Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer

INTRODUCTION — Locally advanced unresectable and metastatic esophageal, gastroesophageal junction (GEJ), and gastric cancer are not curable diseases. The goals of therapy include disease control and improving overall survival. Systemic therapy can also be used to treat and palliate multiple cancer-related symptoms such as dysphagia, nausea, pain, obstruction, perforation, and bleeding. Multidisciplinary input is necessary from gastroenterology, surgical oncology, radiation oncology, and medical oncology. (See "Local palliation for advanced gastric cancer" and "Endoscopic palliation of esophageal cancer".)

Second and later-line systemic therapy in patients with advanced or metastatic esophageal, GE, and gastric cancer will be presented here. Initial systemic treatment and other local treatment approaches for this population are discussed separately.

●(See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer".)

●(See "Local palliation for advanced gastric cancer".)

●(See "Endoscopic palliation of esophageal cancer".)

●(See "Surgical management of invasive gastric cancer", section on 'Metastasectomy'.)

APPROACH TO THE PATIENT

Goals of therapy — As with first-line therapy, the goals of second-line therapy for metastatic esophageal and gastric cancer are to palliate symptoms and improve survival:

●A survival benefit for second-line chemotherapy has been shown in at least five randomized trials of ramucirumab (both alone and with paclitaxel), single-agent docetaxel, and irinotecan [1-5].

●Furthermore, a Cochrane review of salvage systemic therapy for advanced gastric and esophagogastric junction (EGJ) adenocarcinoma after failure of a first-line platinum/fluoropyrimidine-containing regimen concluded that both chemotherapy and immunotherapy using immune checkpoint inhibitors improve survival over placebo in the second-line setting [6].

Patient selection — We do not use any specific algorithm to select patients for second-line treatment. Instead, we make this decision on a case-by-case basis, taking into account performance status, comorbidity, goals of care, patient preference, the overall medical condition, and disease status. For patients with a poor performance status, poorly controlled comorbidity, or a preference for no additional therapy, we suggest supportive care alone rather than second-line therapy.

The criteria to select patients for second-line systemic therapy have not been established. In one study, five factors were identified that were independently associated with poor survival: a performance status of 2, hemoglobin ≤11.5 g/dL, serum carcinoembryonic antigen (CEA) level >50 ng/mL, three or more metastatic sites, and a time to progression of six or fewer months after the first-line regimen [7]. A prognostic index was developed, which divided patients into low- (no risk factors), intermediate- (one or two risk factors), or high-risk (three or more risk factors) groups with different median survival durations (12.7, 7.1, and 3.3 months, respectively). Although this model is prognostic, none of these factors can be used to predict which patients might benefit from a second-line regimen.

Multipanel somatic and germline genomic testing — Somatic (tumoral) and germline genomic testing in order to identify potentially actionable targets is indicated for patients who might be eligible for immunotherapy or molecularly targeted therapy.

The American Society of Clinical Oncology has issued a provisional clinical opinion that supports somatic and germline genomic testing in metastatic or advanced cancer when there are genomic biomarker-linked therapies approved by regulatory agencies for that type of cancer [8]. Given the tissue-agnostic approvals for any advanced cancer with a high tumor mutational burden (TMB) or DNA mismatch repair deficiency (checkpoint inhibitor immunotherapy), or neurotrophic tyrosine receptor kinase (NTRK) fusions (TRK inhibitors), this provides a rationale for testing for all solid tumors, if the individual would be a candidate for these treatments. For patients without an approved genomic biomarker-linked therapy, testing should be considered to determine candidacy for targeted therapies approved for other diseases; however, off-label/off-study use of such therapies is not recommended when a clinical trial is available, or without evidence of meaningful efficacy in clinical trials. We agree with this guidance.

Regimen choice — Patient preference, quality of life, histologic type, the results of genomic testing, and the specific regimen that was used for initial therapy are key considerations when choosing the therapeutic approach for later lines of therapy. For patients who retain an adequate performance status after the first-line regimen there is no standard approach to second-line therapy and beyond. Particularly in view of the lack of data showing benefit of multiagent chemotherapy versus monotherapy [9,10], we emphasize quality of life and minimization of side effects when choosing the regimen.

For most patients, we prefer enrollment in a clinical trial if available. If trials are unavailable or patients are ineligible, our general approach is summarized below:

●Immunotherapy – Immunotherapy targeting programmed cell death 1 (PD-1) is an option for selected patients.

•In many cases, PD-1 targeted therapy will have been administered with the first-line chemotherapy regimen. We would generally not pursue anti-PD-1 immunotherapy for later lines of therapy if disease progression occurred during prior PD-1 targeted therapy given in the first-line setting. Rechallenge may be considered, preferably in the context of a clinical trial, if prior anti-PD-1 immunotherapy was discontinued due to a specific toxicity that has since resolved, and possibly for patients with progression at few sites (oligoprogression) after a prior objective response or prolonged period of stable disease during initial PD-1 targeted immunotherapy. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

The following recommendations apply to patients who did not have progressive disease during front-line immunotherapy:

•Pembrolizumab is an option for second-line therapy in patients whose tumors have a deficiency in mismatch repair (dMMR) or high levels of TMB if they did not receive front-line immunotherapy. (See 'Defective mismatch repair' below and 'High tumor mutational burden' below.)

•For squamous cell cancers, pembrolizumab is also an option for those with high levels of programmed cell death ligand 1 (PD-L1) expression (combined positive score [CPS] ≥10), and nivolumab or camrelizumab (where available) are options for second-line treatment and beyond regardless of PD-L1 expression status. (See 'Efficacy in squamous cell cancer' below.)

•The use of biomarkers other than PD-L1, TMB, or dMMR to select patients with adenocarcinoma for anti-PD-1 immunotherapy is in evolution. Pembrolizumab is no longer approved in the United States for treatment of refractory PD-L1-overexpressing esophageal, gastric, or EGJ adenocarcinomas. Yet, in Japan, nivolumab is approved for advanced gastric cancer that has progressed after conventional therapy, without regard to the number of prior regimens or specific biomarker expression. We would consider off-label use of pembrolizumab in patients with high levels of PD-L1 overexpression (ie, CPS ≥5) on a case by case basis, emphasizing the uncertainty of benefit, potential toxicity, and financial cost. (See 'Efficacy in adenocarcinoma' below.)

•For eligible patients, we generally suggest a trial of immunotherapy for second line rather than a later line of therapy. (See 'Timing of immunotherapy' below.)

●Approach to adenocarcinomas not eligible for immunotherapy

•For most patients with adenocarcinoma who retain an excellent performance status and are not eligible for immunotherapy or human epidermal growth factor receptor 2 (HER2)-targeted therapy, we suggest ramucirumab plus paclitaxel after progression on or prior treatment with fluoropyrimidine- or platinum-containing chemotherapy. For patients with existing neuropathy who are sufficiently fit for a multiagent regimen, FOLFIRI plus ramucirumab is an alternative. (See 'Single-agent chemotherapy' below.)

•For patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma who progress on initial therapy with chemotherapy (fluoropyrimidine plus platinum) plus trastuzumab, second-line treatment options include ramucirumab plus paclitaxel, fam-trastuzumab deruxtecan, FOLFIRI with or without ramucirumab, or single-agent chemotherapy. Selection of therapy is discussed below. (See 'HER2-positive adenocarcinoma' below.)

•Trifluridine-tipiracil is a reasonable option for third-line therapy or beyond in patients who retain a good performance status after two or more other regimens. (See 'Trifluridine-tipiracil' below.)

●Approach to squamous cell carcinoma ineligible for immunotherapy

•For patients with squamous cell carcinoma (SCC) who retain an excellent performance status and who are not eligible for immunotherapy, utilization of other active chemotherapy agents not used in the first-line regimen is reasonable, either in combination or as serial single agents. For example, patients who received FOLFOX (oxaliplatin plus leucovorin and short-term infusional fluorouracil [FU]) initially could be offered single-agent irinotecan, a taxane, or FOLFIRI (irinotecan plus leucovorin and short-term infusional FU (table 1)). (See 'Single-agent chemotherapy' below.)

