783 Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: a report from the International RRD consortium
Notice bibliographique
Résumé
Background Response to immune checkpoint inhibition (ICI) is encouraging for patients with progressive, DNA replication-repair deficient, high-grade glioma (RRD-HGG).1 However, the clinical outcomes and biological mechanisms for subsequent immune-directed salvage approaches after progression on anti-PD1 monotherapy remain unknown. Methods The International RRD Consortium performed a registry study of patients managed using central molecular, genomic, radiological review and treatment recommendations between 2015–2021. Treatment after progression on anti-PD1 monotherapy included re-irradiation where feasible, and continuation of anti-PD1 with either anti-CTLA4 (ipilimumab), or a MEK-inhibitor (trametinib). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were analyzed centrally. Results Among 75 patients with RRD-HGG receiving PD-1 blockade, 20 remain progression-free at a median follow-up of 44.6-months. For 55 patients with 2nd-relapse/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p<0.001). The combination of ipilimumab/nivolumab (n=24) resulted in response/stable disease in 75%, with median OS2 of 12.1-months. The addition of MEK-inhibitor led to response in 3/5 patients with prolonged survival. Re-irradiation improved OS2, especially for RRD-HGG with lower mutation burden (p=0.002), and those receiving ipilimumab (median OS2=33-months). Several important insights were gained from the biomarker-analyses. Survival was impacted by extreme mutation burden, but not genomic microsatellite instability. Delayed, sustained responses were observed in ultra-hypermutant RRD-HGG, associated with changes in mutational spectra and immune microenvironment. RRD-HGG showed elevated CTLA4 expression over time, explaining the responses to ipilimumab. The remarkable sensitivity to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8; COSMIC),2 suggesting selective immune-editing. Early radiological immune ‘flare’ was observed in 33% of patients on combined immunotherapy and radiation who did not demonstrate flare on monotherapy, suggesting immune-synergism. Enrichment of RAS-MAPK mutations in genomically unstable RRD-HGG explained responses to MEK-inhibitors. Additionally, reinvigoration of peripheral immune response was observed. In all cohorts, immune adverse events were a major cause of treatment interruption, with higher prevalence in patients with bi-allelic mismatch-repair deficiency vis-à-vis Lynch syndrome. Conclusions We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage. Our data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to ICI beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit. Acknowledgements AD would like to acknowledge the supports of the St Baldrick Foundation, Stand up to Cancer and Hold’em for Life Foundations for his fellowship and research. References Das A, Sudhaman S, Morgenstern D, et al. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency. Nat Med. 2022;28:125–135. Kocakavuk E, Anderson KJ, Varn FS, et al. Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet. 2021;53:1088–1096. Ethics Approval The study was approved by the SickKids Research Ethics Board (REB number: 1000048813) Consent Consent was obtained from study participants and/or their parents, as applicable.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».