Safety and efficacy results from the expansion phase of the first-in-human study evaluating TGFβ inhibitor SAR439459 alone and combined with cemiplimab in adults with advanced solid tumors.

Abstract

2524 Background: SAR439459 (SAR459) is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR459 with an anti-PD-1 showed improved anti-tumor activity compared to SAR459 single agent. In the dose escalation, acceptable tolerability was observed, the MTD was not reached and the preliminary RP2D was 22.5mg/kg Q3W when combined with cemiplimab (CEMI; S. Williamson et al. J Clin Oncol 39, 2021[suppl 15; #2510]). Reduction of plasma TGFβ was ≥90% at doses ≥0.25mg/kg Q2W, with a trend of a decrease in intra-tumoral TGFβ (D. Robbrecht et al. JITC 2021;9 [suppl 2; #250]). Here we report safety and efficacy results of the dose expansion. Methods: The expansion phase of this open-label, phase 1/1b study aimed to determine the optimal dose of SAR459 (7.5 mg/kg or 22.5 mg/kg Q3W) in patients (pts) with advanced melanoma (MEL) resistant to anti-PD(L)1 therapy (Part 2A); and the ORR (confirmed responses) in all treated pts with SAR459 22.5 mg/kg + CEMI 350 mg Q3W in pts with MEL, Non-small Cell Lung Cancer (NSCLC), or Hepatocellular Carcinoma (HCC), resistant to anti-PD(L)1; as well as in pts with mesenchymal Colorectal Cancer (CRC) or Urothelial Cancer (UC), anti-PD(L)1 naïve (Part 2B). Results: From October 2019 to September 2021, 109 pts with ECOG PS 0-1 enrolled in Part 2A (14) and Part 2B (95). Overall, the median age was 63 years and 83% of pts received up to 3 prior treatment lines for advanced disease (range 1-8). Based on preliminary data, the ORR in Part 2B was 8% (Table). No significant association between clinical response and plasma TGFb level at baseline or modulation upon treatment was observed. The correlation between tumor TGFb level and clinical benefit is inconclusive due to limited number of tumor biopsies. No response was observed in Part 2A. Overall, 100% of pts had at least one treatment emergent adverse event (AE), 67% were G≥3, 34% related G≥3, 17% G5, and 4% related G5. The limited number of patients treated with SAR459 alone at the RP2D did not allow to demonstrate added toxicity due to the combination. Overall, 51 pts (47%) reported hemorrhagic AE of any grade, 8 pts (7%) had G≥3 and 5 pts (5%) had fatal outcome. The rate of bleeding and severe hemorrhagic AE was higher in HCC pts compared to the other cohorts: 11/14 (79%) pts had a hemorrhagic AE, of which 3 (21%) G≥3 and fatal. An exploratory analysis showed a trend for higher frequency of any grade SAR459-related and fatal hemorrhagic AE in patients with higher exposure. Conclusions: The NCT03192345 study was discontinued due to a lack of efficacy, and a high bleeding risk particularly in pts with HCC. Clinical trial information: NCT03192345. [Table: see text]

Biomarker and pharmacodynamic activity of the transforming growth factor‐beta (TGFβ) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors

“…The study demonstrated that while SAR439459, when combined with anti‐PD‐1 therapy, elicited the expected peripheral PD effects in peripheral blood, there is inadequate evidence of induced CD8 + T cell infiltration in the tumor microenvironment upon treatment with SAR439459 due to limited sample size and intratumoral heterogeneity. The current biomarker data are complementary to this recent publication on the clinical activity of SAR439459 alone or in combination with cemiplimab in an unselected population of advanced solid tumors, 13 and these data contribute to our understanding of the lack of enough therapeutic benefit from the treatment and the potential patient enrichment strategies to future clinical studies on TGFβ blockade therapy in cancer patients. However, this study was limited due to the small sample size, especially the paired tumor biopsy, from a homogeneous population to confirm the dose‐dependent target engagement and PD effects in the tumor microenvironment.…”

“…The clinical data from the phase I/Ib study of SAR439459, alone and in combination with anti‐PD‐1, were recently presented. However, the study was discontinued due to lack of sufficient antitumor response and the observed bleeding risk particularly in the HCC cohort 13 . Herein, PD and patient enrichment biomarker data from this first‐in‐human study are presented to enhance our understanding of peripheral and tumor PD effects of SAR439459.…”

“…LLOQ, lower limit of quantitation; TGFβ, transforming growth factor-beta. cemiplimab in an unselected population of advanced solid tumors, 13 and these data contribute to our understanding of the lack of enough therapeutic benefit from the treatment and the potential patient enrichment strategies to future clinical studies on TGFβ blockade therapy in cancer patients. However, this study was limited due to the small sample size, especially the paired tumor biopsy, from a homogeneous population to confirm the dose-dependent target engagement and PD effects in the tumor microenvironment.…”

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

“…Nevertheless, the study was discontinued due to a lack of efficacy and a high risk of bleeding. No significant association between clinical response and plasma TGF-β level at baseline or modulation upon treatment was observed [ 50 ].…”

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

“… 13 However, SAR439459 was discontinued in a clinical trial (NCT03192345) due to insufficient efficacy and bleeding risk. 18 Overall, combination therapies tested in advanced solid tumors showed limited objective responses. 19 …”