Combination Therapy Shows Antitumor Activity in Advanced Gastric, GEJ Adenocarcinoma

The combination of the VEGFR-2 inhibitor ramucirumab (Cyramza) plus the anti—PD-L1 agent durvalumab (Imfinzi) demonstrated antitumor activity in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from a phase Ia/b study presented at the 2018 Gastrointestinal Cancers Symposium.¹

This is an ongoing, multi-cohort study that enrolled patients with prior progression on 1 or 2 lines of systemic therapy, had measurable disease, and baseline tumor tissue (NCT02572687). Patients received 8 mg of ramucirumab and 750 mg of durvalumab, both intravenously, every 2 weeks for a 28-day cycle. The primary objective of this study was to assess safety and tolerability of the combination.

“It is a small study, but [the] response rates are good, especially in PD-L1—positive gastric cancer patients. This study suggests that this combination may work in some patients with gastric cancer,” said lead author Yung-Jue Bang, MD, PhD, in a statement to OncLive.

Investigators noted that PD-L1 expression was assessed using SP-263 immunohistochemistry and microsatellite instability (MSI) status by pathologic complete response. The median age was 55 years old with 69% of the 29 patients treated being male. Of these patients, 48% expressed PD-L1 ≥25% in tumor or immune cells, and 3.5% were MSI-high tumors. Seventy-two percent of patients received the regimen as a second-line treatment for advanced disease.

There is preclinical evidence that suggests blocking VEGFR-2 and the PD-1/PD-L1 pathway induces synergic antitumor effects. This promotes access of cytotoxic T cells to tumors, while avoiding the exhaustion of T cells.

Results showed that median duration of treatment was 2.5 months for ramucirumab and 3 months for durvalumab. Of the 29 patients, 5 (17%) achieved a confirmed partial response, as per the preliminary efficacy data by RECIST v1.1 criteria. Additionally, the overall response rate for patients who expressed PD-L1 ≥25% was 36%, and median progression-free survival (PFS) was 2.6 months (95% CI, 1.45-6.28).

Treatment-emergent adverse events (TEAEs) occurred in all 29 patients, with 21 (72%) of patients experiencing grade 3/4 TEAEs. Although treatment-related adverse events occurred in 24 patients (83%), no one discontinued treatment. All-grade treatment-related adverse events occurring in ≥10% of patients included hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%), and decreased appetite (10%). As of data cut-off, 6 patients (21%) remain on treatment

“The combination of durvalumab and ramucirumab in patients with gastric cancer did not reveal any unexpected safety signals,” Bang said. “Moving forward, we are looking to phase II and phase III trials.”

This therapy could be impactful, Bang added, as gastric cancer is the third leading cause of cancer-related death globally. As it is often diagnosed at an advanced stage, the disease has a poor prognosis.

Targeted therapies against the VEGF pathway, such as ramucirumab, elicit effects on tumor antigenicity and intratumoral T-cell infiltration—providing rationale for combining antiangiogenic therapies with immunotherapies, according to Bang.

Ramucirumab was FDA approved in 2014 for the treatment of patients with unresectable gastric and GEJ adenocarcinoma following fluoropyrimidine- or platinum-containing therapy, based on a significant extension in OS.

This approval was based on the phase III REGARD study, in which 355 patients with advanced gastric cancer or GEJ adenocarcinoma were randomized 2:1 to receive best supportive care plus either ramucirumab (n = 238) or placebo (n = 117). The median PFS was 2.1 versus 1.3 months, respectively (HR, 0.483; 95% CI, 0.376-0.620; P <.0001). Median OS was 5.2 months with ramucirumab versus 3.8 months with placebo (HR, 0.776; 95% CI, 0.603-0.998; P = .047).²

In December 2017, the topline results from phase III RAINFALL study showed that adding ramucirumab to cisplatin and capecitabine or 5-FU (5-fluorouracil) in the frontline setting did not improve OS in patients with HER2-negative metastatic gastric or GEJ adenocarcinoma, although the study did meet its primary endpoint of PFS.

Durvalumab is currently FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Additionally, durvalumab was granted breakthrough designation by the FDA for patients with non—small cell lung cancer who have locally advanced, unresectable disease that has not progressed following platinum-based chemoradiation.

Although durvalumab is not currently approved for the treatment of patients with gastric or GEJ adenocarcinoma, data suggest that there is activity with acceptable safety profiles across a range of tumors.

References

• Bang YJ, Golan T, Lin CC, et al. Interim safety and clinical activity in patients with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab plus durvalumab. J Clin Oncol. 2018;36, (suppl 4S; abstr 92).
• Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet. 2014;383(9911):31-39. doi: 10.1016/S0140-6736(13)61719-5.