●Not candidates for intensive therapy – For patients with either adenocarcinoma or SCC who are not eligible for anti-PD-1 immunotherapy and have only an adequate performance status, or those for whom limiting treatment-related toxicity is an important goal, we suggest monotherapy rather than combination chemotherapy. Options include irinotecan, weekly paclitaxel, weekly nanoparticle albumin-bound paclitaxel (nabpaclitaxel), apatinib (where available), or ramucirumab monotherapy (for patients with adenocarcinoma).

EFFICACY OF INDIVIDUAL TREATMENTS

Single-agent chemotherapy — In general, clinical trials assessing the efficacy of a variety of second-line therapy regimens after failure of the first-line regimen in advanced esophagogastric cancer have shown that response rates are lower than they are in previously untreated patients, and toxicity rates tend to be higher [11-30].

The choice of regimen is empiric. No single regimen has emerged as a clear "winner," and few trials have compared different regimens [31,32]:

●A Japanese trial comparing second-line irinotecan monotherapy (150 mg/m² on days 1 and 15 every four weeks) with weekly paclitaxel (80 mg/m² on days 1, 8, and 15 every four weeks) concluded that neither regimen was superior in terms of efficacy or tolerability [33]. A similar conclusion was reached in a second similar trial from South Korea [34].

●No differences in outcomes could be shown in two trials comparing irinotecan plus cisplatin versus irinotecan alone, and in one trial comparing single-agent nanoparticle albumin-bound paclitaxel (nabpaclitaxel) versus solvent-based paclitaxel (although hypersensitivity reactions were less common with nabpaclitaxel) [10,35,36].

●On the other hand, a randomized phase II trial of every three week docetaxel versus weekly paclitaxel in 78 patients with esophageal squamous cell carcinoma (SCC) refractory to fluoropyrimidine and platinum-based chemotherapy concluded that paclitaxel was more efficacious (response rate 26 versus 6 percent, median progression-free survival (PFS) 4.4 versus 2.1 months) and less toxic [37].

Single-agent versus combination chemotherapy — Combination regimens containing agents not used in the first-line setting are also reasonable in the second line setting (eg, FOLFIRI [irinotecan plus leucovorin and short-term infusional fluorouracil (FU)], or taxane-based therapy, after initial therapy with FOLFOX [oxaliplatin plus leucovorin and short-term infusional FU]). (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Irinotecan-containing regimens' and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Docetaxel-containing'.)

However, monotherapy is an acceptable option. In some clinical trials, multiagent chemotherapy in the second-line setting failed to show a survival benefit and had greater treatment-related toxicity compared with single-agent chemotherapy [9,10]. Quality of life and minimization of side effects are key considerations when choosing a chemotherapy regimen for second-line therapy, particularly for patients with a less than ideal performance status.

Any of these approaches could be considered appropriate for second-line treatment of adenocarcinomas or squamous cell cancers. Further subsequent-line treatment options for adenocarcinomas are discussed separately. (See 'Treatments restricted to adenocarcinomas' below.)

●FOLFIRI – In observational studies and phase II clinical trials, second-line therapy with FOLFIRI in gastric and esophageal adenocarcinoma resulted in objective response rates (ORRs) between 12 to 29 percent, median progression-free survival (PFS) of two months, and overall survival (OS) of approximately six to seven months [9,18,38]. However, in a randomized phase II trial of 59 patients with advanced gastric cancer who progressed on initial platinum-based chemotherapy, FOLFIRI had similar PFS (median 3 versus 2.2 months), OS (median 6.7 versus 5.8 months) and ORRs (20 versus 17 percent), with higher grade ≥3 toxicity (28 versus 21 events) relative to single-agent irinotecan [9].

The efficacy of FOLFIRI plus ramucirumab as later-line therapy in gastric and GEJ adenocarcinoma is discussed below. (See 'FOLFIRI plus ramucirumab' below.)

Checkpoint inhibitor immunotherapy — Immunotherapeutic approaches to cancer therapy are based on the premise that the immune system plays a key role in surveillance and eradication of malignancy and that tumors evolve ways to elude the immune system. We would only pursue immunotherapy if it was not administered in the frontline setting. We would generally not pursue anti-PD-1 immunotherapy for second-line therapy or beyond for patients who progressed while receiving prior PD-1 targeted therapy. There is no evidence to support benefit from a switch to a different immune checkpoint inhibitor for patients whose disease has progressed on one immune checkpoint inhibitor, regardless of histology. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

Biomarkers and benefit from PD-1 inhibitors

Defective mismatch repair — For patients who have advanced SCC or adenocarcinoma of the esophagus or stomach with DNA mismatch repair deficiency (dMMR), we suggest pembrolizumab, if it was not administered for front-line therapy.

Tumors that lack the mismatch repair mechanism (ie, they have dMMR, the biologic footprint of which is high levels of microsatellite instability [MSI-H]) harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such mismatch repair defects. It is hypothesized that the neoantigens generated by mutations such as these are more immunogenic than those generated by other mutations.

Several steps are required for the immune system to effectively attack tumor cells. Several immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, such immune checkpoints can result in immune tolerance and contribute to unchecked tumor growth. Inhibition of these checkpoints might be expected to halt/reverse disease progression. One well-characterized checkpoint being targeted in several tumor types, including esophagogastric cancer, is programmed cell death-1 (PD-1). PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by PD-L1 expressed by the tumor or other immune cells infiltrating the tumor tissue can lead to T cell inactivation and a release of the "brake" on immune-mediated tumor eradication. (See "Principles of cancer immunotherapy".)

Proof of principle that cancers with dMMR might be particularly susceptible to inhibition of the PD-L1/PD-1 interaction was initially provided by a study of pembrolizumab in dMMR colorectal cancer. Subsequently, it has been established that immune checkpoint inhibitor immunotherapy appears to benefit a subset of patients with dMMR tumors, regardless of anatomic site of origin or tissue histology. As a result, in May 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for treatment of a variety of advanced solid tumors, including gastric cancers, that had MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Other tumors with MSI-H/dMMR'.)

Approximately 3 to 7 percent of esophagogastric adenocarcinomas are dMMR/MSI-H, most of which also overexpress PD-L1 [39-48]. Efficacy of pembrolizumab in dMMR esophagogastric cancer has been shown in the following studies:

●In the phase II KEYNOTE-158 study, which enrolled 24 patients with gastric cancer [49], there were 11 objective responses (46 percent), four of which were complete, and median PFS was 11 months.

●A subsequent post-hoc analysis of data from KEYNOTE-059 (third-line pembrolizumab), KEYNOTE-061 (second-line pembrolizumab versus chemotherapy) and KEYNOTE-062 (first-line pembrolizumab, versus pembrolizumab plus chemotherapy versus chemotherapy alone) also demonstrated that compared with the overall study population, the subset of patients with dMMR/MSI-H tumors experienced greater benefit from pembrolizumab alone or in combination with chemotherapy regardless of the line of treatment [48]. We would generally not pursue anti-PD-1 monotherapy for second-line therapy or beyond if disease progression occurred during prior PD-1-targeted therapy. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

The approach to testing for dMMR is addressed in detail elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing dMMR as a predictive marker'.)

