Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study)

Abstract

Purpose: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear.

Methods: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety.

Results: Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity.

Conclusion: The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi.

Conflict of interest statement

Michael A. PostowConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Array BioPharma, NewLink Genetics, Incyte, Merck, Eisai, PfizerResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Array BioPharma (Inst), Infinity Pharmaceuticals (Inst), Regenix (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst) Debra A. GoldmanEmployment: RegeneronStock and Other Ownership Interests: Johnson & Johnson Alexander N. ShoushtariConsulting or Advisory Role: Immunocore, Bristol Myers SquibbResearching Funding: Immunocore, Bristol Myers Squibb, Xcovery, Polaris, Novartis (Inst), Pfizer (Inst)Patents, Royalties, Other Intellectual Property: UpToDate Allison Betof WarnerHonoraria: LG ChemConsulting or Advisory Role: Nanbiotix, Iovance Biotherapeutics, Novartis, Shanghai Jo’Ann Medical Technology, BluePath Solutions, PfizerResearch Funding: Leap Therapeutics Margaret K. CallahanEmployment: Bristol-Myers Squibb (I), Celgene (I), Kleo Pharmaceuticals (I), Bristol-Myers Squibb (I)Consulting or Advisory Role: AstraZeneca, Moderna Therapeutics, Merck, ImmunocoreResearching Funding: Bristol Myers Squibb (Inst)Other Relationship: Clinical Care Options, Potomac Center for Medical Education Omar EtonSpeakers’ Bureau: MerckResearching Funding: Bristol Myers Squibb (Inst) Suresh G. NairStock and Other Ownership Interests: Moderna Therapeutics, Novavax, Biotech, Gilead SciencsResearch Funding: Bristol-Myers Squibb, Merck, Nektar (Inst) Katherine S. PanageasStock and Other Ownership Interests: AstraZeneca, Pfizer, Sunesis Pharmaceuticals Jedd D. WolchokStock and Other Ownership Interests: Tizona Therapeutics, Inc, Adaptive Biotechnologies, Imvaq Therapeutics, Beigene, Linnaeus Therapeutics, Arsenal IO, Geogiamune, LLC, Maverick Therapeutics, Apricity Therapeutics, Trieza TherapeuticsConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Sellas Life Sciences, Lilly, Tizona Therapeutics, Inc,, Amgen, Chugai Pharma, Adaptive Biotechnologies, Ascentage Pharma, PsiOxus Therapeutics, F-Start Biotechnology, Surface Biotechnology, Apricity Therapeutics, PsiOxus Therapeutics, F-Star Biotechnology, Surface Oncology, Apricity Therapeutics, PsiOxus Therapeutics, Astellas Pharma, Recepta Biopharma, Arsenal IO, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo,Inc, Dragonfly Therapeutics, Geogiamune, Kyowa Kirin Pharmaceutical, Maverick Therapeutics, Werewolf Therapeutics, Trishula Therapeutics, Idera, Imvq Therapeutics, Biscara TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: I am a co-inventor on an issued patent for DNA vaccines for treatment for cancer in companion animals, I am a co-inventor on a patent for use of oncolytic Newcaste Disease virus, I am a co-inventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells. I am co-inventor and receive royalties for a petent for immune modulating antibododies. I am a co-inventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer. I am a co-inventor on a patent for Anti-CD40 agonist mAb fused to Monophosphory Lipid A (MPL) for cancer therapy, Alphavirus Replicon Particles Expressing TRP2, Engineered Vaccinia Viruses for Cancer Immunotherapy, Recombinant Poxviruses for Cancer Immunotherapy Paul B. ChapmanConsulting or Advisory Role: Merck, Pfizer, Black Diamond TherapeuticsResearch Funding: Pfizer, NCI (Inst), GenentechNo other potential conflicts of interest were reported.

Figures

FIG 1.

Patient event histories by non-FATE versus FATE at week 6. For patients who experienced a grade 3-4 toxicity, a purple triangle represents the timing of first grade 3-4 toxicity. Bars are colored by RECIST 1.1 response starting at the week 6 scan and change color if a patient's response changed during the duration of study. Patients who died have a red X at the end of follow-up, and patients who are still alive by the data lock have a black right triangle. The teal circles represent doses of nivo + ipi combination immunotherapy. Three patients in the non-FATE group do not have colored bars to indicate response (two died of treatment-related toxicity and did not have response assessment and one had clinical progression without RECIST response assessment). As demonstrated by three patients in the FATE group with > 2 teal circles, three patients in the FATE group received > 2 doses of nivo + ipi (two patients' treatments were protocol violations and one had concern for clinical progression). CR, complete response; FATE, favorable antitumor effect; IPI, ipilimumab; irTox, immune-related toxicity; nivo + ipi, nivolumab + ipilimumab; PD, progressive disease; PR, partial response; SD, stable disease. The ADAPT-IT study showed that patients with melanoma may only need two doses of nivolumab + ipilimumab.

FIG 2.

Kaplan-Meier curves for PFS (A) and OS (B) with blue shading reflecting the 95% CI. Vertical dotted lines with respective values reflect the estimated PFS/OS at 6, 12, and 18 months. OS, overall survival; PFS, progression-free survival.

FIG A1.

Study schema. aFollowing week 12, patients received maintenance nivo but were eligible for additional nivo + ipi if they had tumor growth. Nivo + ipi, nivolumab + ipilimumab.

FIG A2.

Duration of response among all patients with a RECIST response. Blue shading reflects the 95% CI. Vertical dotted lines with respective values reflect the estimated rates of ongoing response at 6 and 12 months following initial response.

FIG A3.

PFS (A) and OS (B) among patients with FATE at week 6. Blue shading reflects the 95% CI. Vertical dotted lines with respective values reflect the estimated rates at 12 and 24 months from the week-6 CT scan. CT, computed tomography; FATE, favorable antitumor effect; OS, overall survival; PFS, progression-free survival.

FIG A4.

Each column represents a patient broken down by FATE versus non-FATE at week 6. Rows represent treatment-related side-effect categories as per CTCAE with colors reflecting CTCAE grade. CTCAE, Common Terminology Criteria for Adverse Events; FATE, favorable antitumor effect.

FIG A5.

Cumulative incidence of any grade 3-5 treatment-related adverse events. IRTox, immune-related toxicity.