Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study.

Abstract

LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

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“…ORR in TPS <1% has not reported to date. 88 Although no new safety signals were identified, grade 3-4 toxicity leading to discontinuation was higher for nivolumab-ipilimumab vs chemotherapy (13% vs 5%), particularly after accounting for the shorter treatment duration of nivolumab-ipilimumab. These data suggest that these chemoimmunotherapy and dual-immunotherapy combinations may be potential firstline options for selected patients with unresectable advanced or metastatic ESCC whose tumors are TPS >1%.…”

“…Greatest benefit was observed in patients with PD-L1 ≥10% (n=104 in camrelizumab and n=98 in placebo; HR 0.52 [95% CI, 0.35-0.79]), as compared with PD-L1 <10% (n=188 and n=195, respectively; HR 0.78 [95% CI, 0.59-1.02]), PD-L1 <5% (n=145 and 155, respectively; HR 0.77 [95% CI, 0.56-1.04]) or PD-L1 <1% (n=126 and n=130, respectively; HR 0.79 [95% CI, 0.57-1.11]). 87 Lastly, recently presented data from the phase III CHECKMATE-648 study, which evaluated the efficacy of doublet chemotherapy (cisplatin/FP) alone vs in combination with nivolumab or combination with nivolumab and ipilimumab in the first-line setting in 970 patients with unresectable advanced or metastatic ESCC, revealed a statistically significant and clinically meaningful OS benefit with the addition of nivolumab to either chemotherapy or ipilimumab, compared with chemotherapy alone, among patients with tumor PD-L1 TPS ≥ 1% ( 88 Higher ORR was also observed with nivolumab plus chemotherapy and nivolumab plus ipilimumab, compared with chemotherapy alone, in both patients with PD-L1 TPS ≥ 1% (53% vs 35% vs 20%, respectively). ORR in TPS <1% has not reported to date.…”

“…15.4 mos vs 9.1 mos [HR=0.54, 99.5% CI 0.37-0.80; p<0.0001] and 13.7 mos vs 9.1 mos [HR=0.64, 98.6% CI 0.46-0.90; p=0.001], respectively) and in the all-HR=0.74, 99.1% CI 0.58-0.96; p=0.0021] and 12.8 mos vs 10.7 mos [HR=0.78, 98.2% CI 0.62-0.98; p<0.0011], respectively) (Table2) 88. This OS benefit was not observed in patients with tumor PD-L1 TPS < 1% when comparing nivolumab plus chemotherapy (HR 0.98; med-…”

Immunotherapy for Esophageal Cancers: What Is Practice Changing in 2021?

“…The CheckMate 648 trial randomized patients into one of these three arms: (i) the combination of nivolumab plus ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyteassociated protein 4) antibody, (ii) nivolumab plus chemotherapy, or (iii) chemotherapy alone. Recently presented results show that both nivolumab plus ipilumumab (median OS 13.7 months; HR 0.64; 98.6% CI 0.46-0.90; p = 0.001) and nivolumab plus chemotherapy (median OS 15.4 months; HR 0.54; 99.5% CI 0.37-0.80; p < 0.0001) are superior to chemotherapy alone (median OS 9.1 months) in patients with tumor cell PD-L1 ≥ 1% [44]. There was some benefit for PD-L1-negative patients in both experimental groups compared to chemotherapy alone, and longer follow-up will help us decide the extent of this benefit.…”

The safety of current treatment options for advanced esophageal cancer after first-line chemotherapy

“…Given these data, nivolumab plus ipilimumab could be a promising therapy for metastatic or recurrent EC in terms of efficacy; in a cross-trial comparison, the frequency of serious irAEs in ICI combination therapy seemed to be higher than that in ICI monotherapy, such as nivolumab or pembrolizumab. A CheckMate-648 phase III trial comparing nivolumab plus cisplatin and fluorouracil or nivolumab plus ipilimumab with cisplatin and fluorouracil as first-line chemotherapy for untreated patients with metastatic or recurrent ESCC is released in the ASCO 2021 [42]. The trial showed the superiority of nivolumab plus cisplatin and fluorouracil group and nivolumab plus ipilimumab group compared to conventional cisplatin and fluorouracil group, regarding OS in PD-L1 (TPS) ≥ 1% and all populations.…”