Frontline nivolumab + chemo ups survival in advanced gastric/oesophageal cancer

Adding nivolumab to chemotherapy in the first-line setting significantly improves survival compared with chemotherapy alone in patients with HER2-negative advanced gastric/gastroesophageal (G/GEJ) cancer or oesophageal adenocarcinoma (EAC), shows the CheckMate 649 study presented at ESMO 2020.

After a minimum follow-up of 12 months, the primary endpoint of overall survival (OS) in patients whose tumours expressed PD-L1 combined positive score (CPS) ≥5 was significantly extended in the nivolumab arm than the chemotherapy alone arm (median, 14.4 vs 11.1 months; hazard ratio [HR], 0.71; p<0.0001). [ESMO 2020, abstract LBA6_PR]

Similar OS benefit was seen in the subgroup of patients with PD-L1 CPS ≥1 tumours (median, 14.0 vs 11.3 months; HR, 0.77; p=0.0001) as well as in all randomized patients (median, 13.8 vs 11.6 months; HR, 0.80; p=0.0002).

“OS consistently favoured nivolumab + chemotherapy versus chemotherapy [alone] across multiple prespecified subgroups,” said presenting author Dr Markus Moehler from Johannes Gutenberg University Clinic, Mainz, Germany.

Progression-free survival (PFS) in patients with PD-L1 CPS ≥5 tumours, a coprimary endpoint, was also longer with the addition of nivolumab vs chemotherapy alone (median, 7.7 vs 6.1 months; HR, 0.68; p<0.0001).

“Overall response rate [ORR] was higher with NIVO + chemo versus chemo, and responses were more durable,” Moehler reported. Median duration of response in the nivolumab arm was 9.5 months compared with 7.0 months in the chemotherapy alone arm (ORR, 60 percent vs 45 percent; p<0.0001).

There were no new safety signals identified. The most common (≥ 25 percent) treatment-related adverse events (TRAEs) of any grade were diarrhoea, nausea, and peripheral neuropathy for both arms. Grade 3–4 TRAEs events occurred in ≤5 percent of patients and no grade 5 events were reported.

Calling the results “clinically very relevant,” session chair Professor Salah-Eddin Al-Batran, Krankenhaus Nordwest-University Cancer Centre, Frankfurt, Germany, said: “Based on this trial, for patients with HER2-negative G/GEJ cancer or EAC with PD-L1 CPS ≥5 tumours, the addition of nivolumab to chemotherapy will become the standard of care for first-line treatment.”

“The open question is the effect in patients who have a PD-L1 CPS <5,” he raised.

The phase III CheckMate 649 study randomized 1,581 patients with previously untreated HER2-negative advanced G/GEJ or EAC to receive nivolumab (360 mg Q3W or 240 mg Q2W) + chemotherapy (XELOX Q3W or FOLFOX Q2W) or chemotherapy alone in a 1:1 ratio.

Consistent benefit in Asians

The PFS benefit with nivolumab was also seen in Asian patients with G/GEJ cancer, according to ATTRACTION-4, another study presented during ESMO 2020.

ATTRACTION 4 was similar to CheckMate 649, with the exception of two major differences: participants comprised of only Asians and it was designed such that the primary outcomes involved all-comers, rather than those meeting a prespecified CPS level. [ESMO 2020, abstract LBA7_PR]

A total of 724 Asian patients with advanced or recurrent G/GEJ cancer were randomized 1:1 to receive nivolumab + chemotherapy (S-1 + oxaliplatin or capecitabine + oxaliplatin) or chemotherapy alone in the double-blind phase III study.

At 1 year, 45.4 percent of the patients receiving nivolumab were still alive and free of disease progression compared with 30.6 percent in the chemotherapy alone arm. The corresponding median PFS was 10.5 vs 8.3 months, in favour of nivolumab (HR, 0.68; p=0.0007).

While the improvement in PFS was significant, the final OS was not (median, 17.5 vs 17.2 months; HR, 0.90; p=0.257), after a median follow-up of 26.6 months.

“OS was not improved, possibly because all-comers were treated or because patients in Asia receive more subsequent therapies than Western populations,” explained Al-Batran.

“[Nonetheless,] the prespecified [primary] objective … was achieved, showing clinically meaningful efficacy,” said lead author Dr Narikazu Boku of National Cancer Center Hospital, Tokyo, Japan.

ORR was also higher in the nivolumab arm (57.5 percent vs 47.8 percent; p=0.0088), with more durable response seen compared with the chemotherapy alone arm (median, 12.91 vs 8.67 months).

In addition, the nivolumab + chemotherapy regimen demonstrated a manageable safety profile, Boku pointed out. The rates of grade 3–5 TRAEs were 57.9 percent in the nivolumab arm and 49.2 percent in the chemotherapy alone arm.

“The improvement in PFS was clinically relevant and the trial strongly supports the results of CheckMate 649,” Al-Batran commented.