High tumor mutational burden — Between 5 and 19 percent of gastric adenocarcinomas and approximately 2.4 percent of esophageal cancers have high levels of tumor mutational burden (TMB) [50,51], although this has been variably quantified. High TMB tumors have lower mutational levels than do those with dMMR, but TMB appears to be an independent biomarker of benefit for immune checkpoint inhibitor immunotherapy. Based upon an early report of the KEYNOTE-158 trial (which did not include patients with advanced esophageal or gastric cancer), pembrolizumab is now approved for patients with any solid tumor, including esophagogastric cancer, that has a TMB ≥10 mutations per megabase (mut/Mb), after progression on standard regimens. We would only pursue anti-PD-1 monotherapy for second-line therapy or beyond if prior PD-1 targeted therapy had not been administered front-line. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden' and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

Although it remains uncertain whether this is the appropriate threshold to define high TMB in esophagogastric cancer, particularly in patients without MSI [52], as validation studies were conducted mainly in lung and urothelial cancers, and thresholds for TMB are likely to vary across tumor types, we suggest using a next-generation sequencing (NGS) platform to assess TMB, and the use of a threshold TMB of ≥10 mut/Mb to select patients for immune checkpoint inhibitor immunotherapy. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing for high levels of TMB'.)

PD-L1 overexpression — The predictive value of programmed cell death ligand 1 (PD-L1) expression to select patients who might benefit from PD-1-blocking antibodies in esophagogastric cancer is in evolution [53]. PD-L1 expression is required for some indications but not others. In many cases, responses to PD-1 inhibitors seem to be less frequent (but not completely absent) in patients with low level or PD-L1-nonexpressing tumors. As examples (see 'Efficacy in adenocarcinoma' below and 'Efficacy in squamous cell cancer' below):

●In the United States, pembrolizumab is approved as a second-line treatment for esophageal squamous cell cancers that express high levels of PD-L1 (combined positive score [CPS] ≥10) and we reserve this approach for those who did not receive first-line immunotherapy. (See 'Efficacy in squamous cell cancer' below.)

Pembrolizumab is no longer approved for third-line treatment of patients with esophagogastric adenocarcinomas and any level of PD-L1 expression. However, we would still consider off-label use on a case by case basis for those with adenocarcinoma and high levels of PD-1 expression (ie, CPS ≥10), as long as prior PD-1 targeted immunotherapy was not used front-line. (See 'Efficacy in adenocarcinoma' below.)

●On the other hand, in the United States, nivolumab is approved for treatment of patients with unresectable, advanced, recurrent, or metastatic esophageal squamous cell cancer after prior fluoropyrimidine- and platinum-based chemotherapy, without regard for PD-L1 overexpression. (See 'Efficacy in squamous cell cancer' below.)

In Japan, nivolumab is approved for the treatment of unresectable, advanced, or recurrent gastric cancer that has progressed after "conventional chemotherapy," also without regard to specific biomarker expression.

Issues surrounding the assessment of PD-L1 overexpression are discussed in detail elsewhere. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'PD-L1 expression status in upper GI tract cancers'.)

Efficacy in adenocarcinoma

●Pembrolizumab – Pembrolizumab is an anti-PD-1 monoclonal antibody. Activity in advanced refractory PD-L1-expressing esophagogastric adenocarcinoma had been suggested in early phase I KEYNOTE-012 and 028 trials [54,55], and in the following later studies:

•The superiority of pembrolizumab over systemic chemotherapy (investigators' choice of paclitaxel, docetaxel, or irinotecan) for second-line therapy in patients with an esophageal or esophagogastric junction (EGJ), Siewert type I (figure 1), cancer whose tumors express high levels of PD-L1 (CPS 10 or more) was shown in the phase III KEYNOTE-181 trial, in which the predominant population was SCC [56]. (See 'Efficacy in squamous cell cancer' below.)

•In an early report of the KEYNOTE-059 cohort of 259 patients with previously treated gastric or EGJ adenocarcinoma, the objective response rate in the entire cohort was 11.6 percent (2.3 percent complete) [57]. Among those with PD-L1-positive tumors (CPS ≥1 percent), the objective response rate was 15.5 percent, with 13.5 percent partial and 2 percent complete responses. By contrast, the objective response rate in those with PD-L1-negative tumors was only 6.4 percent, with 2.8 percent experiencing a complete response. Grade 3 to 5 treatment-related adverse events developed in 18 percent, and two were fatal (acute kidney injury, pleural effusion).

Largely on the basis of these early data, pembrolizumab received accelerated approval from the FDA for treatment of patients with PD-L1-expressing recurrent or advanced gastric or EGJ adenocarcinoma who had received two or more lines of prior chemotherapy. The continued approval of this agent was contingent on positive data from the phase III second-line KEYNOTE-061 and first-line KEYNOTE-062 trials. Accelerated approval was withdrawn in January 2022 when these two trials failed to achieve their primary endpoints. However, given the potential for benefit, as shown in the KEYNOTE-181 and 061 trials, we would still consider off-label use on a case by case basis for those with adenocarcinoma and high levels of PD-1 expression (ie, CPS ≥10), as long as prior PD-1 targeted immunotherapy was not used front-line.

Data from these two trials are discussed below (See 'Timing of immunotherapy' below.)

●Nivolumab – Early reports also suggest meaningful activity for nivolumab [58,59], another anti-PD-1 antibody, in patients with advanced, treatment-refractory gastroesophageal adenocarcinoma, not previously treated with PD-1 targeted immunotherapy:

•The benefit of nivolumab was explored in a phase 3 trial (ONO-4538, the ATTRACTION-2 trial) in which 493 patients with advanced gastric or EGJ cancer who had failed two or more standard chemotherapy regimens were randomly assigned to nivolumab (3 mg/kg) or placebo every two weeks until unacceptable toxicity or disease progression [60]. The objective response rate with nivolumab was 11 percent, and median overall survival was modestly but significantly improved compared with placebo (5.3 versus 4.1 months [hazard ratio (HR) 0.63, 95% CI 0.51-0.78], 12-month survival 27 versus 11 percent); median PFS was also improved (1.61 versus 1.45 months [HR 0.60, 95% CI 0.49-0.75]). Severe (grade ≥3) adverse reactions were infrequent with nivolumab (11.5 versus 5.5 percent with placebo).

Notably, the trial did not restrict therapy to any subset of patients expressing a biomarker such as PD-L1 and it was conducted entirely in Asian populations.

•A comparable degree of benefit in Western populations was suggested in the CheckMate-032 study, in which 160 patients with disease progression on or intolerance of at least one systemic chemotherapy regimen for advanced gastric, esophageal, or EGJ cancer were randomly assigned to nivolumab alone (3 mg/kg) every two weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (nivo 1/ipi 3) every three weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (nivo 3/ipi 1) every three weeks [61]. Ipilimumab is another immune checkpoint inhibitor that targets a separate immune checkpoint, cytotoxic T-lymphocyte-associated protein 4.

Seventy-nine percent had received two or more prior therapies. Nivolumab, with or without ipilimumab, led to durable responses and long-term overall survival, and responses were observed regardless of tumor PD-L1 status. Twelve-month PFS rates for nivolumab alone, nivo 1/ipi 3, and nivo 3/ipi 1 were 8, 17, and 10 percent; the corresponding rates of 12-month survival were 39, 37, and 24 percent; and objective responses were seen in 12, 24, and 8 percent, respectively. Grade 3 or worse treatment-related adverse events were reported in 17, 47, and 27 percent of the three groups, respectively.

Given the lack of a chemotherapy control arm in these two trials, it is difficult to know if these results are better than could be achieved by chemotherapy.

●Avelumab – On the other hand, benefit for avelumab, a PD-1 inhibitor, could not be shown in the phase III JAVELIN Gastric 300 trial, in which 371 patients failing two prior lines of systemic therapy were randomly assigned to avelumab or to systemic therapy of the clinician's choice (either weekly paclitaxel or irinotecan monotherapy; patients ineligible for systemic therapy received best supportive care only) [62]. Avelumab did not improve overall survival or PFS.

