Patients with stage IIIb/IIIc or stage IV melanoma at high risk of recurrence following complete surgical resection had greater recurrence-free survival (RFS) with adjuvant nivolumab compared to adjuvant ipilimumab, according to results from the phase III CheckMate 238 study reported at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Jeffrey Weber of the Perlmutter Cancer Center, NYU Langone Health in New York, USA presented the first results on behalf of an international research team from the CheckMate 238 trial (NCT02388906), which directly compared nivolumab to ipilimumab in patients with resected stage IIIb/c/IV melanoma at high risk of recurrence.
CheckMate 238 is an ongoing phase III, randomised, double-blind study of nivolumab versus ipilimumab in patients greater than 15 years of age who have undergone complete resection of stage IIIb/IIIc or stage IV melanoma. The trial randomised 906 patients, 453 patients per treatment arm, to receive either nivolumab at 3 mg/kg i.v. every two weeks or ipilimumab at 10 mg/kg i.v. every 3 weeks for four doses and every 12 weeks thereafter until documented disease progression or unacceptable toxicity, up to a maximum treatment duration of one year.
The primary endpoint of recurrence-free survival was met in the ongoing study
The primary endpoint in the study was RFS, defined as the time between randomisation and the date of first recurrence or death.
Overall, stage IIIb, IIIc, and IV disease was reported for 34%, 47%, and 19% of patients, respectively. Thirty-two percent of patients had ulcerated primary disease, 48% had macroscopic lymph node involvement, and 42% of patients were positive for the BRAF mutation.
RFS was significantly improved with nivolumab over ipilimumab at a median follow-up of 18.5 months; the 18-month RFS rates were 66.4% versus 52.7%, respectively, hazard ratio [HR] 0.65; 97.56% confidence interval [CI] 0.51, 0.83 (p < 0.0001).
Median RFS was not reached in either treatment arm.
Findings from prespecified subgroup analyses demonstrated consistent hazard ratios favouring nivolumab
Safety results also favour nivolumab
Fewer grade 3/4 treatment-related adverse events (TRAEs) were observed with nivolumab. Grade 3/4 TRAEs occurred in 14% of patients treated with nivolumab and 46% of patients on ipilimumab.
Study discontinuation due to an adverse event of any grade was reported in 10% of nivolumab and 43% of ipilimumab patients.
The incidence of grade 3/4 immune-related TRAEs for the following organ systems with nivolumab and ipilimumab was: gastrointestinal 2.0% versus 16.8%, hepatic 1.8% versus 10.8%, and skin 1.1% versus 6.0%.
No deaths due to study drug toxicity were reported for nivolumab; however, two (0.4%) patient deaths due to colitis and medullary aplasia occurred in patients more than 100 days after last ipilimumab dose.
Both drugs are currently approved for treatment of advanced melanoma
Nivolumab and ipilimumab are immune checkpoint inhibitors that restore immune anti-tumour activity by different mechanisms. Nivolumab blocks the programmed death 1 (PD-1) receptor and ipilimumab targets the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecule on T cells.
Both drugs have demonstrated significant benefit and have been approved for advanced melanoma. Ipilimumab has also been approved in the adjuvant setting for patients with resected stage III melanoma in the United States since 2015, based on results from the phase III international, double-blind EORTC 18071 trial. This trial showed that ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo (HR 0.75; 95% CI, 0.64-0.90; p < 0.002).1
Despite surgical intervention and possible adjuvant treatment, most patients with stage IIIb/IIIc melanoma experience disease recurrence and many progress to advanced disease. By five years, 68% of patients with stage IIIb and 89% of patients with stage IIIc melanoma experience disease recurrence, making development of successful adjuvant therapy a priority in melanoma.
Nivolumab administered as adjuvant therapy significantly improved RFS compared to ipilimumab for patients with stage IIIb/c/IV melanoma at high risk of recurrence.
Nivolumab also demonstrated a superior safety profile.
Reinhard Dummer of the Skin cancer Unit Dermatology, Cancer Center Zürich, University Hospital, Zürich, Switzerland who discussed the study results said that his personal perspective in term of implications for approvals is that in USA, nivolumab will fully substitute the approval of ipilimumab in all stages including stage IIIA in the adjuvant setting and in Europe, nivolumab will be approved for stage IIIB and higher, dabrafenib/trametinib for stage IIIA-IIIC. His personal conclusions in term of surgical and medical management of stage III melanoma are that IFN and ipilimumab are no longer recommended in the adjuvant setting; in clinical trials, these control arms should be discontinued; adjuvant treatment options are nivolumab for all and dabrafenib/trametinib for BRAF mutant patients. He underlined that nessecity of complete lymphnode dissection is questionable and there is a need for urgent investigation. Neoadjuvant therapy is still experimental and must be applied in the context of clinical trials only.
The study results are simultaneously published in The New England Journal of Medicine.
This trial was sponsored by Bristol-Myers Squibb.
- Eggermont AM, et al. Lancet Oncol 2015;16(5):522-530.
The co-senior authors for this abstract are Dr. J. Larkin and Dr. P.A. Ascierto.
LBA8_PR – Weber J, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238).