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.

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.