The introduction of immune checkpoint inhibitors has changed first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). Long-term follow-up is now helping define how durable these benefits remain beyond the initial trial results.
On August 10, 2026, Annals of Oncology published the study titled “Nivolumab plus chemotherapy or ipilimumab versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 5-year follow-up results from CheckMate 648.”
Authors: K. Kato, J. Ajani, Y. Doki, J. Xu, L. Wyrwicz, S. Motoyama, T. Ogata, H. Kawakami, C-H. Hsu, A. Adenis, F. el Hajbi, M. Di Bartolomeo, M. Ignez Braghiroli, E. Holtved, T. Makino, M. Blum Murphy, J. Zhang, P. Sharma, B. He, M. Lei, Y. Matsumura, Y. Kitagawa, and I. Chau.
Understanding IPI/NIVO
Nivolumab and ipilimumab target two different immune checkpoints that regulate T-cell activity at different stages of the immune response.
Nivolumab (NIVO) is a monoclonal antibody that targets programmed death-1 (PD-1), an inhibitory receptor expressed on T cells. By blocking the interaction of PD-1 with its ligands, PD-L1 and PD-L2, nivolumab reduces PD-1 pathway-mediated inhibition of the immune response and restores antitumor T-cell activity.
Ipilimumab (IPI) is a monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), another inhibitory immune checkpoint. CTLA-4 competes with the costimulatory receptor CD28 for binding to CD80 and CD86 on antigen-presenting cells, limiting T-cell activation. By blocking CTLA-4, ipilimumab enhances T-cell activation and proliferation and increases antitumor immune responses.
The rationale for combining the two agents is complementary: CTLA-4 blockade enhances T-cell priming and activation, while PD-1 blockade helps restore T-cell activity within the tumor microenvironment. Together, the two approaches provide complementary checkpoint blockade aimed at strengthening the antitumor immune response.
Previous Results From CheckMate 648
The primary results of CheckMate 648 were published in the New England Journal of Medicine on February 2, 2022. At a minimum follow-up of 13 months, both nivolumab plus chemotherapy and nivolumab plus ipilimumab significantly improved overall survival compared with chemotherapy alone.
Among patients with tumor cell PD-L1 expression ≥1%, median OS was 15.4 months with nivolumab plus chemotherapy versus 9.1 months with chemotherapy (HR 0.54; P<0.001), and 13.7 months with nivolumab plus ipilimumab versus 9.1 months with chemotherapy (HR 0.64; P=0.001).
In the overall population, median OS was 13.2 months with nivolumab plus chemotherapy and 12.7 months with nivolumab plus ipilimumab, compared with 10.7 months with chemotherapy. PFS was significantly improved with nivolumab plus chemotherapy in patients with tumor cell PD-L1 ≥1%, but not with nivolumab plus ipilimumab.
Five-Year Follow-Up of CheckMate 648
CheckMate 648 (NCT03143153) was a global, randomized, open-label phase III trial evaluating first-line nivolumab-based treatment in patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC.
A total of 970 patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. Chemotherapy consisted of fluorouracil plus cisplatin. The primary endpoints were OS and BICR-assessed PFS in patients with tumor cell PD-L1 expression ≥1%. Key secondary endpoints included OS and BICR-assessed PFS in all randomized patients.
At the January 13, 2025 data cutoff, the median follow-up was 71.5 months. Nearly half of patients, 49%, had tumor cell PD-L1 expression ≥1%.
Nivolumab Plus Chemotherapy Maintained an OS Benefit
Among patients with tumor cell PD-L1 expression ≥1%, median OS was 15.0 months with nivolumab plus chemotherapy compared with 9.1 months with chemotherapy alone. Nivolumab plus chemotherapy reduced the risk of death by 38%, with an HR of 0.62. At 5 years, 12% of patients receiving nivolumab plus chemotherapy were alive compared with 7% receiving chemotherapy.
The survival advantage was also maintained across the overall randomized population. Median OS was 13.2 months with nivolumab plus chemotherapy versus 10.7 months with chemotherapy, corresponding to an HR of 0.77. Five-year OS rates were 13% and 9%, respectively.
In patients with tumor cell PD-L1 ≥1%, median PFS was 6.8 months with nivolumab plus chemotherapy compared with 4.4 months with chemotherapy, with an HR of 0.67. Five-year PFS rates were 3% and 0%, respectively. The objective response rate also remained higher with nivolumab plus chemotherapy. Among patients with tumor cell PD-L1 ≥1%, ORR was 53% compared with 20% with chemotherapy. In the overall population, ORR was 47% versus 27%.
Complete responses were also more frequent with nivolumab plus chemotherapy, occurring in 17% versus 4% of patients with tumor cell PD-L1 ≥1% and in 15% versus 6% of the overall population.
