Nivolumab Plus Chemotherapy Extends PFS With Durable Responses in Gastric/GEJ Cancers

Narikazu Boku, MD, PhD

In the phase 3 ATTRACTION-4 study, nivolumab (Opdivo) added to chemotherapy led to a statistically significant improvement in progression-free survival (PFS) and induced higher overall response rates in patients with previously untreated advanced or recurrent gastric and gastroesophageal junction cancer (GEJ), according to results presented during the 2020 ESMO Virtual Congress.¹

“The prespecified objective of the phase 3 part of the ATTRACTION-4 study was achieved, showing good, clinically meaningful efficacy,” said Narikazu Boku, MD, PhD, deputy director of the National Cancer Center Hospital in Tokyo, Japan. “Nivolumab plus chemotherapy demonstrated a manageable safety profile, [as well].”

Results from the interim analysis presented during the 2020 ESMO Virtual Congress revealed that patients who were given nivolumab plus chemotherapy (n = 362) experienced a median PFS of 10.45 months (95% CI, 8.44-14.75) versus 8.34 months (95% CI, 6.97-9.40) in those who were given chemotherapy plus a placebo (n = 362; HR, 0.68; 98.51% CI, 0.51-0.90; P = .0007). The 1-year PFS rate was determined to be 45.4% in the nivolumab/chemotherapy arm versus 30.6% in the chemotherapy-alone arm.

However, no statistically significant improvement in overall survival (OS) was observed with nivolumab plus chemotherapy. Specifically, the median OS was 17.45 months (95% CI, 15.67-20.83) in the investigational arm versus 17.15 months (95% CI, 15.18-19.65) in the control arm (HR, 0.90; 95% CI, 0.75-1.08; P = .257).

“Although the OS was slightly higher in the nivolumab arm than the placebo arm,” Boku explained. “However, the [investigational] arm did not [experience a] significant survival benefit.”

Previously, nivolumab demonstrated a notable survival benefit in this heavily pretreated patient population; that activity supported the rationale to launch the randomized, multicenter, phase 2/3 ATTRACTION-4 study, according to Boku.² Results from the phase 2 portion of the trial also showed encouraging activity with the combination.³

To be eligible for enrollment on the double-blind, controlled study, which was conducted in 130 centers across Japan, Taiwan, and Korea, patients needed to have been diagnosed with unresectable, advanced or recurrent HER2-negative gastric or GEJ cancer. Patients also needed to be chemotherapy naïve with an ECOG performance status of 0 or 1. However, neoadjuvant or adjuvant chemotherapy was permitted if it was completed within 180 days prior to disease recurrence.

For the trial, patients were randomized 1:1 to receive either 360 mg of intravenous nivolumab and S-1 plus oxaliplatin (SOX) or capecitabine and oxaliplatin therapy or placebo plus SOX or CapeOX therapy. Stratification factors included country, performance status, PD-L1 expression, and disease status.

Treatment continued until disease progression, intolerable toxicity, or consent was withdrawn. The co-primary end points of the trial were PFS per central assessment by IRRC and OS. Key secondary end points included investigator-assessed PFS, ORR, duration of response (DOR), time to response (TTR), best overall response, and safety.

At the data cutoff for the interim PFS analysis, which was October 31, 2018, the median follow-up period was 11.6 months. The median follow-up at the January 31, 2020 data cutoff for the final analysis of OS was 26.6 months. A total of 724 patients underwent randomization from March 2017 to May 2018.

Notably, the primary objective could only be achieved if at least 1 of the null hypotheses of the primary end points is rejected. Additionally, the level of significance, which was 2-sided, was set at 4% and 1% for PFS and OS, respectively, for the final analysis. Should the PFS null hypothesis be rejected, the OS analysis would be performed at a reallocated level of significance, explained Boku. The interim PFS analysis was planned at approximately 323 events, while the final OS analysis was planned at approximately 464 events.

The median age of participants in the nivolumab/chemotherapy arm was 63.5 years versus 65.0 years in the placebo/chemotherapy arm. The majority of patients enrolled on the study were male (69.9% and 74.6%, respectively) with a female minority (30.1% and 25.4%, respectively). Between the 2 arms, 54.7% of those on the nivolumab arm and 54.4% of those in the placebo arm were from Japan, 40.9% and 39.5%, respectively, were from Korea, and 4.4% and 6.1%, respectively, were from Taiwan.