Efficacy in squamous cell cancer — The benefits of second-line therapies targeting the PD-1 pathway in esophageal SCC have been shown in the following trials:

●Pembrolizumab – The superiority of pembrolizumab (an anti-PD-1 monoclonal antibody [MoAb]) over systemic chemotherapy (investigators' choice of paclitaxel, docetaxel, or irinotecan) for second-line therapy was shown in the phase III KEYNOTE-181 trial, which enrolled 628 patients with advanced/metastatic SCC (64 percent) or adenocarcinoma of the esophagus or EGJ, Siewert type I, unselected for PD-L1 expression status [56]. Among the 222 patients who had highly PD-L1-positive tumors (PD-L1 CPS ≥10, defined as the number of PD-L1-positive cells divided by the total number of tumor cells and then multiplied by 100), median overall survival was superior with pembrolizumab (9.3 versus 6.7 months), twice as many individuals remained alive at 12 months (43 versus 20 percent), and there were fewer grade 3 to 5 drug-related adverse events (18 versus 41 percent). The survival benefit in individuals with SCC (a coprimary endpoint) was also significant (median 8.2 versus 7.1 months, HR 0.78, 95% CI 0.63-0.96), but there was no improvement in overall survival with pembrolizumab in the entire intent-to-treat population, which included the 496 patients without high levels of PD-L1 overexpression (n = 628, median 7.1 months in both groups). In unplanned subgroup analysis, among those with CPS ≥10, the survival benefit was significant for SCC (HR 0.64, 95% CI 0.46-0.90) but not adenocarcinoma (HR 0.93, 95% CI 0.52-1.65). Additionally, when the analysis was limited to SCC, the survival benefit for pembrolizumab was restricted to those with CPS ≥10 and not lower levels.

Largely based on these data, in July 2019, the FDA approved single agent pembrolizumab for patients with recurrent locally advanced or metastatic SCC of the esophagus whose tumors express high levels of PD-L1 (CPS ≥10) and who have disease progression after one or more prior lines of systemic therapy (ie, second-line therapy).

●Nivolumab – Nivolumab, another anti-PD-1 MoAb, is also active in esophageal SCC, although it is not clear whether PD-L1 expression status is important to tumor response:

•In an early, uncontrolled trial of nivolumab, objective responses were seen in 11 of 65 patients (17 percent) with refractory metastatic esophageal SCC, but the median time to progression was only 2.8 months; the safety profile was expected and manageable [58]. This trial did not restrict enrollment to any subset of patients expressing a biomarker such as PD-L1.

•Support for second-line nivolumab was also provided by the phase 3 ATTRACTION-3 trial, in which 419 patients with previously treated (at least one fluoropyrimidine- and platinum-based regimen), advanced esophageal SCC were randomly assigned to nivolumab (240 mg every two weeks) or a single-agent taxane (investigators' choice of paclitaxel or docetaxel) [63]. Patients were unselected for biomarker expression; approximately one-half had PD-L1 expression levels in tumor cells <1 percent (using a different assay than that used to determine PD-L1 overexpression in the KEYNOTE-181 trial). Overall survival was significantly better with nivolumab (median 10.9 versus 8.4 months, HR for death 0.77, 95% CI 0.62-0.96), and many fewer patients had grade 3 or 4 treatment-related adverse effects (18 versus 63 percent). The survival benefit was independent of PD-L1 expression status in the tumor; survival benefit according to PD-L1 expression in immune and tumor cells (ie, the CPS) has not been reported, making it more difficult to compare directly with pembrolizumab. The survival advantage persisted with longer term follow-up, and nearly twice as many nivolumab-treated individuals were alive at three years (15.3 versus 8.7 percent) [64].

Largely based on the early report of this study, in June 2020, the FDA approved nivolumab for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal SCC after prior fluoropyrimidine- and platinum-based chemotherapy, regardless of biomarker expression [65]. We would generally not pursue anti-PD-1 immunotherapy for second-line therapy or beyond for patients who progressed while receiving prior PD-1 targeted therapy. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

●Camrelizumab and tislelizumab

•Camrelizumab, a third anti-PD-1 MoAb, which is approved in China for treatment of relapsed or refractory classical Hodgkin lymphoma [66], also appears to be active in advanced esophageal SCC [67]. In the randomized phase III ESCORT trial, in which 457 patients previously treated with first-line platinum-based chemotherapy were randomly assigned to camrelizumab or chemotherapy (docetaxel or irinotecan), second-line camrelizumab significantly improved overall survival (8.3 versus 6.2 months, HR 0.71, 95% CI 0.57-0.87), and benefit was irrespective of PD-L1 overexpression.

•The anti-PD-1 monoclonal antibody tislelizumab is approved in China for a variety of indications, including advanced nasopharyngeal, urothelial, and non-small cell lung cancer. A significant survival benefit versus chemotherapy (irinotecan or taxane monotherapy) for second-line treatment of advanced or metastatic esophageal SCC was shown in the RATIONALE-302 trial (median 8.6 versus 6.3 months, HR 0.70, 95% CI 0.57-0.85), but the magnitude benefit was more pronounced in those with high levels of PD-L1 positivity (tumor area positivity ≥10 percent, median overall survival 10.3 versus 6.8 months) [68].

Timing of immunotherapy — For patients who are eligible for immunotherapy, we suggest PD-1 targeted immunotherapy rather than chemotherapy for second-line treatment after progression on the first-line regimen, as long as prior PD-1 targeted therapy was not administered first-line.

There is disagreement as to the appropriate timing (ie, second-line or beyond) for a trial of a PD-1 inhibitor in patients with advanced esophagogastric cancer that has not received frontline PD-1 targeted immunotherapy. In the United States, pembrolizumab is no longer approved for third-line treatment of PD-L1-overexpressing adenocarcinomas after failure of two separate chemotherapy regimens, but it is approved as a single agent for advanced or metastatic SCC of the esophagus that expresses PD-L1 at a CPS ≥10 and has progressed after one or more prior lines of systemic therapy, and for tumors with dMMR/MSI-H or high levels of TMB that have progressed following prior treatment and for which there are no satisfactory alternative treatment options. Nivolumab is approved for advanced SCC after prior fluoropyrimidine- and platinum-based chemotherapy, regardless of PD-L1 expression status.

Three trials have directly compared pembrolizumab or nivolumab versus chemotherapy in the second-line setting:

●Pembrolizumab

•In the KEYNOTE-061 trial, 592 patients with advanced gastric or EGJ cancer that had progressed on chemotherapy using a platinum and fluoropyrimidine combination were randomly assigned to pembrolizumab (200 mg every three weeks for up to two years) or paclitaxel monotherapy (80 mg/m² on days 1, 8, and 15 every 28 days) [69]. Patients were initially enrolled without regard to PD-L1 overexpression, but enrollment was restricted to those with a CPS ≥1 after an interim analysis suggested inferior results with pembrolizumab in those with a CPS <1. When the analysis was limited to the 395 randomly allocated patients with a CPS ≥1, pembrolizumab did not significantly prolong overall survival (median 9.1 versus 8.3 months, HR 0.82, 95% CI 0.66-1.03), and the objective response rates were similar (16 versus 14 percent). However, the adverse event profile was better with pembrolizumab (grade 3 to 5 treatment-related adverse events in 14 versus 35 percent). The main differences were in fatigue, neuropathy, and cytopenia. In a post hoc analysis, which should be considered hypothesis-generating only, the pembrolizumab treatment effect appeared to be greater for patients with a PD-L1 CPS ≥10 and for patients whose tumors were MSI-H irrespective of the CPS.

This was confirmed in a later update of these results, presented at the 2020 American Society of Clinical Oncology (ASCO) annual meeting, in which the duration of response with pembrolizumab was significantly longer than with paclitaxel in the entire population of CPS ≥1 (median 19.1 versus 5.2 months), and in subgroup analysis, the overall survival benefit for pembrolizumab was greatest in those with PD-L1 CPS ≥10 [70]. The survival improvement with second-line pembrolizumab for the entire group with CPS ≥1 was 9.1 versus 8.3 months (HR 0.81, 95% CI 0.66-1.00), for those with CPS ≥5 it was 10.4 versus 8.3 months (HR 0.72, 95% CI 0.53-0.99), and for CPS ≥10 it was of a similar magnitude but not statistically significant (10.4 versus 8.0 months, HR 0.69, 95% CI 0.46-1.05).

