Is front-line checkpoint blockade ATTRACTIVE in advanced gastric cancer?

Immune checkpoint inhibitors are transforming oncological practice. Approvals in advanced disease have signified a landmark shift in the treatment paradigms of many cancers. Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are now approved in the chemorefractory setting for Asian patients and a subset of PD-L1-positive patients with advanced gastro-oesophageal adenocarcinoma [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 (1179) Google Scholar, 2.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 (906) Google Scholar]. Responses in gastro-oesophageal adenocarcinoma have, however, been mixed. Anti-PD-1 and anti-PD-L1 antibodies in the second and third lines, respectively, versus chemotherapy, have failed to show an overall survival (OS) benefit [3.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 (666) Google Scholar, 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 of 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 (264) Google Scholar] and therefore outside clinical trials, the role of checkpoint inhibitors is currently limited to PD-1 inhibition for selected patients in the third or subsequent line with the exception of mismatch repair (MMR)-deficient disease [5.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3375) Google Scholar]. Globally, gastric cancer (cardia and non-cardia) is the fifth most common cancer and third leading cause of cancer-related mortality [6.Bray F. Ferlay J. Soerjomataram I. et al.Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (45035) Google Scholar]. Survival for patients with advanced disease is poor and treatment options beyond first line are limited. Only trastuzumab, for human epidermal growth factor receptor 2 (HER2)-positive cancers in the first-line advanced setting [7.Bang Y.-J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (4928) Google Scholar] and ramucirumab in the second-line [8.Wilke H. Muro K. Van Cutsem E. et al.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.Lancet Oncol. 2014; 15: 1224-1235Abstract Full Text Full Text PDF PubMed Scopus (1512) Google Scholar], has shown significant benefit in addition to standard chemotherapy, underlining the need for novel therapies and the unmet need in this area, especially given the lack of progress in recent years in the front-line setting [9.Waddell T. Chau I. Cunningham D. et al.Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.Lancet Oncol. 2013; 14: 481-489Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 10.Lordick F. Kang Y.K. Chung H.C. et al.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol. 2013; 14: 490-499Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar, 11.Shah M.A. Bang Y.J. Lordick F. et al.Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial.JAMA Oncol. 2017; 3: 620-627Crossref PubMed Scopus (158) Google Scholar, 12.Catenacci D.V.T. Tebbutt N.C. Davidenko I. et al.Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1467-1482Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 13.Fuchs C.S. Shitara K. Di Bartolomeo M. et al.RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) ad.J Clin Oncol. 2018; 36: 5Crossref Google Scholar]. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized phase 2 trial (ATTRACTION-4) is a two-part study designed to evaluate nivolumab in combination with chemotherapy. In this issue, Boku et al. report results of the safety and efficacy of a randomised phase II study of nivolumab (360 mg q3w) in combination with S1(S)/capecitabine(Cape) plus oxaliplatin (OX) in patients with untreated, unresectable, advanced or recurrent HER2-negative gastric/gastroesophageal junction adenocarcinoma, part 1 [14.Boku N. Ryu M.-H. Kato K. et al.Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).Ann Oncol. 2019; 30: 250-258Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. Safety was the primary end point and upon condition that the combination was safe and tolerable and ≥2 of 15 patients achieved a complete or partial response the phase III study, part 2 was initiated. In part 1, both chemotherapy backbones were found to be safe with objective response rates (ORR) of 57.1% [95% confidence interval (CI) 34.0%–78.2%) and 76.5% (95% CI 50.1%–93.2%) observed for nivolumab plus SOX and nivolumab plus CapeOX, respectively. Median progression-free survival was 9.7 months (5.8 to not reached) and 10.6 months (5.6–12.5) in the nivolumab plus SOX and nivolumab plus Cape/OX groups, respectively. Median OS was not reached with a median follow-up of 13.2 months. No significant differences in safety or efficacy were seen between the two groups. These results merit validation in the ongoing phase III ATTRACTION-4 study (part 2) comparing investigators choice SOX/CapeOX plus nivolumab versus SOX/CapeOX plus placebo in chemotherapy naive patients. There is sound rationale to evaluating immune checkpoint inhibition in earlier lines of therapy. Response rates to monotherapy PD-1 inhibition in chemorefractory disease are modest with 11%–12% objective response reported [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 (1179) Google Scholar, 15.Janjigian Y.Y. Bendell J. Calvo E. et al.CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer.J Clin Oncol. 2018; 36: 2836-2844Crossref PubMed Scopus (316) Google Scholar]. Beyond the cytotoxic effects of oxaliplatin-based chemotherapy, induced effects on the immune stimulation have the potential to be beneficial in combination with immune checkpoint blockade [16.Gotwals P. Cameron S. Cipolletta D. et al.Prospects for combining targeted and conventional cancer therapy with immunotherapy.Nat Rev Cancer. 2017; 17: 286-301Crossref PubMed Scopus (522) Google Scholar]. In preclinical lung adenocarcinoma mouse models, immunogenic chemotherapy (oxaliplatin combined with cyclophosphamide) has been shown to sensitise tumours lacking T-cell infiltrates to PD-1 antibodies [17.Pfirschke C. Engblom C. Rickelt S. et al.Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy.Immunity. 2016; 44: 343-354Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar]. In ATTRACTION-4, part 1, the combination of oxaliplatin/fluoropyrimidine chemotherapy together with nivolumab was considered to have a manageable toxicity profile. It is worth commenting, however, that all patients in the safety population (n = 39) experienced treatment related adverse event (TRAE) leading to dose delay or reduction in 94.9% and 15.4% developed grade ≥3 treatment-related serious adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [18.NIH NCI Division of Cancer Treatment and Diagnosis Common Terminology Criteria for Adverse Events (CTCAE) Version 5.2017https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference:5x7.pdfGoogle Scholar]. Most frequently reported TRAEs in both groups were expected adverse events associated with oxaliplatin and/or fluoropyrimidines. TRAEs led to treatment discontinuation for three patients (14.3%) in the nivolumab plus SOX group and two patients (11.1%) in the nivolumab plus Cape/OX group. In ATTRACTION-2, the proportion of patients with toxicity leading to discontinuation of therapy was in fact very low, 1% (n = 4) which supports data suggesting the majority of toxicity was associated with standard of care chemotherapy. Given the small safety population in the study, comparisons between arms cannot be made, none the less the overall high rate of TRAEs across arms could impact patient care and standard chemotherapy dose intensity. The small cohort sizes limit conclusions on efficacy. Results appear encouraging in the efficacy population (n = 38) with an overall ORR of 65.8% (95% CI 48.6%–80.4%) across the two groups and a median duration of response (DOR) of 9.9 months (95% CI 5.8 to not reached). However, the sample size (intent to treat n = 40) is more reflective of a safety run-in rather than a true randomised phase II design and the results are too preliminary to draw comparisons or conclusions against first-line standard of care chemotherapy. As with previous studies of nivolumab in oesophagogastric cancer, antitumour response in this study appeared independent of tumour PD-L1 status. In patients with PD-L1-positive tumours, the ORR was 2/4 (50%) and 1/1 (100%) in the Nivolumab plus SOX and Cape/OX groups, respectively, compared with 10/17 (58.8%) and 12/16 (75%) in the PD-L1-negative tumours. By comparison, in KEYNOTE-059 Cohort 2, PD-L1-positive patients appeared to be derived more benefit with an ORR of 68.8% versus 37.5% [19.Bang Y.-J. Muro K. Fuchs C.S. et al.KEYNOTE-059 cohort 2: safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer.J Clin Oncol. 2017; 35: 4012Crossref PubMed Google Scholar]. Clearly, the value of PD-L1 as a predictive biomarker is uncertain and whilst PD-L1 may not be a selection biomarker for immunotherapy in oesphago-gastric cancer, identifying those patients who achieve durable responses to immune checkpoint inhibition is of clinical and economic importance. Of The Cancer Genome Atlas (TCGA) subgroups, Epstein–Barr virus (EBV) positive (+) and microsatellite instability (MSI)-high (H) gastric cancers demonstrate higher PD-L1 expression not seen in other gastric cancers [20.Derks S. Liao X. Chiaravalli A.M. et al.Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.Oncotarget. 2016; 7: 32925-32932Crossref PubMed Scopus (194) Google Scholar]. Moreover, an interferon-γ signature, a putative biomarker of sensitivity to immunotherapy, is enriched in EBV+ and MSI-H gastric cancers with dramatic overall responses to pembrolizumab in EBV+ and MSI-H metastatic gastric cancer reported by Kim et al., 100% and 85.7%, respectively, in these subgroups [21.Kim S.T. Cristescu R. Bass A.J. et al.Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer.Nat Med. 2018; 24: 1449-1458Crossref PubMed Scopus (607) Google Scholar]. Should patients with EBV+ or MSI-H gastric cancer be present in the ATTRACTION-4 efficacy population, this may inflate response rates emphasising the importance of prospective biomarker analysis in immunotherapy trials. Finally, whilst ATTRACTION-2 demonstrated a clear survival benefit for chemorefractory disease, this study was conducted exclusively in Japan, South Korea and Taiwan without prospective biomarker analysis. Consequently, neither the Food and Drug Administration nor European Medicines Agency (EMA) have granted a licence for nivolumab in this setting, raising a question of global application of ATTRACTION-4, particularly in the absence of quality of life data, an important end point in other geographical areas. Differences in gene expression signatures relating to immune function exist between Asian and non-Asian gastric cancers with the potential to impact treatment response [22.Lin S.J. Gagnon-Bartsch J.A. Tan I.B. et al.Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.Gut. 2015; 64: 1721-1731Crossref PubMed Scopus (141) Google Scholar]. Integrated tumour biopsies and biomarker studies in ATTRACTION-4 part 2 may aid our understanding of differential response across populations. Moreover, CheckMate 649 will provide a large, randomised global parallel [23.Janjigian Y.Y. Adenis A. Aucoin J.-S. et al.Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junct.J Clin Oncol. 2017; 35 (TPS213): TPS213Crossref Google Scholar]. This phase III study in chemotherapy naive patients with adenocarcinoma of the stomach and gastro-oesphageal junction will provide further evidence evaluating immune checkpoint blockade in combination with oxaliplatin/fluoropyrimidine chemotherapy for a population where advances in the first line are lacking. All authors would like to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. None declared.