Nivo–ipi, nivo–chemo present new first-line treatments for advanced oesophageal SCC

The combination of nivolumab–ipilimumab (nivo–ipi) or nivolumab–chemotherapy (nivo–chemo) improved overall survival (OS) compared with chemotherapy alone in the first-line treatment of advanced oesophageal squamous cell carcinoma (ESCC), results of the phase III CheckMate 648 study showed.

“Nivo is the first PD-1 inhibitor to demonstrate superior OS and durable responses in combination with either chemo or ipi vs chemo alone, in previously untreated patients with advanced ESCC,” presented Dr Ian Chau from the Royal Marsden Hospital, London & Surrey, UK, at ASCO 2021.

“Nivo–chemo and nivo–ipi each represent a new potential first-line standard of care (SoC) for patients with advanced ESCC,” he added.

Participants were 970 patients with unresectable, advanced, recurrent, or metastatic ESCC and ECOG performance status 0–1 with no prior systemic treatment for advanced disease. They were randomized 1:1:1 to receive nivolumab (240 mg Q2W) + chemotherapy (fluorouracil 800 mg/m² on days 1–5 and cisplatin 80 mg/m² on day 1 Q4W; median age 64 years, 79 percent male), nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W; median age 63 years, 83 percent male), or chemotherapy only (fluorouracil + cisplatin Q4W; median age 64 years, 85 percent male).

Seventy percent of patients were Asian, almost 60 percent had de novo metastatic disease, and just under half had PD-L1 expression ≥1 percent. 

Patients were followed up for a minimum 12.9 months. Patients in the nivo–chemo, nivo–ipi, and chemo-only arms were treated for a median 5.7, 2.8, and 3.4 months, respectively. Treatment discontinuation was mainly due to disease progression (59, 54, and 63 percent, respectively). Fifty-five percent of patients received subsequent treatment, primarily chemotherapy.

OS was significantly improved with nivo–chemo vs chemo-only in the population of patients with PD-L1 expression ≥1 percent (median 15.4 vs 9.1 months; hazard ratio [HR], 0.54, 99.5 percent confidence interval [CI], 0.37–0.80; p<0.0001; 12-month OS: 58 percent vs 37 percent) and among all randomized patients (overall population; median 13.2 vs 10.7 months; HR, 0.74, 99.1 percent CI, 0.58–0.96; p=0.0021; 12-month OS: 54 percent vs 44 percent). [ASCO 2021, abstract LBA4001]

Progression-free survival (PFS), as per blinded independent central review, was also significantly improved with nivo–chemo vs chemo-only in the PD-L1 ≥1 percent population (median 6.9 vs 4.4 months; HR, 0.65, 98.5 percent CI, 0.46–0.92; p=0.0023; 12-month PFS: 25 percent vs 10 percent), but not the overall population (median 5.8 vs 5.6 months; HR, 0.81, 98.5 percent CI, 0.64–1.04; p=0.0355; 12-month PFS: 24 percent vs 16 percent). However, there was an improvement in PFS with nivo–chemo vs chemo-only in the investigator-assessed analysis (HRs, 0.53 and 0.69 in the PD-L1 ≥1 percent and overall populations, respectively).

Objective response rate (ORR) was improved with nivo–chemo vs chemo-only in the PD-L1 ≥1 percent (53 percent vs 20 percent) and overall populations (47 percent vs 27 percent), with longer duration of response (DoR; median 8.4 vs 5.7 months and 8.2 vs 7.1 months, respectively).

OS was also significantly improved with nivo–ipi vs chemo-only in both the PD-L1 ≥1 percent (median 13.7 vs 9.1 months; HR, 0.64, 98.6 percent CI, 0.46–0.90; p=0.0010) and overall populations (median 12.8 vs 10.7 months; HR, 0.78, 98.2 percent CI, 0.62–0.98; p=0.0110), with 12-month OS rates of 57 percent vs 37 percent and 54 percent vs 44 percent, respectively. 

The OS results for both nivo–chemo or nivo–ipi vs chemo-only were consistent across most prespecified subgroups.

PFS in both the PD-L1 ≥1 percent and overall populations were not significantly improved with nivo–ipi vs chemo-only. 

ORR was improved with nivo–ipi vs chemo-only in the PD-L1 ≥1 percent population (35 percent vs 20 percent), with a median DoR of 11.8 vs 5.7 months. In the overall population, ORR was 28 percent vs 27 percent with a median DoR of 11.1 vs 7.1 months.

Complete response rates were tripled with both nivo–chemo and nivo–ipi vs chemo-only in the PD-L1 ≥1 percent population.

 

Acceptable safety

Grade 3–4 treatment-related adverse events (TRAEs) occurred in 47, 32, and 36 percent of patients in the nivo–chemo, nivo–ipi, and chemo-only groups, respectively, and serious grade 3–4 TRAEs in 18, 23, and 13 percent, respectively. Grade 3–4 TRAEs led to discontinuation of any drug in 9, 13, and 5 percent, respectively. There were five treatment-related deaths each in the nivo–chemo and nivo–ipi groups and four in the chemo-only group.

The most common (≥10 percent) any-grade AEs in the nivo–chemo and chemo-only groups were nausea, decreased appetite, and stomatitis, and in the nivo–ipi group, rash, pruritus, and hypothyroidism. TRAEs of potential immunologic aetiology were generally grade 1–2, with grade 3–4 events occurring in ≤6 percent of patients.

“No new safety signals were identified with nivo–chemo or nivo–ipi,” noted Chau.

 

A new SoC emerges

Oesophageal cancer accounts for >500,000 deaths globally each year, with ESCC, the predominant histological subtype, accounting for 85 percent of cases, said Chau.

“Standard first-line chemotherapy for advanced metastatic ESCC carries a poor prognosis with a median of around 10 months,” he continued.

“The clinically meaningful improvements in survival [with nivo–chemo and nivo–ipi] highlight immunotherapy’s impact on cancer care and should bring new therapeutic options to a group of patients that are often diagnosed when disease has already spread,” concluded Chau.