Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma

Abstract

Background: Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.

Materials and methods: We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.

Results: In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.

Conclusion: For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.

Implications for practice: The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.

Keywords: Gastroesophageal adenocarcinoma; Randomized controlled trials; Systemic therapy; Treatment sequencing.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) diagram for study inclusion and exclusion. The PRISMA flow chart details the number of articles identified in the literature search and the number of articles included and excluded at each stage. Note that articles from the SLR‐MA search that met the inclusion criteria for reference list review to identify potential primary RCT publications are listed in the PRISMA diagram as excluded at level 2 for reason “other” (as these articles are not primary RCTs).Abbreviations: 2L, second line; 3L, third line; MA, meta‐analysis; RCT, randomized controlled trial; SLR, systematic literature review.

Figure 2

First‐line, second‐line, and third‐line study overview.Abbreviations: ph1, phase I; ph2, phase II; ph3, phase III.

Figure 3

First‐line, second‐line, and third‐line and beyond interventions. (A): First‐line interventions. Targeted therapies include bevacizumab, cetuximab, lapatinib, onartuzumab, panitumumab, rilotumumab, trastuzumab, pertuzumab, and ramucirumab. Chemotherapy includes capecitabine, cisplatin, docetaxel, epirubicin, oxaliplatin, paclitaxel, S‐1, tegafur, 5‐fluorouracil, and leucovorin (folinic acid). Eleven studies compared the efficacy of chemotherapy doublets. (B): Second‐line interventions. In the center of the diagram, “12 studies TT vs. CM/PB” include 12 studies with single‐agent (SA) chemotherapy in both arms: six assessing the efficacy of SA versus SA and six assessing SA plus targeted therapy versus control. (C): Third‐line interventions. Targeted therapies include avelumab, TAS‐102, nivolumab (ICI), and ipilimumab (ICI). Chemotherapy includes irinotecan and paclitaxel.Abbreviations: ↑, increased/higher dose; BSC, best supportive care; CM, chemotherapy; DB, doublet; ICI, immune checkpoint inhibitor; Pac, paclitaxel; PB, placebo; Pembro, pembrolizumab; TP, triplet; Traz, trastuzumab; TT, targeted therapy; TX, taxane; VP, valproic acid.

Figure 4

Potential treatment sequencing algorithm. The proposed sequential algorithm is based on the current analysis of randomized controlled trials as described in this systematic literature review. Recent approvals and key trial readouts are highlighted under “Key Considerations” and discussed in this article (see Discussion section). Checkmate‐649, KEYNOTE‐590, and KEYNOTE‐811 are noted under 1L options that should be considered in treatment planning; HER2‐ tumors will be assessed and dichotimzed into PD‐L1 CPS ≥5 or ≥10 and eligible for anti‐PD1 therapy, or HER2‐/PD‐L1‐ and receive chemotherapy alone. These sequences were not tested in a clinical trial setting. 3L options also include irinotecan or taxane, whichever not yet used previously. Pembrolizumab in 3L had its approval recently voluntarily withdrawn; nivolumab approved for 3L only in Asia.Abbreviations: 1L, first line; 2L, second line; CAPOX, capecitabine plus oxaliplatin; CPS, combined positive score; DCF, docetaxel plus cisplatin/5‐fluorouracil; FOLFOX, folinic acid plus 5‐FU plus oxaliplatin; FOLFIRI, folinic acid plus 5‐fluorouracil plus irinotecan; HER2+, HER2 overexpressing; HER2−, HER2 negative; ICI, immune checkpoint inhibitor; MSI‐h, high microsatellite instability; SOX, S‐1 plus oxaliplatin; TAS‐102, trifluridine/tipiracil; T‐DXd, trastuzumab deruxtecan; TMB, tumor mutational burden.