Sintilimab-chemo improves PFS in advanced NSCLC

Combining the anti-PD-1 antibody sintilimab with a pemetrexed-platinum chemotherapy regimen improved survival outcomes in patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC), interim analysis of the phase III ORIENT-11* trial from China showed.

“This study demonstrated that the addition of sintilimab to chemotherapy significantly improved progression-free survival (PFS) and nominally improved overall survival (OS), with an acceptable safety profile in [patients with] first-line nonsquamous NSCLC,” said Professor Li Zhang from the Sun Yat-Sen University Cancer Center, Guangzhou, China.

“[T]he combination regimen could provide a new treatment option for this patient population,” said Zhang and colleagues.

Participants were 397 individuals aged 18–75 years (median age 61 years) with untreated locally advanced or metastatic nonsquamous NSCLC ineligible for surgery or radiotherapy and with no EGFR or ALK alterations. They were randomized 2:1 to receive sintilimab (200 mg) or placebo plus pemetrexed (500 mg/m²) and platinum-based chemotherapy (cisplatin [75 mg/m²] or carboplatin [AUC 5]) Q3W for four cycles. This was followed by a maintenance regimen of sintilimab or placebo plus pemetrexed for ≤24 months.

Most patients had stage IV disease (92.1 and 88.5 percent of sintilimab and placebo recipients, respectively) and received carboplatin (73.3 and 74.8 percent, respectively). Brain metastases was present in 13.5 and 16.8 percent, respectively. Patients were treated for a median 7.1 and 5.5 months, respectively.

After a median 8.9 months of follow-up, PFS was significantly improved in the sintilimab-chemo vs the placebo-chemo group (median 8.9 vs 5.0 months; hazard ratio [HR], 0.482, 95 percent confidence interval [CI], 0.362–0.643; p<0.00001). [WCLC 2020 Virtual Presidential Symposium, abstract 1]

The PFS findings favouring sintilimab were consistent across multiple subgroups including sex, age, choice of platinum chemotherapy, smoking status, and presence of brain metastases. 

PFS appeared to improve with sintilimab vs placebo with increasing PD-L1 expression (tumour proportion score [TPS] <1 percent: median 7.3 vs 5.1 months; HR, 0.664; p=0.10295; TPS 1–49 percent: median 7.1 vs 4.8 months; HR, 0.503; p=0.02506; TPS ≥50 percent: median not reached vs 5.0 months; HR, 0.310; p<0.00001).

OS results, though immature, showed a trend toward improved outcomes with sintilimab vs placebo (6-month OS: 89.6 percent vs 80.4 percent; HR, 0.609, 95 percent CI, 0.400–0.926; p=0.01921).

However, 31.3 percent of placebo recipients crossed over to receive sintilimab at progression, pointed out Zhang. “[This] may attenuate the survival benefits seen with sintilimab in the investigational arm,” he said.

Overall response rate was also higher in the sintilimab vs placebo group (51.9 percent vs 29.8 percent; p=0.00003), as was disease control rate (86.8 percent vs 75.6 percent). Patients on sintilimab had a faster time to response than those on placebo (median 1.5 vs 2.6 months) with a longer duration of response (median not reached vs 5.5 months). Three patients on sintilimab had a complete response vs none on placebo, and partial response was achieved by 50.8 and 29.8 percent, respectively.

Grade 3–5 adverse events (AEs) occurred in 61.7 and 58.8 percent of sintilimab and placebo recipients, respectively, and serious AEs in 28.2 and 29.8 percent, respectively. AEs led to treatment discontinuation in 6.0 and 8.4 percent of sintilimab and placebo recipients, respectively, and death in six and nine patients, respectively. The most common (≥20 percent) grade 3–5 AEs in both groups were anaemia and decreased neutrophil or white blood cell count. Grade 3–5 immune-related AEs occurred in 15 sintilimab and eight placebo recipients, the most common (≥2 percent) being rash in the placebo group and elevated amylase in the sintilimab group.

“[G]iven the promising results from the preliminary analysis, we expect that the benefit observed in the sintilimab … group would be maintained with longer follow-up,” said the researchers, though long-term results, particularly for OS, are awaited.