Figure 2: Confirmed objective response rates in KEYNOTE-021
Onkologie 14. November 2016
Immune checkpoint inhibition: the picture is slowly completing itself
KEYNOTE-024: first-line, PD-L1–enriched population
The anti–PD-1 antibody pembrolizumab has been approved for treatment of patients with PD-L1–expressing, advanced NSCLC. The KEYNOTE-024 study focused on the first-line comparison of pembrolizumab with platinum-doublet chemotherapy . Chemotherapy regimens comprised five options, two of which (pemetrexed plus carboplatin; pemetrexed plus cisplatin) were used with non-squamous non-small–cell lung cancer (NSCLC) only. In all, 305 patients were randomised across 142 sites in 16 countries. The population was enriched for PD-L1 expression, as a key eligibility criterion was PD-L1 tumour proportion score (TPS) ≥ 50 % (i. e., PDL1 expression on at least 50 % of tumour cells). Approximately 20 % of patients had tumours with squamous histology.
Figure 1: Progression-free survival in KEYNOTE-024: benefit obtained with pembrolizumab compared to chemotherapy
Six complete responses were observed with the anti-PD-1 antibody. Despite longer exposure to pembrolizumab (7.0 vs. 3.5 months), adverse event (AE) rates of all grades were lower in the experimental arm. The Data Monitoring Committee recommended stopping the trial because of this superior efficacy with pembrolizumab.
Pembrolizumab plus chemotherapy: KEYNOTE-021
There is a rationale for combining chemotherapy and immunotherapy, as chemotherapy itself has several immunological effects and can induce PD-L1 expression on tumour cells. Clinical data in this area were provided by the multi-cohort phase I/II KEYNOTE-021 trial that evaluated pembrolizumabbased combination therapy for patients with advanced NSCLC . The patients in Cohort G of this study, who had untreated stage IIIB or IV non-squamous NSCLC, were randomised to either pembrolizumab 200 mg every 3 weeks for 2 years plus carboplatin and pemetrexed (n = 60), or carboplatin plus pemetrexed only (n = 63). Pemetrexed maintenance therapy was permitted.
OS improvement of 4 months with atezolizumab in OAK
The anti–PD-L1 antibody atezolizumab showed superiority with regard to OS over docetaxel in patients with advanced NSCLC in the phase II POPLAR study [3, 4]. In the randomised phase III setting, the OAK trial compared atezolizumab 1,200 mg every 3 weeks with docetaxel 75 mg/m2 every 3 weeks, in patients with locally advanced or metastatic NSCLC who had received one or two prior lines of chemotherapy, including at least one platinum-based regimen . Patients were recruited regardless of their PD-L1 expression status. Crossover was not allowed. The co-primary endpoint consisted of OS in the ITT population and OS in patients with PD-L1 expression on ≥ 1 % of their tumour cells (TCs) or immune cells (ICs). The OAK data are the first phase III results obtained for a PD-L1–directed antibody, with a total of 1,225 patients projected to be recruited into the study.
Figure 3: OAK trial: OS according to PD-L1 expression for atezolizumab and docetaxel
As patients with both non-squamous and squamous histological subtypes were included in the OAK trial, the investigators also assessed the OS effects of the treatments in these subgroups. In both cohorts, the HRs were 0.73 in favour of atezolizumab. A similar OS advantage was seen across most subgroups irrespective of gender, age, ECOG performance status, number of prior treatment lines, smoking history, and baseline CNS metastasis. The only exception to this were patients with EGFR-activating mutations, who did not benefit from this treatment with the anti–PD-L1 antibody. This phenomenon has already been observed with other PD-L1 inhibitors.
News from the pivotal pembrolizumab trial
The phase III KEYNOTE-010 study demonstrated the efficacy and safety of pembrolizumab in comparison with docetaxel in 1,034 previously treated patients with PD-L1–expressing, advanced NSCLC . This thus provided the basis for European approval of pembrolizumab for this indication. An updated analysis after six additional months of follow-up showed that OS continued to be superior with pembrolizumab 2 mg/ kg and 10 mg/kg compared to docetaxel in the TPS ≥ 50 % and ≥ 1 % populations . PFS was similar to that previously observed, and responses continued to be durable. Overall, these findings confirm pembrolizumab as a standard of care in patients with pre-treated, PD-L1–expressing, advanced NSCLC.
Two-year data: CheckMate 017 and 057
Nivolumab is a standard of care for previously treated NSCLC patients based on the results of the global, randomised, open-label, phase III CheckMate 017 and 057 trials. In both studies, nivolumab significantly prolonged OS compared with docetaxel in previously treated patients with squamous NSCLC (CheckMate 017)  or with non-squamous NSCLC (CheckMate 057) .
Hardly any first-line benefits in CheckMate 026
Negative results were obtained for firstline nivolumab in patients with stage IV or recurrent PD-L1–positive NSCLC. The open-label, international, phase III, CheckMate 026 study compared firstline nivolumab with platinum-based doublet chemotherapy in this population . PD-L1 expression of ≥ 1 % was mandatory. Crossover to nivolumab in the case of progression was optional. The results for the primary endpoint, which was PFS by independent radiological review in the ≥ 5 % PD-L1–positive population, did not differ significantly between the two regimens (4.2 vs. 5.9 months, for nivolumab and chemotherapy, respectively). This also applied to OS (14.4 vs. 13.2 months). Progressive disease was more common in the nivolumab arm (27.5 % vs. 9.9 %), but when responses were seen, they lasted more than twice as long with nivolumab than in the chemotherapy-treated population (12.1 vs. 5.7 months).
Neoadjuvant use of nivolumab
Preliminary, but aspirational, data have been generated with neoadjuvant nivolumab in a trial that enrolled 18 patients with newly diagnosed, resectable stage I (> 2 cm)/II/IIIA NSCLC . The rationale for neoadjuvant use of anti– PD-1 strategies in early-stage NSCLC results from the fact that stage I to III NSCLC, albeit considered early-stage disease, has poor prognosis, and only modest benefits are seen with adjuvant chemotherapy. Nivolumab was administered at a dose of 3 mg/kg at 4 weeks and 2 weeks prior to surgical resection. The primary endpoint was safety and tolerability. Exploratory endpoints included various correlative analyses of blood and the tumour, as well as other clinical outcome parameters, such as pathological response.
Figure 4: Pathological responses in tumours of 17 patients with early NSCLC after neoadjuvant administration of two nivolumab doses
1 Reck M et al., KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 TPS
© 2016 Springer-Verlag GmbH, Impressum
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