Immunotherapy is not for all comers in chemotherapy-refractory advanced gastric cancer. Better predictive biomarkers are needed
Authors: E.C. Smyth, A. Cervantes
Journal: Annals of Oncology (2018)

Over the past year, patients with advanced gastric and gastroesophageal cancer (GC) which has previously been treated with two or more lines of chemotherapy have seen incremental gains in overall survival (OS) associated with two new therapeutic options. The anti-progressive disease (PD)-1 antibody nivolumab and the oral chemotherapy trifluridine-tipiracil improved OS compared with placebo and best supportive care in the ATTRACTION-2 and TAGS trials respectively [1.Kang Y.K. Boku N. Satoh T. et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 2461-2471Abstract Full Text Full Text PDF PubMed Scopus (1349) Google Scholar, 2.Tabernero J. Shitara K. Dvorkin M. et al.LBA-002 Overall survival results from a phase III trial of trifluridine/tipiracil versus placebo in patients with metastatic gastric cancer refractory to standard therapies (TAGS).Ann Oncol. 2018; 29Google Scholar]. ATTRACTION-2 was a landmark study, which provided the first randomised evidence of efficacy of immune checkpoint blockade in GC, however recruited solely an Asian (Japanese, Taiwanese and South Korean) population [1.Kang Y.K. Boku N. Satoh T. et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 2461-2471Abstract Full Text Full Text PDF PubMed Scopus (1349) Google Scholar]. After ATTRACTION-2, comparable efficacy of another anti-PD-1 antibody, pembrolizumab, was shown in chemorefractory GC patients in the global, non-randomised KEYNOTE-059 trial [3.Fuchs C.S. Doi T. Jang R.W. et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.JAMA Oncol. 2018; 4: e180013Crossref PubMed Scopus (1053) Google Scholar]. Recently, the initial enthusiasm surrounding targeting PD-1 in GC has been tempered by accumulating data suggesting that the efficacy of immune checkpoint blockade may be limited to a relatively small subset of GC patients. The results of the JAVELIN 300 trial, presented by Bang et al. in this issue of Annals of Oncology, confirm the limitations of anti-PD-L1 monotherapy in advanced GC [4.Bang Y.-J. Ruiz E.Y. Van Cutsem E. et al.Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.Ann Oncol. 2018; 29: 2052-2060Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar]. In JAVELIN 300, 379 patients with GC who had previously been treated with at least two lines of chemotherapy were randomised to the anti-PD-L1 antibody avelumab or investigators choice of chemotherapy with paclitaxel or irinotecan. The primary end point of the study, an improvement in OS for avelumab-treated patients, was not met {median OS was 4.6 months for avelumab versus 5 months for chemotherapy [hazard ratio (HR) 1.1] [95% confidence interval (CI) 0.9–1.4]; P = 0.81). Although radiological response rates were similar in avelumab- and chemotherapy-treated patients (2.2% versus 4.0%, respectively), progression-free survival (PFS) was better in chemotherapy-treated patients in every subgroup [overall PFS HR = 1.73 (95% CI 1.4–2.2)]. Based on these results, avelumab cannot be recommended as a treatment of chemorefractory advanced GC. The results of JAVELIN 300 are reminiscent of the findings in KEYNOTE-061, which recently failed to demonstrate a survival advantage for pembrolizumab compared with paclitaxel in second-line PD-L1-positive GC patients [5.Shitara K. Özgüroğlu M. Bang Y.J. et al.Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018; 392: 123-133Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar]. In both JAVELIN 300 and KEYNOTE 061, many patients experienced relatively rapid disease progression when treated with immune checkpoint blockade. For example, the median PFS was 1.4 months for avelumab-treated patients in JAVELIN 300. Also, in keeping with the results of KEYNOTE-061, in JAVELIN 300, patients who did not experience progression on avelumab appear to have a survival advantage. In a post hoc analysis, avelumab-treated patients who had disease control (22.2%) had better OS than patients who had disease control with chemotherapy (median OS 12.5 months versus 8.0 months, respectively). Avelumab therapy may also be better tolerated than chemotherapy; in JAVELIN 300, more patients treated with chemotherapy had grade 3 or greater adverse events (9.2% versus 31.6%) associated with treatment. However, many chemotherapy-associated adverse events are haematological, which in the absence of febrile neutropenia may go unnoticed by the patient. Quality-of-life data are essential to understand whether the reduced number of adverse events associated with avelumab in JAVELIN 300 translates into better quality of life for patients. In JAVELIN 300, no difference in OS was observed according to PD-L1 status, which in this study was characterised as PD-L1 staining on ≥1% of tumour cells. Results were the same when PD-L1 was also assessed on immune cells, although the methodology for this assessment is not described. These findings highlight the inconstancy of the relationship between PD-L1 status and responses to immune checkpoint blockade in GC. In ATTRACTION-2, PD-L1 was retrospectively assessed only on tumour cells and had no predictive value [1.Kang Y.K. Boku N. Satoh T. et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 2461-2471Abstract Full Text Full Text PDF PubMed Scopus (1349) Google Scholar]. However, in KEYNOTE-059, the efficacy of pembrolizumab was increased in patients who were PD-L1 positive [≥1% staining using the combined positive score (CPS), which is a proportional assessment of PD-L1 staining on both tumour and immune cells] [3.Fuchs C.S. Doi T. Jang R.W. et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.JAMA Oncol. 