Nivolumab/Paclitaxel Combo Shows Antitumor Activity in EBV-Related, MSI-H, PD-L1+ Advanced Gastric Cancer

Nivolumab in combination with paclitaxel showed clinical activity and a manageable safety profile when used as second-line therapy for patients with Epstein-Barr virus–related, microsatellite instability–high/mismatch repair deficient or PD-L1–positive advanced gastric cancer.

Nivolumab (Opdivo) in combination with paclitaxel showed clinical activity and a manageable safety profile when used as second-line therapy for patients with Epstein-Barr virus–related, microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) or PD-L1–positive advanced gastric cancer, according to findings from a phase 1/2 study (NCT02951091) presented during Week 1 of the virtual AACR Annual Meeting 2021.1

At a median follow-up of 10.8 months, data from the phase 2 cohort (n = 48) showed that the combination led to a median progression-free survival (PFS) of 3.9 months (95% CI, 2.7-5.5), and a median overall survival (OS) of 11.2 months (95% CI, 6.0-18.7).

“The combination of nivolumab and paclitaxel demonstrated significant antitumor activity with durable overall survival, and a manageable toxicity profile, as a second-line treatment for [Epstein Barr]-virus related, MSI-H or PD-L1–positive advanced gastric cancer patients,” lead study author Sun Young Rha, MD, of the Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, South Korea, said in a virtual presentation of the data.

Second-line treatment for patients with advanced gastric cancer includes paclitaxel, irinotecan, docetaxel, and ramucirumab (Cyramza) either alone or plus paclitaxel. While PD-L1 is overexpressed in advanced gastric cancer and infiltrating T cells, the efficacy of checkpoint blockade in this setting is limited.

Nivolumab as a single agent, however, has shown benefit in this patient population who had previously received at least 2 chemotherapy regimens, as seen in the phase 3 ATTRACTION-2 study (NCT02267343).2

In this open-label, phase 1/2 trial presented during the meeting, which is part of a biomarker umbrella study conducted at multiple sites in South Korea, investigators evaluated the combination of nivolumab and paclitaxel in patients with EBV-related, MSI-H/dMMR or PD-L1–positive advanced gastric cancer who progressed on frontline chemotherapy with a platinum and fluoropyrimidine.

To be eligible for enrollment, patients had to have histologically confirmed advanced gastric cancer, had failed previous first-line chemotherapy with fluoropyrimidine and platinum, and had evaluable disease. In the phase 1b portion of the trial (n = 6), the biomarker-based selection was in all-comers and the phase 2 portion (n = 48) was in those with EBV-related, MSI-H/dMMR, or PD-L1–positive disease.

Patients were enrolled between February 2018 and December 2019. The phase 1b portion focused on the recommended phase 2 dose (RP2D) and dose-limiting toxicities (DLTs) and was done in a 3+3 and single-center design from Yonsei Cancer Center. Nivolumab was given at 3 mg/kg on days 1 and 15 and paclitaxel was given at 70 mg/m2 or 80 mg/m2 on days 1, 8, and 15, all in 28-day cycles. The 80-mg/m2 dose was chosen as the RP2D without any DLTs reported in either level.

In the phase 2 portion of the trial, which was from 7 sites in South Korea, nivolumab and paclitaxel was given until disease progression or unacceptable toxicity. Patients were assessed via RECIST v1.1 criteria every 6 weeks. The primary end point of the trial was PFS at the RP2D; secondary end points were OS, objective response rate (ORR), disease control rate (DCR), 6-month PFS rate, safety, and correlative studies.

Regarding baseline characteristics in the phase 2 portion, the median age was 57 years (range, 37-79), and three-fourths of patients were male. Most patients (66.7%) had an ECOG performance status of 1 and 40.4% of patients had more than 3 metastatic organs.

Also, in the phase 2 cohort, 60.4% of patients had a PD-L1 combined positive score (CPS) of greater than 10, 10.4% had EBV positivity, and 4.2% of patients were MSI-H.

The data cutoff date was January 31, 2021. Additional results showed that the 6- and 12-month PFS rates were 33.3% and 16.7%, respectively, and the 6- and 12-month OS rates were 64.1% and 46.4%, respectively.

When stratified by PD-L1 expression level, the median PFS was 3.6 months for those who had a PD-L1 CPS of less than 50 (n = 36) compared with 5.0 months for those with a PD-L1 of 50 or greater (n = 12; P = .385). The median OS was 9.07 months vs 20.3 months, respectively (P = .127).

Out of 30 patients with measurable disease, 56.7% of patients (n = 17/30) had target lesion shrinkage according to RECIST v1.1 criteria, and target lesion shrinkage was greater than 30% in 33.3% of patients (n= 10/30).

The ORR was 23.3%, which comprised a 13.3% complete response rate and a 10.0% partial response rate. Seventeen patients (56.7%) had stable disease and 6 patients (20.0%) had progressive disease. The DCR was 80.0%, and the median DOR in the 7 responding patients was 17.0 months (95% CI, 2.6–not reached).

Five patients remain on treatment or follow-up, Rha noted.

No unexpected adverse events (AEs) from this combination were reported, and no treatment-related deaths occurred. Grade 3/4 AEs occurred in 41.6% of patients, which Rha said were mostly related to paclitaxel. These included decreased neutrophil count (25.0%), neuropathy (2.1%), anorexia (2.1%), pneumonitis (2.1%), and fatigue (2.1%).

In-house panel sequencing of 33 patients demonstrated that baseline tumor mutational burden was not related to survival outcomes. Additionally, it was found that the median PFS in patients with RTK/RAS pathway genes alterations was 4.0 months vs 2.3 months for those who were RTK/RAS wild-type (P = .0082). The median PFS was for TP53/DNA repair pathway alterations was 5.5 months compared with 2.7 months for those who were TP53/DNA repair pathway wild-type (P = .0129).

These panel sequencing data are encouraging, but require longer follow-up, said Rha.


  1. Rha SY, Lee JB, Kim HS, et al. Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT159.
  2. Kang YKm Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461-2471. doi:10.1016/S0140-6736(17)31827-5