Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysisBMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3529 (Published 10 September 2018) Cite this as: BMJ 2018;362:k3529
All rapid responses
KEYNOTE-059 is a non-randomized trial and its primary endpoint is overall response rate (ORR) in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. Based on the results from KEYNOTE-059, the U. S. Food and Drug Administration (FDA) granted accelerated approval of pembrolizumab for the treatment of patients whose tumors express PD-L1 . It was concurrently with the approval of the Premarket Approval Application supplement, the Dako PD-L1 IHC-22C3 pharmDx assay, for the identification of patients that were PD-L1 positive. However, because ORR is just a surrogate endpoint for long-term benefit in cancer treatment, Merck is required to conduct confirmatory trials to verify the benefit of pembrolizumab for patients that are PD-L1 positive. KEYNOTE-061 is a phase III randomized trial and its primary endpoints are overall survival and progression free survival in patients that are PD-L1 positive . Unfortunately, KEYNOTE-061 revealed that pembrolizumab did not significantly improve the overall survival for gastric or GEJ cancer that express PD-L1. Accordingly, current evidence implies that neither PD-L1 positive nor PD-L1 negative patients with gastric or GEJ cancer can benefit from pembrolizumab treatment. It also suggests PD-L1 expression status is a poor biomarker in patient selection for PD-1 or PD-L1 blockade therapy, which is consist with our major conclusion.
As for urothelial cancer, because both KEYNOTE-361 and IMvigor130 are ongoing trials, no data regarding these two trials have been published currently. However, we included KEYNOTE-045 in our study. KEYNOTE-045 is a phase III randomized trial investigating the efficacy of pembrolizumab as second-line therapy for urothelial cancer . Data from KEYNOTE-045 revealed that pembrolizumab was associated with significantly longer overall survival in patients that were PD-L1 positive (hazard ratio 0.61, 95% confidence interval 0.43 to 0.86) but not in patients that were PD-L1 negative (hazard ratio 0.89, 95% confidence interval 0.66 to 1.20). For some patients that were PD-L1 negative, it meant pembrolizumab was associated with a reduced survival, which is consist with the preliminary report from KEYNOTE-361 and IMvigor130. In fact, most single trials included in our study showed similar results: patients that were PD-L1 positive, but not PD-L1 negative, could benefit from PD-1 or PD-L1 inhibitors. However, with the accumulating evidence and enlarged sample size, we had enhanced the statistical power to examine the efficacy of PD-1 or PD-L1 inhibitors in patients with PD-L1 negative cancer, and provided more precise and reliable estimates. Our data clearly indicated that patients with PD-L1 negative cancer could achieve long-term benefit from PD-1 or PD-L1 blockade treatment.
We thank Mr. O’Connor for his insightful comments. However, based on available evidence, we believe our primary conclusion is solid and reliable. PD-L1 expression status alone is not an adequate biomarker in patient selection for routine clinical practice.
1. Fashoyin-Aje L, Donoghue M, Chen H, et al. FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1. Oncologist 2018; 10.1634/theoncologist.2018-0221.
2. 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. The Lancet; 10.1016/S0140-6736(18)31257-1.
3. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.
Competing interests: No competing interests
I read with interest the meta-analysis by Shen and Zhao. They present a timely review of the efficacy of PD-1 or PD-L1 inhibitor monotherapy in advanced cancer relative to PD-L1 biomarker expression. The authors correctly attest that an optimal biomarker is important for patient selection as responses to these promising biological agents have been observed in a minority of patients only.
Unfortunately, they incorrectly state that PD-L1 expression status has not been approved for patient selection. Prior to the systematic search cut-off date, the FDA had approved pembrolizumab monotherapy in pre-treated advanced gastric cancer in patients with PD-L1 positive tumours only, based on results from the Keynote-59 trial.  In Europe, the EMA restricted the marketing approval of two PD-1 inhibitors to PD-L1 expressing tumours in the monotherapy setting for metastatic urothelial cancer. Preliminary data from the Keynote-361 and IMvigor130 trials showed a reduced survival with pembrolizumab and atezolizumab compared with chemotherapy in patients with untreated advanced urothelial cancer who had not received prior therapy and whose tumours had low expressions of PD-L1.  Furthermore, the Keynote-61 trail halted enrolment recruitment of patients with PD-L1 negative status prior to study termination due to a lack of response in the second line setting in advanced gastric cancer. 
In contrast to monotherapy, PD-1 or PD-L1 inhibitors have shown more promising results in combination with chemotherapy in a first line setting, irrespective of PD-L1 expression status. This was demonstrated in non-small cell lung cancer  with ongoing phase 3 trials including gastric cancer and ovarian cancer where stratification according to PD-L1 expression status may provide important guidance for patient selection. The authors have highlighted some limitations of PD-L1 expression testing and certainly attainment of a more precise biomarker should be considered if available. However the assertions in their conclusion that PD-1 or PD-L1 blockade is preferable even in PD-L1 negative patients, and that the role of PD-L1 testing should decline in practice, are perhaps immature given the totality of evidence.
 Journal of Clinical Oncology 35, no. 15_suppl (May 20 2017) 4003-4003. DOI: 10.1200/JCO.2017.35.15_suppl.4003
 Shitara K 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 Jul 14;392(10142):123-133. doi: 10.1016/S0140-6736(18)31257-1
 Gandhi L et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:2078-2092 DOI: 10.1056/NEJMoa1801005
Competing interests: The author assesses clinical trials for a national competent authority.