Abstract LB040: Targeting CD38 and PD-1 with isatuximab (Isa) plus cemiplimab (Cemi) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label, multicenter study
Bibliographic record
Abstract
Abstract Background: CD38 is implicated in noncanonical adenosine synthesis and its overexpression on tumor cells has been implicated in T-cell exhaustion and resistance to immune checkpoint blockade. Preclinical data suggest that concurrent treatment of anti-CD38 and anti-PD-1/PD-L1 antibodies substantially reduce primary tumor growth via suppressing acquired resistance to immune checkpoint blockade, and thus enhancing anti-PD-1/PD-L1 efficacy. Methods: This Phase 1/2 study (NCT03367819) enrolled pts with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of Phase 1 were safety and tolerability of Isa (anti-CD38 monoclonal antibody) + Cemi (anti-PD-1 monoclonal antibody) in pts with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase 2 used a Simon's 2-stage design with response rate (RR) as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) pts receiving Isa+Cemi were enrolled in Phase 2. Tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All pts experienced ≥1 treatment-emergent adverse event. Grade ≥3 events occurred in 13 (54.2%) mCRPC pts and 12 (60.0%) NSCLC pts. Based on PCWG3 criteria, assessment of best overall response (BOR) with Isa+Cemi in mCRPC revealed no complete responses (CR), 1 unconfirmed partial response (PR) (4.2%), and 5 (20.8%) pts with stable disease (SD). Per RECIST 1.1, NSCLC pts receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. Isa+Cemi resulted in ~40% reduction in CD38+ tumor-infiltrating immune cells in post-therapy biopsies. The combination triggered a significant increase in peripheral activated and cytolytic T cells, but decreased NK cells. In addition, low baseline CD38 levels on tumor cells were observed in NSCLC pts who progressed on prior checkpoint inhibitor treatment. No significant modulation of Tregs or PD-L1 in the TME or CD38 expression on tumor cells was observed. Conclusions: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, this was not associated with significant antitumor activity in these small cohorts of mCRPC and NSCLC pts. Citation Format: Chia-Chi Lin, Paolo Zucali, Bradley Carthon, Todd M. Bauer, Marcello Tucci, Antoine Italiano, Roberto Iacovelli, Wu-Chou Su, Christophe Massard, Monsoor Saleh, Gennaro Daniele, Alastair Greystoke, Martin Gutierrez, Shubham Pant, Ying-Chun Shen, Matteo Perrino, Robin Meng, Giovanni Abbadessa, Helen Lee, Yingwen Dong, Marielle Chiron, Rui Wang, Laure Loumagne, Johann de Bono, Johann de Bono. Targeting CD38 and PD-1 with isatuximab (Isa) plus cemiplimab (Cemi) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label, multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB040.
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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) | 0.002 | 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) | 0.003 | 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".