2018; 4: e180013Crossref PubMed Scopus (1053) Google Scholar]. In KEYNOTE-061, although the trial was negative for an improvement in OS with pembrolizumab in the overall PD-L1-positive (CPS ≥1) population, patients who expressed high levels of PD-L1 (CPS ≥10) had a pronounced benefit from treatment with pembrolizumab (HR 0.64, 95% CI 0.41–1.02) [5.Shitara K. Özgüroğlu M. Bang Y.J. et al.Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018; 392: 123-133Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar]. More work on standardisation of PD-L1 assays as a GC biomarker is required, as in addition to variability in PD-L1 antibody usage and the methodology of PD-L1 quantification, heterogeneity of PD-L1 expression is likely to pose a challenge in GC, as has been the case with HER2. Trial results according to mismatch repair deficiency status are not reported in this article, but this should be prioritised in any subsequent translational protocol. However, patients with microsatellite unstable tumours form a small minority of advanced GC patients, and therefore a focus on identifying novel biomarkers to predict response to immunotherapy for the majority of microsatellite stable patients is also essential [3.Fuchs C.S. Doi T. Jang R.W. et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.JAMA Oncol. 2018; 4: e180013Crossref PubMed Scopus (1053) Google Scholar, 5.Shitara K. Özgüroğlu M. Bang Y.J. et al.Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018; 392: 123-133Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar]. For example, in KEYNOTE-059, an 18 gene T-cell inflamed gene expression signature was significantly associated with the likelihood of response to pembrolizumab and PFS [3.Fuchs C.S. Doi T. Jang R.W. et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.JAMA Oncol. 2018; 4: e180013Crossref PubMed Scopus (1053) Google Scholar]. A non-linear relationship between the T-cell inflamed signature and PD-L1 status was demonstrated, highlighting the variable value of both biomarkers in this setting. Tumour mutation burden (TMB) is a robust predictor of response to immune checkpoint blockade across tumour types [6.Hellmann M.D. Ciuleanu T.E. Pluzanski A. et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med. 2018; 378: 2093-2104Crossref PubMed Scopus (2009) Google Scholar, 7.Yarchoan M. Hopkins A. Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition.N Engl J Med. 2017; 377: 2500-2501Crossref PubMed Scopus (1701) Google Scholar]. A subset of patients with gastroesophageal adenocarcinoma, who are microsatellite stable, but have high TMB, have been identified using whole exome sequencing [8.Secrier M. Li X. De Silva N. et al.Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.Nat Genet. 2016; 48: 1131-1141Crossref PubMed Scopus (234) Google Scholar]. This high mutation load population, which would fall into the large predominantly immunologically 'cold' TCGA chromosomally unstable (CIN) subgroup, also had high levels of infiltrating lymphocytes which is suggestive of an active immune response [8.Secrier M. Li X. De Silva N. et al.Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.Nat Genet. 2016; 48: 1131-1141Crossref PubMed Scopus (234) Google Scholar, 9.Sohn B.H. Hwang J.E. Jang H.J. et al.Clinical significance of four molecular subtypes of gastric cancer identified by the Cancer Genome Atlas Project.Clin Cancer Res. 2017; 23: 4441-4449Crossref Scopus (249) Google Scholar]. These results imply that TMB could also be associated with sensitivity to immune checkpoint blockade in GC: therefore, this hypothesis warrants prospective evaluation. In summary, the negative results of JAVELIN 300 are disappointing for patients with advanced GC. To optimise the benefits of single-agent immunotherapy, work on predictive biomarkers is necessary to identify the minority of GC patients who are likely to experience prolonged disease control before treatment. For most GC patients, who have immunologically evasive tumours, development of combination therapies to overcome resistance to immune checkpoint blockade is likely to be the most successful way forward. This work was supported in part by grants from the Spanish Government, Ministerio de Economía y Competitividad (FIS PI12/02767 and PI15/02180 to AC) and Generalitat Valenciana (PROMETEO 2013-005 to AC) and CIBERONC (no grant number is applicable).