Durable Survival With Nivolumab Plus Ipilimumab
Nivolumab plus ipilimumab also continued to demonstrate a long-term OS advantage. Among patients with tumor cell PD-L1 ≥1%, median OS was 13.1 months with nivolumab plus ipilimumab versus 9.1 months with chemotherapy. The risk of death was reduced by 38%, with an HR of 0.62.
The difference became particularly evident in long-term survival. At 5 years, 18% of patients receiving nivolumab plus ipilimumab were alive compared with 7% receiving chemotherapy. In the overall population, median OS was 12.7 months with nivolumab plus ipilimumab versus 10.7 months with chemotherapy, with an HR of 0.77. Five-year OS rates were 16% and 9%, respectively.
Unlike the OS results, nivolumab plus ipilimumab did not improve median PFS compared with chemotherapy. In patients with tumor cell PD-L1 ≥1%, median PFS was 4.0 months versus 4.4 months, with an HR of 1.03. In the overall population, median PFS was 2.9 months versus 5.6 months, with an HR of 1.25. However, a long-term PFS tail was observed. Among patients with tumor cell PD-L1 ≥1%, 5-year PFS was 9% with nivolumab plus ipilimumab and 0% with chemotherapy.
The investigators noted that the PFS curves crossed at approximately 6.5 months, after which a sustained separation favored nivolumab plus ipilimumab. They noted that this observation may be explained by the delayed treatment effect of immunotherapy compared with chemotherapy.
Response Durability With Dual Immunotherapy
Among patients with tumor cell PD-L1 ≥1%, ORR was 35% with nivolumab plus ipilimumab compared with 20% with chemotherapy. The complete response rate was 18% versus 4%, respectively. Median duration of response was also longer with nivolumab plus ipilimumab, at 11.8 months compared with 5.7 months with chemotherapy.
In the overall population, ORR was the same with nivolumab plus ipilimumab and chemotherapy, at 27%. However, median duration of response remained longer with dual immunotherapy, at 11.1 months versus 6.9 months.
Notably, among responders in the overall population, 17% of those receiving nivolumab plus ipilimumab had responses lasting at least 60 months, compared with 3% in the chemotherapy group.
PD-L1 and Long-Term Benefit
The greatest magnitude of OS benefit with both nivolumab-based regimens was observed among patients with tumor cell PD-L1 expression ≥1%. For nivolumab plus chemotherapy, increasing PD-L1 expression beyond this threshold did not appear to substantially enrich the OS benefit.
For nivolumab plus ipilimumab, analysis using PD-L1 combined positive score suggested increasing OS benefit at higher CPS thresholds. The HR for OS was 0.76 at CPS ≥1, 0.72 at CPS ≥5, and 0.66 at CPS ≥10.
Benefit Extended Beyond First Progression
An exploratory analysis of PFS on next-line therapy, or PFS2, also favored both nivolumab-containing regimens. Among patients with tumor cell PD-L1 ≥1%, median PFS2 was 12.5 months with nivolumab plus chemotherapy compared with 7.1 months with chemotherapy, corresponding to an HR of 0.52.
For nivolumab plus ipilimumab, median PFS2 was 9.9 months versus 7.1 months, with an HR of 0.60. Similar advantages were observed in the overall randomized population.
Safety Remained Consistent With Previous Reports
No new safety signals emerged with longer follow-up. Grade 3–4 treatment-related adverse events occurred in 49% of patients receiving nivolumab plus chemotherapy, 33% receiving nivolumab plus ipilimumab, and 37% receiving chemotherapy. Any-grade treatment-related adverse events were reported in 96%, 80%, and 90% of patients, respectively.
The most common treatment-related adverse events with nivolumab plus chemotherapy included nausea, decreased appetite, and stomatitis. With nivolumab plus ipilimumab, the most frequent events included rash, pruritus, and hypothyroidism. Treatment-related deaths occurred in 2% of patients in each treatment group. No additional treatment-related adverse events leading to discontinuation and no new treatment-related deaths were identified with longer follow-up.
What the Five-Year Results Show
With a minimum follow-up of 5 years, CheckMate 648 demonstrates that the survival advantage initially observed with both nivolumab plus chemotherapy and nivolumab plus ipilimumab is maintained over time. In patients with tumor cell PD-L1 ≥1%, the 5-year OS rates were 12% with nivolumab plus chemotherapy, 18% with nivolumab plus ipilimumab, and 7% with chemotherapy alone.
Nivolumab plus chemotherapy produced higher response rates than chemotherapy and a PFS advantage in patients with tumor cell PD-L1 ≥1%, while nivolumab plus ipilimumab showed no PFS benefit compared with chemotherapy but demonstrated durable responses and long-term OS benefit.
The investigators concluded that these results further support nivolumab combined with chemotherapy or ipilimumab as first-line treatment for patients with advanced ESCC, with long-term survival benefit and no new safety signals.