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Clinical Trial
. 2024 Aug 15;30(16):3407-3415.
doi: 10.1158/1078-0432.CCR-23-3643.

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

James W Smithy  1 , Hannah L Kalvin  1 , Fiona D Ehrich  1 , Ronak Shah  1 , Matthew Adamow  1 , Vladislav Raber  1 , Collen A Maher  1 , Jenna Kleman  1 , Deborah A G McIntyre  1 , Alexander N Shoushtari  1   2 , Allison Betof Warner  1   2 , Margaret K Callahan  1   2 , Parisa Momtaz  1   2 , Omar Eton  3 , Suresh Nair  4 , Jedd D Wolchok  1   2 , Paul B Chapman  1   2 , Michael F Berger  1 , Katherine S Panageas  1 , Michael A Postow  1   2
Affiliations
Clinical Trial

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

James W Smithy et al. Clin Cancer Res. .

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 = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 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.

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Conflict of interest statement

J. Smithy: Research funding - IO Biotech (Inst); H.L. Kalvin: No disclosures; F. Ehrich: No disclosures. R. Shah: Intellectual Property Rights- SOPHiA Genetics; M. Adamow: No disclosures; V. Raber: No disclosures; C.A. Maher: No disclosures; J. Kleman: No disclosures; D.A.G. McIntyre: Employment - Regeneron; Stock and Other Ownership Interests - Johnson & Johnson, Regeneron; A.N. Shoushtari: Consulting or advisory role - Bristol-Myers Squibb, Novartis, Erasca; Research funding - Bristol-Myers Squibb (Inst), Immunocore(Inst), Novartis(Inst), Targovax(Inst), Pfizer(Inst), Alkermes(Inst), Checkmate Pharmaceuticals, (Inst), Foghorn Therapeutics (Inst), Linnaeus Therapeutics (Inst), Prelude Therapeutics (Inst), Iovance Biotherapeutics (Inst); A. Betof Warner: Consulting or Advisory Role - BluePath Solutions, Bristol-Myers Squibb/Medarex, immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Novartis, Pfizer; Research Funding - Iovance Biotherapeutics; Travel, Accommodations, Expenses - Iovance Biotherapeutics; M.K. Callahan; Employment - Bristol-Myers Squibb (I); Celgene (I); Kleo Pharmaceuticals (I); Transition Bio (I); Merus (I); Consulting or Advisory Role - AstraZeneca, Bayer, Immunocore, Merck, Moderna Therapeutics; Research Funding - Bristol-Myers Squibb (Inst); Other Relationship - Clinical Care Options; Potomac Center for Medical Education; P. Momtaz: No disclosures; O. Eton: Speakers’ Bureau - Merck; Research Funding - Bristol-Myers Squibb (Inst); S. Nair: Research Funding - Bristol-Myers Squibb (Inst), Merck (Inst), Nektar (Inst), Strata Oncology (Inst), Mirati Therapeutics (Inst); J.D. Wolchok: Consulting or Advisory Role - Apricity, Ascentage Pharma, AstraZeneca, BeiGene, Bicara Therapeutics, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Psioxus, Recepta, Takeda, Tizona, Trishula Therapeutics, Sellas; Research Support- Bristol Myers Squibb, Sephora; Equity: Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, Xenimmune; Patents, Royalties, Other Intellectual Property - ALPHAVIRUS REPLICON PARTICLES EXPRESSING TRP2 (Inst); Anti-GITR antibodies and methods of use thereof (Inst); Antigen-binding proteins targeting melanoma differentiation antigens and uses thereof (Inst); Antigen-binding proteins targeting melanoma differentiation antigens and uses thereof CTLA 4 (Inst); CD40 BINDING MOLECULES AND USES THEREOF (Inst); CD40 binding Molecules and uses thereof (Inst); Engineered Vaccinia Viruses for Cancer Immunotherapy (Inst); I am a co-inventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells. (Inst); I am a co-inventor on a patent for Anti-CD40 agonist mAb fused to Monophosphoryl Lipid A (MPL) for cancer therapy (Inst); I am a co-inventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer (Inst); I am a co-inventor on a patent for use of oncolytic Newcastle Disease virus. (Inst); I am a co-inventor on an issued patent for DNA vaccines for treatment of cancer in companion animals. (Inst); I am co-inventor and receive royalties for a patent for immune modulating antibodies. (Inst); Immunosuppressive follicular helper-like T cells modulated by immune checkpoint blockade (Inst); Peripheral Blood Phenotype Linked to Outcomes After Immunotherapy Treatment (Inst); Phosphatidylserine Targeting Agents and uses thereof for adoptive T-cell therapies (Inst); RECOMBINANT POXVIRUSES FOR CANCER IMMUNOTHERAPY (Inst); WITH IMMUNOMODULATORY THERAPEUTICS AND METHOD OF MONITORING ABSCOPAL EFFECTS DURING SUCH TREATMENT (Inst), ANTIGEN-RECOGNIZING RECEPTORS TARGETING B7-H3 AND USES THEREOF (Inst); P. B. Chapman: Stock and Other Ownership Interests - Rgenix; Consulting or Advisory Role - Black Diamond Therapeutics, GigaGen, Merck, Pfizer, Research Funding - Genentech; GigaGen, Merck, NCI (Inst), Pfizer; M. Berger: Consulting - Eli Lilly, AstraZeneca, Paige.AI; Research Support - Boundless Bio; Intellectual Property Rights - SOPHiA Genetics; K. Panageas: Stock and Other Ownership Interests - 23andMe, Adicet Bio, Chinook Therapeutics, Codexis, T2 Biosystems, Vincerx Pharma; Research Funding - AACR (Inst); M. A. Postow: Consulting or Advisory Role - Bristol-Myers Squibb; Cancer Expert Now; Chugai Pharma; Eisai; Erasca, Inc; Intellisphere; Merck; MJH Associates; Nektar; Novartis; Pfizer; WebMD; Research Funding - Array BioPharma (Inst); Bristol-Myers Squibb (Inst); Infinity Pharmaceuticals (Inst); Merck (Inst); Novartis (Inst); Rgenix (Inst)

Figures

Figure 1.
Figure 1.
Updated efficacy outcomes.
Figure 2.
Figure 2.
Plasma IL-6 concentration by best radiographic response
Figure 3.
Figure 3.
Pre- and on-treatment ctDNA by best objective radiographic response
Figure 4.
Figure 4.
Change in immune cell populations from baseline to Week 3
See this image and copyright information in PMC

References

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