ADAPT-IT Raises Question About 4-Dose Schedule of Nivo/Ipi in Patients With Metastatic Melanoma

Findings from the Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT; NCT03122522) reveal the efficacy and toxicity of standard four dose nivolumab (Opdivo) and ipilimumab (Yervoy) induction therapy in melanoma to be likely driven by the first 2 doses.

While the combination of nivolumab and ipilimumab demonstrates high efficacy, it also has can lead to significant toxicity. The standard treatment for advanced melanoma is 4 doses of the combination followed by nivolumab alone. However, whether or not 4 doses of nivolumab and ipilimumab are needed is unclear.

“A computed tomography scan after 2 doses of nivolumab plus ipilimumab identifies most patients who benefit from treatment and may help guide future treatment plans,” wrote the study authors led by Michael A. Postow, MD, a medical oncologist, and chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center.

The ADAPT-IT trial examined the 2 doses of the combination of nivolumab plus ipilimumab to see if it is sufficient for patients with early benefit compared to the standard 4 doses.

Enrollment in the trial was open to patients aged 18 and older with a histologic diagnosis of unresectable 3 or stage 4 metastatic melanoma. Participants must have had at least 1 extracranial, unresectable, non-bony lesion that is measurable radiographically based on RECIST 1.1, no prior CTLA-4 or PD-1/PD-L1 therapy for the treatment of metastatic disease, an ECOG performance status of 0-1, and a life expectancy ≥ 4 months.

The multicenter, single-arm phase 2 clinical trial administered patients 2 doses of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg then followed by a computed tomography scan at week 6.

If patients had received a favorable antitumor effect (FATE) by RECIST at week 6, maintenance with nivolumab alone at 480 mg would be administered every 4 weeks for 2 doses (week 6 & week 10) along with repeat response assessments at week 12. If patients did not achieve FATE at week 6 patients received 2 additional doses of nivolumab plus ipilimumab every 3 weeks & then were assessed for response at week 12.

By week 12, if patients did not reach FATE, patients could continue getting additional doses of ipilimumab plus nivolumab with response reassessments after every 2 doses, so long as approved by the investigator. Additionally, maintenance nivolumab was ongoing until unacceptable toxicity or confirmed disease progression.

If initial clinical benefit from therapy was found in the patient or they subsequently experienced progressive disease at any time, reinduction with combination nivolumab and ipilimumab was allowed.

The primary end point was objective response rate by RECIST 1.1 at week 12 with secondary end points including additional efficacy assessments and safety.

Findings showed that of the 60 patients enrolled, 68% (n = 41) had FATE at week 6 and met criteria for stopping the combination of nivolumab plus ipilimumab. The best overall response rates at week 12 or any time after were 48% (95% CI, 35-62) and 58% (95% CI, 45-71), respectively.

The estimated 18-month progression-free survival and overall survival at a median follow-up of 25 months were 52% and 80%. A total of 57% of patients had grade 3-5 treatment-related toxicity.

Further study in addition to a longer follow up are needed to gain a better understanding of the implications of a shortened induction course of nivolumab plus ipilimumab.

REFERENCES:

1. Postow MA, Goldman DA, Shoushtari AN et al. Adaptive dosing of nivolumab + ipilimumab immunotherapy based upon early, interim radiographic assessment in advanced melanoma (The ADAPT-IT Study). J Clin Oncol.2022; 40(10):1059-1067. doi:10.1200/JCO.21.01570
2. A study to evaluate adaptive dosing of ipilimumab and nivolumab combination immunotherapy. Clinicaltrials.gov. Accessed April 7, 2022. https://bit.ly/3Kb3ACl