Cemiplimab for kidney organ transplant recipients with advanced cutaneous squamous cell carcinoma: CONTRAC-1.
Authors: Hanna Glenn J. , Dharaneeswaran Harita J , Giobbie-Hurder Anita , Harran John J , Liao Zixi , Pai Lori , Tchekmedyian Vatche , Ruiz Emily S. , Waldman Abigail H , Schmults Chrysalyne D. , Lizotte Patrick H. , Paweletz Cloud P. , Riella Leonardo V , Murakami Naoka , Silk Ann W. 
Published: June 2023

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Background: Solid organ transplant recipients are often excluded from immunotherapy trials given the risk of allograft rejection and loss. We report the results of the first prospective study using the PD-1 inhibitor Cemiplimab (Cemi) for kidney transplant recipients (KTR) with advanced, incurable cutaneous squamous cell carcinoma (cSCC), adopting a standardized approach to immunosuppression (IS) with mTOR inhibition and dynamic prednisone (NCT04339062). Methods: This single-arm, open-label prospective clinical trial enrolled KTRs (eGFR ≥30 mL/min without proteinuria) with advanced cSCC, ECOG ≤2, measurable disease (RECIST v1.1), with no prior immunotherapy exposure. KTRs received mTOR inhibition (target trough 4-6 ng/mL) with a prednisone taper each cycle (40 mg on day -1 to 3, 20 mg days 4-6, 10 mg days 7-20) along with Cemi 350 mg IV every 21-days. Primary endpoint: rate of rejection (futility defined as ≥2/3 or 4/6 KTRs with rejection events). Secondary endpoints: overall response rate (ORR), duration of response, progression-free survival (PFS), overall survival (OS), infection rates. Exploratory: baseline tumor PD-L1 score, molecular and immunologic predictors of response. Results: From 11/2020 to 1/2023, 10 KTRs (median years from transplant: 8, range: 3-31) enrolled including 8 (80%) men, median age 64 (range: 43-86), median eGFR 48 (range: 32-60) often with head and neck primaries (9, 90%) and distant metastases (7, 70%). Six (60%) had prior systemic therapy. For mTOR inhibition, 7 (70%) received sirolimus and 3 (30%) everolimus. At a median follow-up of 6.3 months (range: < 1-24.9), no patients experienced kidney allograft rejection or loss. Of 8 evaluable patients, ORR was 50% (2 CR, 2 PRs), while 4 had PD. At data cutoff no responder had progressed, with 2/4 in response > 18 months (range: < 1-22.7+). One patient is pending first restaging; 1 was unevaluable (died before first restaging). One KTR with initial PD experienced a subsequent durable response to cetuximab. Fatigue (40%) and limb edema (30%) were the most common treatment-related adverse events (TRAEs). Grade 3+ TRAEs occurred in 5 (50%) patients including diarrhea, infections (n = 3), and electrolyte derangements; there were no Cemi-related deaths. Median PFS was 7.9 mos (95%CI: 1.2-not reached [NR]); the 3-month OS estimate was 61% (95%CI: 27-83). Baseline tumor PD-L1 scores ranged from 0-5%; median TMB was 49 muts/Mb (range: 10-97). Tumor mutations in TP53, CDKN2A, and NOTCH1 were common. Exploratory tumor/circulating multiparametric immune profiling and circulating tumor (ct)DNA findings will be presented. Conclusions: Using IS with mTOR inhibition and dynamic prednisone resulted in no kidney allograft rejection among KTRs treated with Cemi for advanced cSCC. Durable anti-tumor efficacy was observed. mTOR inhibition with prednisone should be the preferred IS regimen when treating KTRs with anti-PD-1 therapy. Clinical trial information: NCT04339062 .