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.
Bibliographic record
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]
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".