•The superiority of pembrolizumab over systemic chemotherapy (investigators' choice of paclitaxel, docetaxel, or irinotecan) for second-line therapy was also shown in the phase III KEYNOTE-181 trial, which enrolled 628 patients with advanced/metastatic SCC (63 percent of enrollees) or adenocarcinoma of the esophagus or EGJ, Siewert type I [56]. As noted above, among the 222 patients who had PD-L1-positive tumors (CPS ≥10), median overall survival was superior with pembrolizumab (9.3 versus 6.7 months), twice as many individuals remained alive at 12 months (43 versus 20 percent), and there were fewer grade 3 to 5 drug-related adverse events (18 versus 41 percent); neither survival nor health-related quality of life [71] were impacted by the choice of second-line therapy. In unplanned subset analysis, among those with CPS ≥10, a survival benefit favoring pembrolizumab was evident for SCC (HR 0.64, 95% CI 0.46-0.90) but not adenocarcinoma (HR 0.93, 95% CI 0.52-1.65). (See 'Efficacy in squamous cell cancer' above.)

Largely based on these data, in July 2019, the FDA approved pembrolizumab for patients with recurrent locally advanced or metastatic SCC of the esophagus whose tumors express high levels of PD-L1 (CPS ≥10) and who have disease progression after one or more prior lines of systemic therapy (ie, second-line therapy). (See 'Efficacy in squamous cell cancer' above.)

In our view, these data also provide support for off-label use of pembrolizumab in the second-line setting for individuals with highly PD-L1-overexpressing (CPS ≥10) adenocarcinomas of the esophagus, or EGJ, Siewert type I (figure 1).

●Nivolumab – Support for second-line nivolumab over chemotherapy was also provided by the phase 3 ATTRACTION-3 trial, in which 419 patients with previously treated (at least one fluoropyrimidine- and platinum-based regimen) advanced esophageal SCC were randomly assigned to nivolumab (240 mg every two weeks) or a single-agent taxane (investigators' choice of paclitaxel or docetaxel) [63]. Patients were unselected for biomarker expression. Overall survival was significantly better with nivolumab (median 10.9 versus 8.4 months, HR for death 0.77, 95% CI 0.62-0.96), and fewer patients had grade 3 or 4 treatment-related adverse effects. (See 'Efficacy in squamous cell cancer' above.)

Nivolumab is approved in the United States for treatment of advanced esophageal SCC after prior fluoropyrimidine and platinum-based chemotherapy, regardless of biomarker expression. In addition, in Japan, nivolumab is approved for the treatment of unresectable, advanced, or recurrent gastric cancer that has progressed after "conventional chemotherapy." We would generally not pursue anti-PD-1 monotherapy for second-line therapy or beyond if disease progression occurred during prior PD-1 targeted therapy.

Treatments restricted to adenocarcinomas

HER2-positive adenocarcinoma

Selection of second-line therapy — Most patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma receive initial treatment with chemotherapy (fluoropyrimidine plus platinum) plus trastuzumab. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)

For those patients who progress on initial trastuzumab-based therapy, options for second-line therapy include ramucirumab plus paclitaxel; fam-trastuzumab deruxtecan; and FOLFIRI with or without ramucirumab. The optimal regimen is not established as these agents have not been directly compared in randomized trials. Clinical trial enrollment is encouraged, where available. Our approach to second-line therapy is based on reassessing HER2 status on repeat biopsy, patient comorbidities, treatment toxicity profiles, and response to prior therapies.

●HER2-positive on repeat biopsy and no pulmonary disease – For patients with persistently positive HER2 expression confirmed on repeat metastatic tissue biopsy or liquid biopsy (ie, circulating tumor DNA) and no pulmonary disease, we suggest second-line therapy with fam-trastuzumab deruxtecan rather than other systemic agents. In a randomized trial, fam-trastuzumab deruxtecan improved overall survival, but is associated with a risk of interstitial lung disease. Testing for HER2 expression on biopsy samples for gastroesophageal adenocarcinoma is discussed separately (algorithm 1). (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'HER2 overexpression'.)

Fam-trastuzumab deruxtecan has a convenient every-three-week administration schedule but may be difficult for some patients to tolerate due to risk of treatment-related symptoms (ie, fatigue, malaise, decreased appetite, nausea, vomiting) and other toxicities including myelosuppression and interstitial lung disease. (See 'Fam-trastuzumab deruxtecan' below.)

●HER2-negative on repeat biopsy or pulmonary disease – For patients with negative HER2 expression confirmed on either repeat tissue biopsy (defined as 0 or 1+ on IHC staining, or 2+ with negative FISH) or liquid biopsy (circulating tumor DNA), or those with pulmonary disease, we suggest second-line therapy with paclitaxel plus ramucirumab rather than other systemic agents, as this combination improved overall survival in a randomized trial of HER2-negative disease. (See 'Paclitaxel plus ramucirumab' below.)

•FOLFIRI plus ramucirumab is an appropriate alternative to paclitaxel plus ramucirumab for patients with clinically significant neuropathy (eg, due to prior therapy with docetaxel in FLOT or with FOLFOX), based on limited observational data in patients with HER2-positive gastroesophageal adenocarcinoma [72]. This combination is also an option for those with disease recurrence within six months of completing perioperative chemotherapy with FLOT for gastric adenocarcinoma or neoadjuvant/definitive chemoradiation with carboplatin plus paclitaxel for GEJ adenocarcinoma, based on data from a randomized phase II trial (RAMIRIS) [73]. Patients who are ineligible for antiangiogenic agents may be offered FOLFIRI alone. Further evidence for these regimens is discussed separately. (See 'FOLFIRI plus ramucirumab' below and 'Single-agent versus combination chemotherapy' above.)

●Unconfirmed repeat HER2 status – Repeating a biopsy for HER2 status may be challenging to obtain outside of a clinical trial (eg, due to delay in therapy while awaiting biopsy results, clinical deterioration due to extensive or rapidly progressive disease, cost). For patients where the tumor HER2 status cannot be reconfirmed via repeat biopsy, preferred second-line treatment options include paclitaxel plus ramucirumab or fam-trastuzumab deruxtecan. (See 'Paclitaxel plus ramucirumab' below and 'Fam-trastuzumab deruxtecan' below.)

Since either regimen is equally appropriate, the choice of therapy is influenced by patient and clinician preference and patient comorbidities. As examples, we prefer paclitaxel plus ramucirumab in patients with pulmonary disease, to avoid the potential for ILD with fam-trastuzumab. By contrast, we prefer fam-trastuzumab deruxtecan in patients with clinically significant neuropathy or those ineligible for antiangiogenic agents such as ramucirumab (eg, due to poorly controlled hypertension or wound healing concerns).

●Less fit patients – For patients who are anticipated to not tolerate these regimens (eg, less medically fit patients, those with multiple comorbidities), alternative options include single-agent chemotherapy (eg, irinotecan, paclitaxel, docetaxel). (See 'Single-agent chemotherapy' above.)

Fam-trastuzumab deruxtecan

●HER2 overexpressing tumors — For patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma who progress on initial therapy with chemotherapy plus trastuzumab, fam-trastuzumab deruxtecan is one preferred option for second-line therapy. Fam-trastuzumab demonstrated objective response rates of 42 percent as second-line therapy in a non-randomized phase II trial (DESTINY-Gastric02). In a randomized trial (DESTINY-Gastric01), third- or later-line therapy with fam-trastuzumab deruxtecan improved overall survival (OS) and progression-free survival (PFS) compared with single-agent chemotherapy. Fam-trastuzumab is also clinically effective in both Eastern and Western populations with gastric or GEJ adenocarcinoma [74,75]. However, this agent is associated with fatigue, decreased appetite, malaise, nausea, vomiting, severe myelosuppression, and interstitial lung disease (ILD). We also avoid fam-trastuzumab deruxtecan in patients with pulmonary disease due to the risk of ILD.

