Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium
Anirban Das, Nicholas Fernandez, Adrian Levine, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Liana Nobre, Trevor J. Pugh, Derek S. Tsang, Birgit Ertl-Wagner, Daniel Morgenstern, Cynthia Hawkins, Eric Bouffet, Uri Tabori; on behalf of the International RRD Consortium
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 analysed 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.
References: [1] 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.
[2] 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.
Anirban Das, Nicholas Fernandez, Adrian Levine, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Liana Nobre, Trevor J. Pugh, Derek S. Tsang, Birgit Ertl-Wagner, Daniel Morgenstern, Cynthia Hawkins, Eric Bouffet, Uri Tabori; on behalf of the International RRD Consortium
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 analysed 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.
References: [1] 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.
[2] 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.