Early on-treatment assessment of T cells, cytokines, and tumor DNA with adaptively dosed nivolumab + ipilimumab: Final results from the phase 2 ADAPT-IT study Journal Article
| Authors: | Smithy, J. W.; Kalvin, H. L.; Ehrich, F. D.; Shah, R.; Adamow, M.; Raber, V.; Maher, C. A.; Kleman, J.; McIntyre, D. A. G.; Shoushtari, A. N.; Warner, A. B.; Callahan, M. K.; Momtaz, P.; Eton, O.; Nair, S.; Wolchok, J. D.; Chapman, P. B.; Berger, M. F.; Panageas, K. S.; Postow, M. A. |
| Article Title: | Early on-treatment assessment of T cells, cytokines, and tumor DNA with adaptively dosed nivolumab + ipilimumab: Final results from the phase 2 ADAPT-IT study |
| Abstract: | Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. Patients and Methods: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. Results: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P 1⁄4 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR 1⁄4 1.24, 95% confidence interval (CI), 1.01–1.52; P 1⁄4 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P 1⁄4 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR 1⁄4 1.11, 95% CI, 1.01–1.21; P 1⁄4 0.023). Week 12 overall response rate was 47% (95% CI, 35%–59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10–not reached); 76% of responses (95% CI, 64%–91%) persisted at 36 months. Conclusions: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response. ©2024 American Association for Cancer Research. |
| Keywords: | adult; aged; aged, 80 and over; middle aged; unclassified drug; major clinical study; overall survival; clinical trial; mortality; drug efficacy; flow cytometry; outcome assessment; follow up; antineoplastic agent; t lymphocyte; t-lymphocytes; metabolism; allele; interleukin 2; ipilimumab; melanoma; progression free survival; phase 2 clinical trial; antineoplastic combined chemotherapy protocols; interleukin 13; interleukin 4; interleukin 8; antineoplastic activity; pathology; tumor marker; cytokine; immunology; cytokines; dna; immune response; gamma interferon; blood sampling; multicenter study; dna, neoplasm; interleukin 6; immunoassay; interleukin 17; drug therapy; interleukin 12; tumor necrosis factor; tumor microenvironment; phase 2 clinical trial (topic); high throughput sequencing; nivolumab; very elderly; humans; human; male; female; article; circulating tumor dna; biomarkers, tumor; tumor dna |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 16 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-08-15 |
| Start Page: | 3407 |
| End Page: | 3415 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-23-3643 |
| PUBMED: | 38767650 |
| PROVIDER: | scopus |
| PMCID: | PMC11357703 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is James W. Smithy -- MSK author Debra McIntyre's first name is spelled 'Deborah' on the original publication -- Source: Scopus |
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