Randomized phase Ib study to evaluate safety, pharmacokinetics and therapeutic activity of simlukafusp α in combination with atezolizumab ± bevacizumab in patients with unresectable advanced/ metastatic renal cell carcinoma (RCC) (NCT03063762).
Bibliographic record
Abstract
4556 Background: Simlukafusp α ([SIM], FAP-IL2v) is a novel IL-2v immunocytokine engineered to preferentially activate effector CD8 T and NK cells, but not regulatory T cells (Tregs), due to abolished binding to Interleukin-2 receptor α (IL-2Rα) and retained affinity to IL-2Rβγ. High affinity binding of SIM to fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, mediates its accumulation in malignant lesions. Methods: The Dose-Escalation (DE) consisted of: Arm A: SIM 5-25 mg weekly for 4 weeks, and every 2 weeks (Q2W) thereafter in combination with atezolizumab [ATZ] 840mg Q2W; and Arm B: same as Arm A + bevacizumab [BEV] 10 mg/kg Q2W. Patients (pts) not previously treated were evaluated in the Extension Part: Arm C (n=3): SIM + ATZ every 3 weeks (Q3W); or Arm D (n=25): SIM + ATZ + BEV (“triplet”) Q3W. Primary objectives were: finding the recommended dose of SIM and assessment of objective response rate (ORR) by RECIST v1.1. Results: We enrolled 69 pts with unresectable advanced/ metastatic clear-cell and/or sarcomatoid RCC. Median age of patients was 57 years (range: 35-78). The recommended dose for extension of SIM was 10 mg. Median treatment duration in days in each arm were: A: 106 (range: 1-877); B: 324 (8-940); C: 659 (71-768); D: 437 (1-682). Twenty-five pts are evaluable for therapeutic activity in Arm A [ORR: 24% (6 PR; 90% CI 12.95, 40.12)]; 15 in Arm B [46.7% (1 CR, 6PR; 90% CI 27.67, 66.68)]; 3 in Arm C [33.3% (1PR; 90% CI 7.83, 74.65)]; and 23 in Arm D [47.8% (2 CR, 9 PR; 90% CI 35.74, 68.15)]. Twelve patients are ongoing on study treatment. Treatment related grade 3 and 4 adverse events (AE) occurred respectively in 69.7% and 9.1% patients. The most common serious AEs were pyrexia (10.6 %) and infusion-related reactions (9.1%). 65.2% Of the patients reported at least one AE of elevations in liver transaminases/GGT/ alkaline phosphatase/bilirubin. Drug-related AEs led to dose modification/interruption in 37.9 % of the pts, and treatment discontinuation in 3% of the patients. SIM led to preferential expansion and activation of NK and CD8 T cells (but not Tregs) in peripheral blood and augmented tumor infiltration and tumor inflammation. Intriguingly responses were observed not only in pts with PD-L1 positive or inflamed tumors, but also in pts with PD-L1 negative tumors (n=13) or poorly infiltrated tumors classified as immune deserts (n=2). Conclusions: The combination of SIM with ATZ ± BEV was feasible with an acceptable safety profile. Clinical activity was more favorable for the triplet among the study Arms, but comparable to the ATZ + BEV combination in the IMmotion151 (Rini B, et al 2019). Observed pharmacodynamic findings were consistent with the expected effects. Clinical trial information: NCT03063762.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".