In a presentation at the 2018 International Society of Gastrointestinal Oncology Annual Meeting, Yung-Jue Bang, MD, PhD, discusses the most promising biomarkers and treatment approaches for patients with GEJ cancer, highlighting recent and ongoing trials of immunotherapy.
Yung-Jue Bang, MD, PhD
The standard of care for gastric or gastroesophageal junction (GEJ) cancer has grown considerably over the last few years, with immunotherapy and other targeted agents showing significant benefit for selected subgroups.
“We know that about 20% of patients benefit from immunotherapy in GEJ cancer [and] we want to know who they are before we start treatment,” said Yung-Jue Bang, MD, PhD. “We [still] need more research to develop potential biomarkers for patient selection in the future.”
In a presentation at the 2018 International Society of Gastrointestinal Oncology Annual Meeting, Bang, president of the Biomedical Research Institute at the Seoul National University Hospital in South Korea, discussed the most promising biomarkers and treatment approaches for patients with GEJ cancer, highlighting recent and ongoing trials of immunotherapy.
Pembrolizumab (Keytruda) received an accelerated approval from the FDA in September 2017 for the treatment of patients with PD-L1positive recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer who have received ≥2 prior systemic therapies, including chemotherapy, based on findings from the phase II KEYNOTE-059 study.1
Of the 259 patients treated with the PD-L1 inhibitor in the single-arm, multicohort trial, 174 patients (67.2%) were assessed for microsatellite instability (MSI) and 7 (4.0%) had samples that were MSI-high. The overall response rate (ORR) with pembrolizumab for patients with MSI-high tumors was 57.1% (95% CI, 18.4%-90.1%) compared with 9.0% (95% CI, 5.1%-14.4%) among 167 patients with nonMSI-high samples.
“In general, patients with [MSI-high tumors] had better outcomes,” Bang concluded.
The disease control rate (DCR) of 71.4% (95% CI, 29.0%-96.3%) was also notably higher in the MSI-high group compared to 22.2% (95% CI, 16.1%-29.2%) in the nonMSI-high cohort. The complete response rates were 14.3% (95% CI, 0.4%-57.9%) versus 2.4% (95% CI, 0.7%-6.0%), respectively.
In the open-label, phase III KEYNOTE-061 trial, patients (n = 592) with previously treated advanced or metastatic GEJ cancer with a PD-L1 combined positive score (CPS) ≥1 were randomized 1:1 to receive either pembrolizumab or paclitaxel after failure of first-line chemotherapy.2Although it failed to meet its co-primary endpoints of overall survival (OS) and progression-free survival (PFS), Bang suggested that it could still be a viable treatment option for patients with PD-L1 CPS ≥10.
“In patients with PD-L1negative tumors, chemotherapy was clearly better than pembrolizumab,” said Band. “However, in patients with PD-L1–high tumors, pembrolizumab was much better than chemotherapy. This strongly suggests that, in PD-L1–high tumors, pembrolizumab may be [a better option].”
At a median follow-up of 7.9 months and by the data cutoff date of October 26, 2017, the median OS for patients with CPS ≥10 treated with pembrolizumab was 10.4 months (95% CI, 5.9-17.3) versus 8.0 months (95% CI, 5.1-9.9) with paclitaxel. Comparatively, patients with PD-L1 CPS <1 in the pembrolizumab arm was 4.8 months (95% CI, 3.9-6.1) versus 8.2 months (95% CI, 6.8-10.6) in the paclitaxel arm.
The OS, PFS, and ORR for patients with MSI-high tumors (n = 15) were also reported in the study. The median OS for patients with MSI-high tumors treated with pembrolizumab was not reached (NR; 95% CI, 5.6 months-NR) versus 8.1 months (95% CI, 2.0-16.7) with paclitaxel. The median PFS for pembrolizumab was 17.8 months (95% CI, 2.7-NR) versus 3.5 months (95% CI, 2.0-9.8).
Seven of the 15 patients with MSI-high tumors treated with pembrolizumab responded with an ORR of 46.7% (95% CI, 21.3%-73.4%) versus 2 of the 12 patients with MSI-high tumors in the paclitaxel arm with an ORR of 16.7% (95% CI, 2.1%-48.4%).
“These studies suggest that patients with MSI-high or PD-L1-high [GEJ] cancer respond better to immunotherapy,” he said.
During his presentation, Bang highlighted several other potential biomarkers, including tumor mutation burden, immune gene signatures, tumor-infiltrating lymphocytes, and T-cell receptor clonality.
POTENTIAL COMBINATION STRATEGIES
Although PD-L1 antibodies have shown clinical activity as a monotherapy in patients with GEJ cancers, trials are now investigating combination strategies using PD-L1 antibodies as the backbone.
“We are trying many combinations to improve the fraction of patients that can benefit from immunotherapy,” continued Bang. “These include antiPD-L1 with other targeted agents or chemotherapy at this time.”
The open-label, multicohort, phase I/II CheckMate-032 trial investigated nivolumab (Opdivo) monotherapy or the combination of nivolumab and the antiCTLA-4 antibody ipilimumab (Yervoy) in patients with chemotherapy-refractory advanced or metastatic GEJ cancer.3
Of the 160 patients treated, 59 received 3 mg of nivolumab monotherapy, 49 received 1 mg of nivolumab plus 3 mg of ipilimumab, and 52 were treated with a 3-mg dose of nivolumab plus 1 mg of ipilimumab. The median follow-ups were 28, 24, and 22 months across the 3 groups, respectively.
The ORR response rates were 12% (95% CI, 5%-23%), 24% (95% CI, 13%-39%), and 8% (95% CI, 2%-19%) regardless of PD-L1 expression, respectively. The DCR was 32% for patients treated with nivolumab alone, compared with 41% and 37% for patients treated with combination therapy, respectively.
Based on these findings, phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy are underway for patients with GEJ cancer. The combination therapy has demonstrated clinical activity in other solid tumors and is currently FDA approved for the treatment of patients with melanoma.
PD-L1 inhibitors with chemotherapy have also shown promise and there are 4 phase III trials currently under investigation for this combination in PD-L1positive GEJ cancer, according to Bang. “This combination is being tested in both the adjuvant and neoadjuvant setting,” he added.
For example, in a preliminary analysis from the multicohort, phase II KEYNOTE-059 trial, the ORR was 60% (95% CI, 38.7%-78.9%) for patients with advanced GEJ cancer treated with frontline pembrolizumab plus fluorouracil and cisplatin.4
At a median follow-up of 12.2 months, the median PFS was 6.6 months (95% CI, 5.9-10.6) and the median OS was 13.8 months (95% CI, 7.3-not estimable).