Outcomes on anti-VEGFR-2/paclitaxel treatment after progression on immune checkpoint inhibition in patients with metastatic gastroesophageal adenocarcinoma

Abstract

Through our involvement in KEYNOTE-059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti-VEGFR-2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST-defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression-free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5-fold (range 4-121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post-treatment versus pre-treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti-VEGFR-2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti-VEGF(R)/taxane are underway.

Keywords: anti-VEGFR2; gastric/gastroesophageal cancers; immune checkpoint inhibition; paclitaxel; tumor microenvironment.

FIGURE 1

Clinical activity of ramucirumab/paclitaxel in ICI-experienced patients as compared to last chemotherapy before ICI (LCBI) in the same group of patients (Comparison 1, B,C) or compared to ramucirumab/paclitaxel in ICI-naïve patients (Comparison 2, D-F). A, Analytic approach. Comparison 1 was restricted to all 17 patients who received chemotherapy before ICI, and multivariate models were adjusted for ECOG PS immediately prior to a given line of therapy. ICI always included an anti-PD-1 antibody. For Comparison 2, multivariate models were adjusted for the number of prior lines of therapy, age, ECOG PS, serum albumin, and number of metastatic sites—all collected immediately pre-ramucirumab/paclitaxel. B, Tumor regression rates for nonpaired analysis of Comparison 1. Each number (bar) denotes a unique patient. Dots denote patients that were unevaluable for tumor regression during that treatment segment. A separate paired (intrapatient) analysis restricted to 9 patients evaluable for tumor regression during both LCBI and ramucirumab/paclitaxel yielded consistent results (Table S5). C, Progression-free survival for Comparison 1. D, Tumor regression rates, (E) progression-free survival, and (F) overall survival for Comparison 2. ^aFor illustration only, the graphical upper limit for the increase in the sum of target lesions from baseline was set at +100% (five patients during the ICI segment had values of +780%, +468%, +270%, +150%, +104.8% [B] and one patient during ramucirumab/paclitaxel without preceding ICI had a value of +230% [D]). ICI, immune checkpoint inhibition; RAM, ramucirumab; TAX, paclitaxel; LCBI, last chemotherapy before ICI; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; irRECIST, Immune-related Response Evaluation Criteria In Solid Tumors; HR, hazard ratio; UV, univariate; MV, multivariate

FIGURE 2

Immune microenvironment in paired serial tumors collected pre-ICI and on-treatment with immediately subsequent ramucirumab/ paclitaxel in five patients with metastatic gastroesophageal adenocarcinoma. A, Direct immunofluorescence on paired tumor biopsies collected pre-ICI and during response on subsequent ramucirumab/paclitaxel from a single patient with metastatic gastroesophageal adenocarcinoma. In the pretreatment biopsy, Tregs are abundant and in direct contact with CD8+ T cells (inset). Post-treatment, Tregs are sparse and CD8+ T cells remain abundant (left inset shows an uncommon FOXP3+ Treg, right inset shows CD8+ T cell with confirmed DAPI-staining nuclei in dark blue in close proximity to tumor cells). B, Representative mass cytometry images from a single patient with paired biopsies collected endoscopically from the primary tumor. In the pretreatment tumor, Tregs were in close proximity with CD8+ T cells (inset). C, Cell-count densities of FOXP3+ Tregs and (D) ratio of CD8+ T cells to FOXP3+ Tregs on imaging mass cytometry with median values shown as horizontal dotted lines. Mean fold-change on-ramucirumab/paclitaxel vs pre-ICI is 28.4 (95% CI, −35.7 to 92.5) for FOXP3+ Treg frequency and 11.9 (95% CI 1.0 to 22.9) for the CD8/Treg ratio. Tregs, regulatory T cells; ICI, Immune checkpoint inhibition; RAM, ramucirumab; TAX, paclitaxel