The immune checkpoint inhibitors (ICIs) monotherapy has resulted in significant improvements in PFS and OS in advanced NSCLC when compared with chemotherapy alone, and it has become the standard of care as first-line treatment for patients with EGFR- and ALK-negative advanced NSCLC1,2. However, patients with high PD-L1 expression are preferred population and almost more than 50% patients showed limited benefit from the ICIs monotherapy. Therefore, the advent of combination of ICIs with chemotherapy has brought more benefits to a wider population3,4. However, all evidence to date of immunotherapy plus chemotherapy has come primarily from White patients, and data from patients in East Asia has been sparse.5 In the Journal of Thoracic Oncology, Yang and colleagues6 reported the results of the ORIENT-11 study, a phase III, randomized, double-blind trial comparing the PD-1 inhibitor sintilimab plus chemotherapy (pemetrexed plus a platinum-based agent) with chemotherapy alone for Chinese patients with previously untreated, locally advanced or metastatic, nonsquamous NSCLC. The primary end point in intention-to-treat (ITT) patients was PFS. The results again showed that chemotherapy plus sintilimab prolonged PFS (8.9 vs. 5.0 months; HR 0.482, 95% CI: [0.362-0.643]; p < 0.00001). For patients with PD-L1 ≥ 50% there was a statistically significantly improved PFS compared to chemotherapy in this trial, the median PFS was not reached (HR 0.31; 95% CI: [0.20–0.49], p < 0.00001). In contrast, for patients with PD-L1 < 1% there was no significant difference in PFS compared to chemotherapy, median PFS was 7.3 vs. 5.1 months, (HR 0.67; 95% CI: [0.41–1.09], p = 0.103). Although median OS was immature, a trend toward better OS was also observed in the combination group (HR 0.609, 95% CI [0.400-0.926]). Furthermore, adding sintilimab to chemotherapy did not significantly increase treatment-related adverse events of grade 3 or higher, compared with chemotherapy alone (61.7% vs. 58.8%). Overall, the ORIENT-11 study proved the combination of sintilimab with chemotherapy to be efficacious with an acceptable safety profile in Chinese populations.
KEYNOTE-189 and CameL7 were also randomized studies that evaluated the efficacy and safety of ICIs plus chemotherapy versus chemotherapy alone as first-line treatments in advanced nonsquamous NSCLC. In the KEYNOTE-189 study, Caucasians, Asians, and other regions patients with untreated, advanced non-squamous NSCLC were randomly assigned to receive chemotherapy (pemetrexed plus a platinum-based agent) with or without pembrolizumab. An updated analysis from the KEYNOTE-189 study showed that this combination treatment significantly improved both median PFS (9.0 vs. 4.9 months; HR 0.48, 95% CI [0.40-0.58]) and median OS (22.0 vs. 10.7 months; HR 0.56, 95% CI [0.45-0.70]) compared with chemotherapy alone8. The CameL study compared the PD-1 inhibitor camrelizumab plus chemotherapy (pemetrexed plus carboplatin) with chemotherapy alone as first-line treatment in Chinese patients with advanced non-squamous NSCLC. PFS was significantly improved in the camrelizumab plus chemotherapy group when compared to the chemotherapy-alone group (median PFS: 11.3 vs. 8.3 months; HR 0.60, 95% CI: [0.45-0.79]; p = 0.0001). The magnitude of PFS benefit, measured by reduction of the risk of progressive disease in the KEYNOTE-189, CameL, and ORIENT-11 studies, was 48%, 40%, and 52%, respectively. These data further strengthened evidence of the clinical benefits of immunotherapy plus chemotherapy for Asian patients with advanced NSCLC. KEYNOTE-407 was a randomized, double-blind, phase III trial comparing pembrolizumab plus chemotherapy (paclitaxel or nab-paclitaxel plus carboplatin) versus placebo plus chemotherapy. The primary endpoints of this study were PFS and OS. The median PFS was improved with the addition of pembrolizumab to chemotherapy, 6.4 vs. 4.8 months, HR 0.56, 95% CI [0.45-0.70], P<0.001). The OS was also improved with the addition of pembrolizumab to chemotherapy, median OS of 15.9 vs. 11.3 months, HR 0.64, 95% CI: [0.49-0.85], p < 0.001). Furthermore, subgroup analysis of the KEYNOTE-407 study9 showed that Asian patients with cancer seemed to gain more PFS benefits than non-Asian patients with cancer (HR 0.49 vs. 0.58). A recent meta-analysis also indicated that Asian patients with NSCLC may have significantly improved survival benefits compared to non-Asian patients receiving PD-1 inhibitor–based therapy.10 Collectively, ICIs plus chemotherapy have been proven to be effective in Asian patients with advanced NSCLC.
Growing evidence demonstrates that PD-L1 expression is a predictive biomarker for patients who receive ICI monotherapy. However, PD-L1 expression was not mandatory for patients who received ICI plus chemotherapy, as the clinical benefits of ICIs combined with chemotherapy were independent of PD-L1 expression.3,4 Moreover, glycosylation of PD-L1 may shield the PD-L1 diagnostic antibody binding,11 leading to inaccurate PD-L1 quantification and unsatisfactory therapeutic outcomes. Nevertheless, PD-L1 is still indispensable before discovering better biomarkers. Tumor mutational burden (TMB) has arisen as another potential indicator of response to immunotherapy,12,13 but exploratory analyses of the KEYNOTE-021 and KEYNOTE-189 studies found that tissue TMB was not signiﬁcantly associated with the efﬁcacy of pembrolizumab plus chemotherapy.14,15 Therefore, in addition to research on PD-L1 and TMB, efforts to exploit novel biomarkers are still in high demand. Major histocompatibility complex class II (MHC-II)–restricted neoantigen has the potential to be a promising biomarker and target for immunotherapy.16 At the ESMO Virtual Congress 2020, an exploratory analysis from the ORIENT-11 study17 found that the MHC-II antigen presentation pathway was significantly associated with clinical efficacy in a combination group (HR 0.51; 95% CI [0.28-0.91]; p = 0.0230). It was further confirmed that cells with MHC-II presentation capability, such as macrophage, dendritic cell, or immature B cell, contributed to the longer PFS in the immune combination group.
Efficacy of immunotherapy in specific populations such as patients with brain or liver metastases has also gained attention in clinical settings. The ORIENT-11 study revealed that patients with brain metastases in a combination chemotherapy plus immunotherapy group also derived survival benefits (HR 0.578, 95% CI [0.283-1.180]). These findings were consistent with the subgroup analysis of KEYNOTE-189; HR was 0.42 (95% CI [0.26-0.68]) for patients with brain metastases who received chemotherapy plus immunotherapy treatment. Notably, data for patients with liver metastases were not provided in the ORIENT-11 study.
Currently, ICIs are a costly treatment that could drastically hamper healthcare budgets at the patient and hospital level.18 As practitioners already have access to multiple PD-1/PD-L1 inhibitors, different cost-effective therapeutic strategies should also be taken into consideration in future decision-making in clinical practice.
In conclusion, ORIENT-11 suggested a new treatment option for advanced nonsquamous NSCLC and demonstrated that this combination treatment was effective in Chinese patients. However, clinical practice should be customized for each patient on the basis of clinical features, tumor characteristics, and suitable predictive biomarkers. In-depth research on better predictive biomarkers and more therapeutic combinations hold promise for patients with more advanced nonsquamous NSCLC.
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