Fam-trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. For patients with locally advanced unresectable or metastatic gastric or gastroesophageal adenocarcinoma, fam-trastuzumab deruxtecan is administered at 6.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity [76]. Clinicians should monitor for and promptly investigate signs and symptoms, including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Treatment should be permanently discontinued for ≥grade 2 ILD/pneumonitis (table 2) or severe left ventricular dysfunction (table 3).

In a single-arm phase II trial (DESTINY-Gastric02) conducted in the United States and Europe, second-line therapy with fam-trastuzumab deruxtecan was evaluated in 79 patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma. All patients had progressed on initial treatment with platinum-based chemotherapy plus trastuzumab [74]. A repeat biopsy was necessary to reconfirm persistent HER2 positivity. At median follow-up of 10 months, the ORR was 42 percent, including four complete responses (5 percent).

In an open-label randomized phase II trial (DESTINY-Gastric01 trial) conducted in Japan and South Korea, 187 patients with confirmed HER2-positive gastric or gastroesophageal cancer who progressed on two prior therapies (including trastuzumab, a fluoropyrimidine, and a platinum) were randomly assigned to later-line therapy with either fam-trastuzumab deruxtecan or clinician’s choice of chemotherapy (irinotecan [89 percent] or paclitaxel [11 percent]) [75]. HER2 status was assessed based on the most recent archival tissue and not systematically reconfirmed prior to enrollment.

In this study, fam-trastuzumab deruxtecan improved OS (median 13 versus 8 months; one-year OS 52 versus 29 percent, HR 0.59, 95% CI 0.39-0.88), PFS (median 5.6 versus 3.5 months; one-year PFS 30 versus 0 percent, HR 0.47, 95% CI 0.31-0.71), and the objective response rate (ORR; 51 versus 14 percent). ORR was higher for patients with a HER2 score of 3+ (58 percent) relative to those with a score of 2+ and a positive result on fluorescent in situ hybridization (29 percent).

Grade ≥3 toxicities for fam-trastuzumab included myelosuppression (neutropenia [51 percent], anemia [38 percent], thrombocytopenia [10 percent]) and ILD (10 percent). There was one treatment-related death classified as pneumonia. While there were no clinical adverse events of heart failure, the rate of asymptomatic grade 2 decrease in left ventricular ejection fraction (table 3) was 8 percent. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Fam-trastuzumab deruxtecan'.)

Based on data from the DESTINY-Gastric01 trial, the FDA approved fam-trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-overexpressing gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen [76].

●HER2 low tumors – The use of fam-trastuzumab remains investigational in patients with metastatic HER2 low gastroesophageal adenocarcinoma.

Fam-trastuzumab was evaluated in a phase II trial of patients with chemotherapy-refractory HER2 low metastatic gastric or GEJ adenocarcinoma and no prior exposure to HER2 targeted therapy [77]. Objective responses were seen in 5 of 19 patients (27 percent) with IHC 2+ and FISH-negative tumors and in 2 of 21 patients (10 percent) with IHC 1+ tumors.

Paclitaxel plus ramucirumab — Ramucirumab plus paclitaxel is one preferred option for second-line therapy in patients with HER2-positive advanced or metastatic gastric or GEJ adenocarcinoma. (See 'Selection of second-line therapy' above.)

The efficacy of ramucirumab plus paclitaxel as second-line therapy was established in a randomized placebo-controlled phase III trial (RAINBOW) of patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma. Further data for the entire study population are discussed separately. (See 'Ramucirumab with or without paclitaxel' below.)

In this phase III trial, the clinical benefit for paclitaxel plus ramucirumab for patients with HER2-positive gastric or GEJ adenocarcinoma appeared to be similar to that seen in the entire study population, with the caveat that the subgroup of HER2-positive tumors was small. Among the subgroup of 39 patients with HER2-positive disease who progressed on prior trastuzumab-based therapy, the addition of ramucirumab plus paclitaxel improved progression-free survival (4.2 versus 2.7 months, HR 0.40, 95% 0.19-0.82) and objective response rates (45 versus 11 percent). In the entire study population, ramucirumab plus paclitaxel also prolonged overall survival relative to paclitaxel plus placebo, but the difference was not statistically significant (11 versus 7 months, HR 0.68, 95% CI 0.33-1.41) [78].

HER2-targeted agents not used — For patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas who progress on an initial trastuzumab-containing regimen, we do not offer subsequent therapy with trastuzumab [79], lapatinib [80,81], or ado-trastuzumab emtansine [82], as these agents failed to improve overall survival in randomized trials.

Loss of HER2 expression may have contributed to the outcomes of these studies since HER2 status was not reconfirmed prior to initiating subsequent HER2-directed therapy [79,83-85]. In one early phase clinical trial evaluating subsequent therapy with trastuzumab plus ramucirumab and paclitaxel, approximately one-third of patients demonstrated loss of tumor HER2 expression after first-line therapy with trastuzumab-based regimens [86].

Treatments targeting VEGF — Elevated serum and tumor levels of vascular endothelial growth factor (VEGF) are associated with a poor prognosis in patients with resectable gastric adenocarcinoma [87-89]. In animal models of gastric adenocarcinoma, inhibition of vascular endothelial growth factor receptor (VEGFR)-2 reduces tumor growth and vascularity [90]. The importance of VEGFR-2 signaling as a therapeutic target in advanced gastric and EGJ adenocarcinomas was confirmed in the placebo-controlled phase III REGARD trial, which demonstrated a modest but significant survival benefit for the VEGFR-2 inhibitor ramucirumab after progression on first-line chemotherapy.

Ramucirumab with or without paclitaxel — We suggest ramucirumab plus paclitaxel rather than a different chemotherapy regimen for most patients with advanced or metastatic gastric or EGJ adenocarcinomas who have disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy and retain an excellent performance status. For patients with an adequate performance status or those for whom limiting treatment-related toxicity is an important goal, ramucirumab monotherapy is an acceptable alternative.

Ramucirumab is a recombinant monoclonal antibody of the immunoglobulin G1 (IgG1) class that binds to VEGFR-2, blocking receptor activation. At least two trials have shown a survival benefit for therapy with ramucirumab, either as monotherapy (compared with best supportive care) or in combination with paclitaxel (over paclitaxel alone) in patients with previously treated, advanced gastric or EGJ adenocarcinoma [4,5]:

●In the phase III REGARD trial, 355 patients with previously treated, advanced or metastatic gastric or EGJ adenocarcinoma were randomly assigned to best supportive care plus either ramucirumab (8 mg/kg intravenously every two weeks) or placebo [4]. Although the benefits were modest, patients treated with ramucirumab had significantly better median PFS (2.1 versus 1.3 months) and overall survival (5.2 versus 3.8 months, HR 0.78, 95% CI 0.60-0.99). The rate of objective tumor response was 8 versus 3 percent, but the overall disease control rate (objective response plus stable disease) was significantly higher with ramucirumab (49 versus 23 percent). The most common adverse event (all grades) in ramucirumab-treated patients was hypertension (16 versus 8 percent in the placebo group, 8 versus 3 percent grade 3 or worse). Ramucirumab was not associated with increased bleeding, venous thromboembolism, perforation, fistula formation, or proteinuria. There were three grade ≥3 arterial thromboembolism events in the ramucirumab arm versus none with placebo. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

●A survival benefit for ramucirumab was also demonstrated in the phase III RAINBOW trial, which compared weekly paclitaxel (80 mg/m² on days 1, 8, and 15 of each 28-day cycle) plus either ramucirumab (8 mg/kg intravenously every two weeks) or placebo in 665 patients with metastatic gastric or EGJ adenocarcinoma who had disease progression on or within four months after first-line platinum- and fluoropyrimidine-based combination therapy [91]. Median overall survival was significantly better with ramucirumab (9.6 versus 7.4 months, HR 0.807, 95% CI 0.678-0.962), as was PFS (4.4 versus 2.9 months) and the objective response rate (28 versus 16 percent). Grade 3 or worse neutropenia was more common with ramucirumab (41 versus 19 percent), but rates of febrile neutropenia were low and similar in both groups (3 versus 2 percent). Rates of grade ≥3 hypertension were 14 versus 2 percent.