The median duration of treatment in patients who received nivolumab plus SOX (n = 229) was 6.3 months (95% CI, 0-32) and 5.2 months in those who were given nivolumab plus CapeOX (n = 130; 95% CI, 0-33). The median duration of treatment was 5 months (95% CI, 0-31) in the placebo plus SOX arm (n = 230) and 5.7 months (95% CI, 0-33) in the placebo plus CapeOX arm (n = 128). Moreover, 89.7% (n = 322) of patients in the experimental arm discontinued treatment with nivolumab or placebo, while 94.7% (n = 339) of patients in the control arm discontinued treatment.

In the nivolumab cohort, 59.1% of patients discontinued treatment due to disease progression (n = 212), 5.3% due to worsening of clinical symptoms associated with disease progression (n = 19), 6.1% because of unacceptable toxicities (n = 22), 8.6% because of investigator decision (n = 31), and 11.4% due to other reasons (n = 41). Discontinuation in the placebo cohort was due to progressive disease (70.4%; n = 252), worsening of clinical symptoms due to disease progression (6.1%; n = 22), unacceptable toxicities (2.5%; n = 17), investigator decision (4.7%; n = 15), or other reasons (12.3%; n = 44).

“The nivolumab arm showed a greater PFS all [patient subsets],” Boku noted.

The ORR was 57.5% (n = 208) in the nivolumab arm (95% CI, 52.2-62.6) versus 47.8% (n = 173) in the placebo arm (95% CI, 42.5-53.1; P = .0088). Of the patients who received nivolumab plus chemotherapy, 19.3% achieved complete responses (CRs; n = 70), 38.1% had partial responses (PRs; n = 138), 14.4% experienced stable disease (SD; n = 52), and 6.9% had progressive disease (n = 25). Among those who were given placebo plus chemotherapy, 13.3% had CRs (n = 48), 34.5% experienced PRs (n = 125), 20.7% achieved SD (n = 75), and 12.7% had disease progression (n = 46).

Additionally, the disease control rate (DCR) was 71.8% in the nivolumab arm (n = 260; 95% CI, 66.9-76.4) versus 68.5% (n = 248; 95% CI, 63.4-73.3) in the placebo arm. The median TTR was 1.4 months in both arms (nivolumab, 95% CI, 1.0-8.3; placebo, 95% CI, 1.0-15.3). Additionally, the median DOR was 12.91 months (95% CI, 9.89-16.56) in the nivolumab/chemotherapy cohort versus 8.67 months (95% CI, 7.2-11.37) in the placebo/chemotherapy cohort.

Any grade of any adverse effect (AE) was reported in 99.7% (n = 358) of patients who received nivolumab with chemotherapy. Among this cohort, 37.6% (n = 135) experienced any grade of any serious AEs, while 69.4% (n = 249) had grade 3 and 4 of any AE and 2.2% (n = 8) had grade 5 of any AE. In the placebo cohort, 99.7% (n = 357) experienced any grade of any AE, 33.5% (n = 120) experienced any grade of any serious AEs, 63.1% (n = 226) had grade 3-4 of any AE, and 1.7% (n = 6) had grade 5 of any AE.

Patients who received nivolumab plus chemotherapy most frequently experienced any grade of skin (37.3%) and gastrointestinal (35.9%) AEs. Gastrointestinal (5.8%), hepatic (3.9%), and skin (3.9%) were the most commonly reported grade 3 or 4 AEs, with only 1 case of a grade 5 hepatic AE reported with this regimen. The most common any-grade AEs reported in the placebo arm were gastrointestinal (31.6%) and skin (24%). This regimen also led to grade 3 or 4 gastrointestinal (5.3%) and hepatic (3.4%) AEs in patients who received it. No grade 5 AEs were reported in this cohort.

“Nivolumab plus chemotherapy could be considered a new first-line treatment option for patients with unresectable, advanced or recurrent gastrointestinal GEJ cancer,” concluded Boku.

_References:

_{1. Boku N, Ryu MH, Oh DY, et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; virtual. Accessed September 21, 2020. Abstract LBA7_PR.}

_{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.}

_{3. Boku N, Ryu MH, Chung HC, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol. 2019;30(2):250-258. doi: 10.1093/annonc/mdy540.}