Abstract CT183: Phase (Ph) I/II study of MBG453± spartalizumab (PDR001) in patients (pts) with advanced malignancies
Bibliographic record
Abstract
Abstract Background: MBG453 and spartalizumab, humanized IgG4 mAbs, block binding of TIM-3 to PtdSer and PD-1 to PD-L1/2, respectively. Preclinical studies show synergistic anti-tumor activity of TIM-3 and PD-1 co-blockade. Here we report the dose escalation results from a Ph I-Ib/II study of MBG453 ± spartalizumab in metastatic solid tumors (NCT02608268). Methods: Metastatic cancer pts received intravenous MBG453 alone at 80-1200 mg Q2W or Q4W, or combination therapy (Q2W/Q4W) with MBG453 (20-800/80-1200 mg) + spartalizumab (80-240 mg/80-400 mg). The recommended Ph II dose (RP2D) was determined using an adaptive Bayesian logistic regression model guided by escalation with overdose control together with Ph I-Ib endpoints (dose-limiting toxicity [DLT] at 8 weeks). Results: As of July 26, 2018, 87 pts received MBG453 alone (14% were anti-PD-1/PD-L1 pre-treated; common tumors [≥9%]: pancreatic cancer [11%], sarcoma [10%], and colorectal cancer [CRC; 9%]) and 86 pts received MBG453 + spartalizumab (27% were anti-PD-1/PD-L1 pre-treated; common tumors [≥6%]: melanoma [8%], NSCLC [7%], CRC [7%], and ovarian cancer [6%]). One DLT (myasthenia gravis grade [G] 4) was reported in a pt with thymoma treated with MBG453 (240 mg Q4W) + spartalizumab (80 mg Q4W). Treatment-related adverse events (AEs) were reported in 40% and 59% of pts treated with MBG453 and MBG453 + spartalizumab, and G3/4 AEs in 0% and 11% of pts; the most common AE (≥10%) was fatigue in 10% and 15% of pts, respectively. MBG453 exposure generally increased in a dose-proportional manner. Maximum tolerated doses were not identified with the tested dose/schedule. MBG453 800 mg Q4W (n=9 pts treated) and MBG453 800 mg + spartalizumab 400 mg Q4W (n=6 pts treated) were declared as RP2Ds. Stable disease (SD) was seen in 25/87 (29%) pts treated with MBG453 alone (common tumors [≥2 pts]: sarcoma [n=5], and breast cancer, CRC, ovarian cancer, cholangiocarcinoma, and NSCLC [n=2 pts each]); 4 of 25 pts with SD were anti-PD-1/PD-L1 pre-treated. Of 86 MBG453 + spartalizumab pts, partial responses were seen in 4 pts (5%); 1 anti-PD-1/PD-L1 pre-treated pt (out of 6 with NSCLC; DOR: 392 d), 3 anti-PD-1/PD-L1 naïve pts (CRC [n=2 out of 6, DOR: 223 d, 109 d]; SCLC [n=1 out of 3; DOR: 112 d]). SD was seen in 34/86 (40%) MBG453 + spartalizumab pts (common tumors [≥3 pts]: melanoma [n=5; 2 cutaneous, 2 uveal, and 1 non-cutaneous], ovarian cancer [n=3], and urothelial carcinoma [n=3]); 10 of 34 pts with SD were anti-PD-1/PD-L1 pre-treated. RNAseq analysis of screening and on-treatment biopsies revealed a pharmacodynamic trend of increased IFN-γ-associated gene signatures following MBG453 + spartalizumab treatment. Conclusions: MBG453 + spartalizumab was well tolerated with preliminary signs of anti-tumor activity. MBG453 800 mg Q4W and MBG453 800 mg + spartalizumab 400 mg Q4W were selected as the RP2Ds; dose expansion is ongoing in pts with melanoma or NSCLC resistant to anti-PD-1/PD-L1. Citation Format: Giuseppe Curigliano, Hans Gelderblom, Nicolas Mach, Toshihiko Doi, Wai Meng David Tai, Patrick Forde, John Sarantopoulos, Philippe L. Bedard, Chia-Chi Lin, Stephen Hodi, Sofie Wilgenhof, Armando Santoro, Catherine Sabatos-Peyton, Tyler Longmire, Kitty Wan, Panagiotis Nikolopoulos, Luigi Manenti, Aung Naing. Phase (Ph) I/II study of MBG453± spartalizumab (PDR001) in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT183.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".