A similarly designed trial conducted in China (RAINBOW-Asia) in 440 patients with previously treated advanced gastric or EGJ adenocarcinoma concluded that combined therapy with ramucirumab plus weekly paclitaxel improved median PFS (4.14 versus 3.15 months) but not overall survival (median 8.71 versus 7.92 months, HR 0.963, 95% CI 0.771-1.203) compared with weekly paclitaxel alone, and rates of grade 3 or worse neutropenia (54 versus 39 percent) and febrile neutropenia (6 versus <1 percent) were worse [92].

Largely based on the REGARD trial results, the FDA approved single-agent ramucirumab for patients with advanced or metastatic gastric or EGJ cancer and disease progression during or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy. In November 2014, the combination of ramucirumab plus paclitaxel was also approved by the FDA for treatment of advanced gastric or EGJ cancer.

Whether ramucirumab plus paclitaxel is a preferred strategy over ramucirumab monotherapy is unknown given the lack of comparator trials. The REGARD and RAINBOW trials are not directly comparable in that patients in the REGARD trial were more heavily pretreated. In our view, ramucirumab plus weekly paclitaxel is a reasonable choice for patients who are willing to accept more treatment-related toxicity.

FOLFIRI plus ramucirumab — FOLFIRI plus ramucirumab is a reasonable alternative to ramucirumab plus paclitaxel in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma, particularly those with clinically significant neuropathy or prior treatment with taxanes. In a randomized phase II trial (RAMIRIS), second-line therapy with FOLFIRI plus ramucirumab improved objective response rates with lower rates of any grade neuropathy, but failed to improve overall survival over paclitaxel plus ramucirumab [73].

There is interest in second-line regimens that do not include paclitaxel. Patients previously treated with docetaxel (eg, as part of perioperative chemotherapy with FLOT for gastric adenocarcinoma), paclitaxel (eg, definitive/neoadjuvant chemoradiation with carboplatin plus paclitaxel), or oxaliplatin (eg, as part of initial systemic therapy with FOLFOX) may have treatment-related neuropathy that could worsen with the use of second-line therapy with paclitaxel plus ramucirumab. In addition, paclitaxel may not be as effective in patients who previously received taxanes (docetaxel or paclitaxel) due to tumor resistance. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'FLOT'.)

In an open-label phase III trial (RAMIRIS), 110 patients with advanced or metastatic gastroesophageal adenocarcinoma who progressed on (or within six months of completing) initial platinum- and fluoropyrimidine-based chemotherapy were randomly assigned to second-line therapy either FOLFIRI plus ramucirumab or paclitaxel plus ramucirumab [73]. Patients with HER2 positive disease who received prior HER2-targeted therapy were excluded from this study.

●In the entire study population, relative to paclitaxel plus ramucirumab, FOLFIRI plus ramucirumab improved objective response rates (22 versus 11 percent) with similar PFS and overall survival (median 6.8 versus 7.6 months, HR 0.97, 95% CI 0.62-1.52).

●Patients previously treated with taxanes may derive more benefit from FOLFIRI plus ramucirumab than paclitaxel plus ramucirumab. Among the 71 patients (65 percent) who previously received docetaxel, relative to paclitaxel plus ramucirumab, FOLFIRI plus ramucirumab improved objective response rates (25 versus 8 percent) and PFS (median 4.6 months versus 2.1 months, HR 0.49; 95% CI 0.29-0.83) with similar overall survival (7.5 versus 6.6 months).

●Neuropathy of any grade was lower for FOLFIRI plus ramucirumab than paclitaxel plus ramucirumab (25 versus 47 percent). Grade ≥3 toxicity was similar between the treatment arms (75 versus 68 percent)

Other agents

●Bevacizumab – The benefit of bevacizumab, a monoclonal antibody that binds to soluble VEGF and prevents binding to VEGFR, for gastric and EGJ adenocarcinomas is uncertain. Promising results were reported in a phase II study of bevacizumab in combination with cisplatin plus irinotecan in patients with gastric or EGJ adenocarcinoma [93]; however, a survival benefit for adding bevacizumab to capecitabine plus cisplatin could not be shown in the global phase III Avastin in Gastric Cancer (AVAGAST) trial [94]. A similar lack of benefit for the addition of bevacizumab to capecitabine plus cisplatin in Asian patients was also noted in a preliminary report of the AVATAR study presented at the 2012 ASCO Gastrointestinal Cancers Symposium [95].

Until further information is available, we suggest not using bevacizumab for patients with advanced esophagogastric cancer. Biomarkers may prove useful for identifying patients with advanced gastric adenocarcinoma who might benefit from the addition of bevacizumab to chemotherapy, but this is not yet established [96].

●Apatinib – Apatinib (rivoceranib) is an orally active VEGFR-2 inhibitor that is approved for second-line treatment of advanced gastric cancer in China; it is not available in the United States or Europe. The data on activity in advanced gastric cancer are conflicting:

•Activity was shown in a multicenter, randomized, double-blind trial in which 270 patients in China with advanced gastric cancer and prior failure on second-line chemotherapy were randomly assigned in a 2:1 ratio to apatinib (850 mg daily) or placebo [97]. Objective response rates were low with apatinib (3 versus 0 percent with placebo), but mean overall survival was modestly but significantly prolonged (median 6.5 versus 4.7 months).

•On the other hand, activity for apatinib after failure of two prior chemotherapy regimens was not shown in a preliminary report of the placebo-controlled multinational phase III ANGEL trial [98]. The median overall survival was not significantly better with apatinib (5.78 versus 5.13 months, HR 0.93, p = 0.485).

●Regorafenib – Regorafenib is an orally active inhibitor of angiogenic (including VEGFR-1 to VEGFR-3), stromal, and oncogenic receptor tyrosine kinases. Activity was shown in a multicenter, randomized, double-blind phase II trial in which 152 patients with advanced gastric cancer and prior failure on first- or second-line chemotherapy were randomly assigned in a 2:1 ratio to regorafenib (160 mg daily) or placebo [99]. Median PFS was significantly longer with regorafenib (2.6 versus 0.9 months, HR 0.4, 95% CI 0.28-0.59), and there was a trend toward improved overall survival (median 5.8 versus 4.5 months, p = 0.47).

In our view, these data require confirmation before regorafenib can be considered a standard therapy for advanced gastric cancer.

●Sunitinib and sorafenib – Sunitinib and sorafenib are small-molecule TKIs that inhibit VEGFR-1, VEGFR-2, and VEGFR-3, as well as other tyrosine kinases; they are referred to as “multitargeted” TKIs. Early studies have shown mixed results:

•In a phase II trial of sunitinib monotherapy for second-line treatment of metastatic gastric adenocarcinoma, only 2 of 78 patients had an objective partial response (3 percent), while 25 others (32 percent) had stable disease [100]. Median overall survival was 6.8 months. Grade 3 or worse thrombocytopenia and neutropenia were reported in 35 and 30 percent, respectively.

•The combination of sorafenib (400 mg orally, twice daily, continuously), docetaxel (75 mg/m² intravenously on day 1), and cisplatin (75 mg/m² intravenously on day 1) was studied in a phase II trial of 44 chemotherapy-naïve patients with locally advanced or metastatic (80 percent) gastric or EGJ adenocarcinoma [101]. Objective responses were noted in 41 percent, and median overall survival was 13.6 months; the major grade 3 or 4 toxicity was neutropenia (64 percent).

