Sintilimab-chemo a new first-line treatment alternative for GI cancers?

Interim results of two phase III ORIENT trials presented at ESMO 2021 underscore the potential of a combination regimen comprising the PD-1 inhibitor sintilimab and chemotherapy (CT) as a first-line therapeutic alternative for gastrointestinal cancers, particularly advanced, recurrent, or metastatic oesophageal squamous cell carcinoma (SCC) and gastric/gastroesophageal junction (G/GEJ) adenocarcinoma.

ORIENT-15: Oesophageal cancer

A total of 659 patients (86 percent male) were randomized 1:1 to receive cisplatin*-based CT either alone or in combination with IV sintilimab at a dose of 3 mg/kg (for body weight <60 kg) or 200 mg (≥60 kg) Q3W for up to 24 months. [ESMO 2021, abstract LBA52]

After a median follow-up of 11.4 months, sintilimab-CT provided a better survival benefit than CT alone in the overall cohort (median, 16.7 vs 12.5 months, hazard ratio [HR], 0.63 [overall survival (OS)] and median, 7.2 vs 5.7 months; HR, 0.56 [progression-free survival (PFS)]; p<0.0001 for both).

A similar trend was seen in a subgroup of PD-L1-positive patients (ie, CPS** ≥10), both in terms of OS (median, 17.2 vs 13.6 months, HR, 0.64; p=0.0018) and PFS (median, 8.3 vs 6.4 months, HR, 0.58; p<0.0001).

Grade ≥3 treatment-related adverse event (TRAE) rate was higher with the combination regimen vs CT alone (60 percent vs 54 percent), as was the rate of discontinuation owing to TRAEs (21 percent vs 12 percent).

“More than half of new and fatal cases of oesophageal cancer in the world occur in China every year. Oesophageal cancer is the fifth most commonly diagnosed cancer and fourth leading cause of death from cancer in China, and SCC is the predominant histologic type,” said principal study investigator Prof Shen Lin from the Peking University Cancer Hospital and Institute, Beijing, China, in a press release.

“Treatment options for locally advanced or metastatic oesophageal SCC are limited, [hence the] significant unmet clinical need. [Our findings] suggest that sintilimab-CT may represent a first-line treatment option [in this patient setting],” said Lin.

ORIENT-16: G/GEJ cancer

ORIENT-16 looked into the efficacy and safety of an oxaliplatin***-based CT regimen either alone or with sintilimab (dosing similar to ORIENT-15) for untreated, unresectable locally advanced or metastatic G/GEJ cancer (n=650; 61 percent PD-L1 positive [ie, CPS ≥5]). [ESMO 2021, abstract LBA53]

After a median follow-up of 18.8 months, sintilimab-CT bested CT in terms of OS in the intention-to-treat (ITT) cohort (median, 15.2 vs 12.3 months; HR, 0.77; p=0.0090) and in the PD-L1-positive subgroup (median, 18.4 vs 12.9 months; HR, 0.66; p=0.0023). “The OS benefits were consistently observed at all prespecified CPS cutoffs (ie, CPS ≥1, 5, and 10),” said the researchers.

Sintilimab-CT was also superior to CT alone in terms of PFS, both in the ITT (HR, 0.64; p<0.0001) and in the PD-L1-positive cohorts (HR, 0.63; p=0.0002).

Grade ≥3 TRAE rates were similar between the sintilimab-CT and CT alone arms (60 percent vs 52 percent).

“Sintilimab is the first PD-1 inhibitor that demonstrated superior OS and PFS with an acceptable safety profile, in combination with CT, in Chinese patients with G/GEJ cancer regardless of PD-L1 expressions,” said the researchers.

“Gastric cancer is one of the most common malignant tumour types globally, [with] nearly half of all cases diagnosed in China,” said principal investigator Prof Jianming Xu from the Fifth Medical Center of People's Liberation Army General Hospital, Beijing, China, in a press release.

“The prognosis for advanced gastric cancer is very poor. Currently, CT is the primary treatment option and targeted agents have offered limited benefit. [Our findings] have the potential to bring a new and more effective treatment option to people with gastric cancer,” Xu added.