Adding sugemalimab to first-line chemotherapy improves the survival of patients with advanced oesophageal squamous cell carcinoma

Results of the phase III GEMSTONE-304 trial show that adding the PD-L1 inhibitor sugemalimab to standard chemotherapy significantly improves the progression-free (PFS) and overall survival (OS) in the first line treatment of patients with unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma (ESCC). Together with similar results obtained with combinations of chemotherapy and a PD-1 inhibitor, these data provide further support for the use of chemo-immunotherapy in the first line treatment of patients with advanced oesophageal cancer.

Background

ESCC is the most common subtype of oesophageal cancer, representing about 80% of all cases worldwide. In previous phase III studies, combinations of a PD-1 inhibitor with chemotherapy were successfully studied as first line treatment for patients with advanced ESCC. To date, however, there is limited evidence on the potential of combining a PD-L1 inhibitor with chemotherapy in this setting. Sugemalimab is a full-length, fully human IgG4 monoclonal antibody directed against PD-L1. Of note, in contrast to other Fc-null anti-PD-L1 antibodies, sugemalimab has retained its antibody-dependent cellular phagocytosis activity. In a previously reported phase Ib study, the combination of sugemalimab with 5-fluorouracil and cisplatin showed promising efficacy and a manageable safety profile in treatment-naïve patients with advanced ESCC. The 2023 World congress on GI cancer featured the presentation of the results of the primary analysis of GEMSTONE-304, a randomized, double-blinded, phase III study comparing sugemalimab plus chemotherapy (5-fluorouracil plus cisplatin) to chemotherapy alone as first line treatment for patients with advanced ESCC.

Study design

GEMSTONE-304 randomized a total of 540 patients with unresectable locally advanced, recurrent or metastatic ESCC (2:1) to sugemalimab (1200 mg IV, q3w) plus chemotherapy (5-fluorouracil + cisplatin IV, q3w for up to 6 cycles) or chemotherapy alone. Eligible patients did not receive any prior systemic therapy for advanced disease, had an ECOG performance status of 0-1 and had at least one measurable lesion per RECIST v1.1. The co-primary endpoints of the study consisted of PFS by independent review and OS in the intent-to-treat (ITT) population, with objective response rate (ORR), duration of response (DoR) and safety as the most important secondary study objectives.

Results

At the time of the presented analysis (median follow-up 27.7 months in the combination arm vs. 13.8 months in the control arm), treatment was ongoing in 15.4% of patients treated with sugemalimab-chemotherapy as compared to 4.9% in the control arm. The main reason for treatment discontinuation in both arms was disease progression (54.7% vs. 63.2%). The median age of patients in the study was 63 years, with 87% of them being male. All patients had an Asian ethnicity. In both arms, about 11% had a PD-L1 expression of <1%, with 45% and 43% having a PD-L1 expression of 1-10% and ≥10%, respectively. About a third of patients had lung metastasis at baseline, while liver or bone metastasis were seen in 18% and 10% of patients, respectively.

Sugemalimab-chemotherapy was associated with a clinically meaningful and statistically significant PFS improvement compared to chemotherapy alone, with a median PFS of 6.2 and 5.4 months, respectively (HR[95%CI]: 0.67[0.54-0.82]; p= 0.0002). At the 12-month landmark, this translated into a 24.3% PFS rate with the combination, which is more than double the 11.5% 12-month PFS rate seen with chemotherapy alone. This delayed disease progression translated into a significant OS benefit for patients in the sugemalimab-chemotherapy arm, with a median OS of 15.3 months as compared to 11.5 months in the control arm (HR[95%CI]: 0.70[0.55-0.90]; p= 0.0076). The OS rate at 12 and 18 months with the sugemalimab-chemotherapy combination was reported at 63% and 38.9% as compared to 47.1% and 32.5% with chemotherapy alone. Importantly, this benefit in PFS and OS was consistently observed, irrespective of age, gender, the PD-L1 expression levels, the baseline ECOG performance status and the presence of metastasis. Among patients treated with sugemalimab-chemotherapy, 60.1% had an ORR as compared to 45.2% with chemotherapy alone (complete response: 10.9% vs. 5.1%). Responses to the chemo-immunotherapy combination also proved to be more durable with a median DoR of 6.0 months as compared to 4.5 months with chemotherapy alone.

The incidence of grade ≥3 treatment-related adverse events (TRAEs) was similar in both arms at 51.3% with sugemalimab-chemotherapy as compared to 48.4% in the control arm. However, the sugemalimab-chemotherapy combination did come with a higher rate of serious TRAEs than placebo-chemotherapy, with a rate of 21.5% and 13.2%, respectively. Nevertheless, the rate of treatment discontinuation due to AEs was fairly similar in both arms at 13.3% for sugemalimab-chemotherapy and 10.4% with placebo-chemotherapy.

Conclusions

Sugemalimab in combination with chemotherapy induced a statistically significant and clinically meaningful prolongation in PFS and OS and a significant improvement in ORR compared to chemotherapy alone. In this, sugemalimab plus chemotherapy came with a manageable safety profile, without unexpected safety signals. As such, sugemalimab plus chemotherapy (5-fluorouracil and cisplatin) could represent a new first-line treatment option for patients with unresectable locally advanced, recurrent, or metastatic ESCC.

Reference

Li J., et al. GEMSTONE-304: A phase 3 study of sugemalimab plus chemotherapy versus chemotherapy as first-line treatment of patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC). Presented at ESMO World GI 2023; Abstract O-4.