembrolizumab were: ORR per investigator 47%vs.44% (Odds ratio:1.1;95%CI[0.5,2.5]); mPFS 6.3vs.6.1 months (HR:0.937;95%CI[0.541,1.625]); and mOS 16.3 months vs. not reached (HR:1.507;95%CI[0.708,3.209]). Results per blinded independent central review (BICR) were consistent. Treatment discontinuation rate due to AEs doubled in the experimental arm (32%vs.15%). Gr≥3 treatment related adverse events (TRAEs)(62%vs.19%) included anemia(20%vs.0%) and thrombocytopenia(12%vs.2%). Results for pegilodecakin+nivolumab versus nivolumab were: ORR per investigator 15%vs.12% (Odds ratio:1.2;95%CI[0.3,5.9]); mPFS 1.9vs.1.9 months (HR:1.006;95%CI[0.519,1.951]); and mOS 6.7vs.10.7 months (HR:1.871;95%CI[0.772,4.532]). Gr≥3 TRAEs (70.4%vs.16.7%) included anemia(40.7%vs.0%), fatigue(18%vs.0%), and thrombocytopenia(14.8%vs.0%). Biomarker data suggested activation of immunostimulatory signals of IL-10R pathway in pegilodecakin-containing arms.

CONCLUSION: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in 1L/2L NSCLC. Pegilodecakin+CPI demonstrated overall higher toxicity compared to CPI alone, leading to doubling of treatment discontinuation rate due to AEs.

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ePub ahead of print