•However, benefit for sunitinib could not be confirmed in the only randomized trial, in which sunitinib (37.5 mg every day) plus docetaxel (60 mg/m² every three weeks) was compared with docetaxel monotherapy (60 mg/m² every three weeks) for second-line treatment of patients with unresectable or metastatic gastric cancer (n = 107) [102]. Although combined therapy was associated with a significantly higher objective response rate, neither time to disease progression (the primary endpoint, 3.9 versus 2.6 months) nor overall survival (8.0 versus 6.6 months) was significantly improved.

●Aflibercept – Intravenous aflibercept, a recombinant fusion protein consisting of the VEGF-binding portions from human VEGFR-1 and VEGFR-2 fused to the fragment crystallizable (Fc) portion of human IgG1, functions as a decoy receptor that prevents intravascular and extravascular VEGF-A, VEGF-B, and placental growth factor (PlGF) from binding to their receptors. Unfortunately, benefit from the addition of aflibercept to FOLFOX could not be shown in a randomized phase II trial [103].

Subsequent-line therapy

Trifluridine-tipiracil — Trifluridine-tipiracil is an option for third or subsequent line therapy in patients who retain a good performance status after two or more other regimens.

Efficacy for trifluridine-tipiracil was suggested in the TAGS trial, but the comparator arm was placebo and not an alternative chemotherapy regimen [104]. In this trial of 507 heavily pretreated patients (over 60 percent of the patients in each group had received three or more prior chemotherapy regimens) with adenocarcinoma of the stomach or EGJ, trifluridine-tipiracil (35 mg/m² orally twice daily on days 1 through 5 and 8 through 12 of each 28-day cycle) significantly improved overall survival over placebo (median 5.7 versus 3.6 months) and was reasonably well tolerated. The most frequent grade 3 or higher adverse effects were neutropenia and anemia in the trifluridine-tipiracil group.

Largely based on these data, in February 2019, the FDA approved trifluridine-tipiracil for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, human epidermal growth factor receptor 2 (HER2)-targeted therapy.

An important point is that oral absorption of trifluridine-tipiracil appears to be adequate even in the setting of prior gastrectomy [105].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer" and "Society guideline links: Esophageal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Esophageal cancer (The Basics)" and "Patient education: Stomach cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy, patient selection, and regimen choice

•The major goals of systemic chemotherapy for advanced esophagogastric cancer are symptom palliation, improved quality of life, and prolonged survival. (See 'Approach to the patient' above.)

•Decision making for second line treatment must take into account performance status, comorbidity, goals of care, patient preference, the overall medical condition, and disease status.

-For patients with a poor performance status, poorly controlled comorbidity, or a preference for no additional therapy, we suggest supportive care alone. (See 'Patient selection' above.)

-For patients who retain an adequate performance status, preference, symptom burden, quality of life, histologic tumor type, genomic testing, and the nature of the first-line regimen are key considerations. Somatic and germline genomic testing is indicated for those who might be eligible for immunotherapy or molecularly targeted therapy.

•For patients who received prior programmed cell death 1 (PD-1) targeted therapy, we would generally not pursue rechallenge unless prior anti-PD-1 immunotherapy was discontinued due to a specific toxicity that has since resolved, and possibly for patients with progression at few sites after a prior objective response or prolonged period of stable disease. (See 'Regimen choice' above.)

●Our approach – If trials are unavailable or patients are ineligible, our general approach is summarized below:

•Deficient mismatch repair or high TMB – For patients who have either DNA mismatch repair deficiency or high levels of tumor mutational burden (TMB), we suggest pembrolizumab rather than chemotherapy, if it was not administered for frontline therapy (Grade 2C). (See 'Defective mismatch repair' above and 'High tumor mutational burden' above.)

•Other adenocarcinomas

-HER2-positive adenocarcinoma – For patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma who progress on initial therapy with a trastuzumab-based regimen, our approach to second-line therapy is as follows (see 'HER2-positive adenocarcinoma' above):

For patients with persistently positive HER2 expression (algorithm 1) confirmed on repeat metastatic tissue biopsy or liquid biopsy (ie, circulating tumor DNA) and no pulmonary disease, we suggest second-line therapy with fam-trastuzumab deruxtecan rather than other systemic agents (Grade 2C). (See 'Fam-trastuzumab deruxtecan' above.)

For patients with negative HER2 expression confirmed on either repeat tissue biopsy or liquid biopsy, or those with pulmonary disease, we suggest second-line therapy with paclitaxel plus ramucirumab rather than other systemic agents (Grade 2C). FOLFIRI plus ramucirumab is an appropriate alternative for patients with clinically significant neuropathy; or those with disease recurrence within six months of completing perioperative FLOT chemotherapy for gastric adenocarcinoma or chemoradiation with carboplatin plus paclitaxel for GEJ adenocarcinoma. (See 'Paclitaxel plus ramucirumab' above and 'FOLFIRI plus ramucirumab' above.)

For patients where the tumor HER2 status cannot be reconfirmed via repeat biopsy, preferred second-line treatment options include paclitaxel plus ramucirumab or fam-trastuzumab deruxtecan. Since either regimen is equally appropriate, the choice of therapy is influenced by patient and clinician preference and patient comorbidities. (See 'Selection of second-line therapy' above.)

For less medically fit patients, alternative options include single-agent chemotherapy (eg, irinotecan, paclitaxel, docetaxel). (See 'Single-agent chemotherapy' above.)

-HER2-negative, PD-L1 expression – An option for treatment at progression for patients who have high levels of programmed cell death ligand 1 (PD-L1) expression (combined positive score [CPS] ≥10) is off-label use of pembrolizumab (table 4), if an immune checkpoint inhibitor was not administered for front-line therapy. (See 'Efficacy in adenocarcinoma' above.)

Another alternative is chemotherapy

-Chemotherapy – For most patients with HER2-negative non-PD-L1 overexpressing adenocarcinomas who have disease progression with fluoropyrimidine- and platinum-containing chemotherapy, retain an excellent performance status, a favorable comorbidity profile, and a preference for intensive treatment we suggest ramucirumab plus paclitaxel rather than a different regimen (Grade 2C). For patients with clinically significant neuropathy or prior treatment with taxanes, ramucirumab plus FOLFIRI is a reasonable alternative. (See 'Ramucirumab with or without paclitaxel' above and 'FOLFIRI plus ramucirumab' above.)

For patients with an adequate performance status and comorbidity profile or those for whom limiting treatment-related toxicity is an important goal, we suggest monotherapy rather than combination chemotherapy (Grade 2C). Options include irinotecan, weekly paclitaxel, apatinib (where available), or ramucirumab monotherapy.

Trifluridine-tipiracil is a reasonable option for third-line therapy or beyond for patients who retain an adequate performance status. (See 'Trifluridine-tipiracil' above.)

•Squamous cell cancer

-Second-line pembrolizumab is an option for those with high levels of PD-L1 expression (CPS ≥10), and nivolumab or camrelizumab (where available) are options for second-line treatment and beyond regardless of PD-L1 expression status, if an immune checkpoint inhibitor was not administered for front-line therapy. (See 'Efficacy in squamous cell cancer' above.)

-For patients with who are not eligible for immunotherapy and who retain an excellent performance status, a favorable comorbidity profile and preference for intensive treatment, we suggest a combination regimen containing agents not used in the first-line setting (Grade 2C). Options for patients treated with initial FOLFOX include FOLFIRI (irinotecan plus leucovorin and short-term infusional fluorouracil [FU], (table 1)), taxane-based therapy, or cisplatin plus FU. (See 'Single-agent chemotherapy' above.)

-For patients with an adequate performance status and comorbidity profile or those for whom limiting treatment-related toxicity is an important goal, we suggest monotherapy rather than combination chemotherapy (Grade 2C). Options include irinotecan, weekly paclitaxel, or weekly nabpaclitaxel.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Johanna Bendell, MD, who contributed to earlier versions of this topic review.