Frontiers of ctDNA, Targeted Therapies, and Immunotherapy in Non-Small-Cell Lung Cancer

Chennianci Zhu; Weihao Zhuang; Limin Chen; Wenyu Yang; Wen-Bin Ou


Transl Lung Cancer Res. 2020;9(1):111-138. 

In This Article


Tumors can evade immune detection by exploiting inhibitory immune checkpoints, such as the PD-1/PD-L1 pathway. PD-1 signaling, which is driven primarily by the adaptive expression of PD-L1 within the tumor, represses the ability of T lymphocytes to recognize tumor-specific antigens, resulting in tumor progression and metastasis.[191] The PD-1/PD-L1 expression level is mediated directly by EGFR, ALK, and the presence of TKIs that exert their effects by influencing the expression level of EGFR and ALK and downstream signaling cascades. Studies have shown that the expression level of PD-L1 is significantly upregulated in NSCLC cell lines expressing an EGFR driver mutation and the EML4-ALK fusion protein.[192,193] The EGFR-TKIs gefitinib and erlotinib both increased the expression of PD-L1 in NSCLC cell lines with mutant EGFR.[194]


The introduction of ICIs, such as monoclonal antibodies that target CTLA-4 and PD-1/PD-L1, has shed light on a new strategy to treat NSCLC patients. Currently, three widely used agents (two PD-1 inhibitors, nivolumab and pembrolizumab, and one PD-L1 inhibitor, atezolizumab) are approved as standard treatment options for pretreated NSCLC patients. Clinical trials of durvalumab and avelumab are underway.

A phase III study of nivolumab revealed the increased overall survival (OS) of patients with advanced-stage NSCLC who exhibited disease progression after cytotoxic therapy treated with nivolumab (12.2 months) compared to the OS of those treated with docetaxel (9.4 months) for the first time.[195] Other studies have also shown the increased OS of nivolumab-treated NSCLC patients (17%) compared to that of docetaxel-treated NSCLC patients (8%).[196] Pembrolizumab and atezolizumab also showed greater efficacy than platinum-based cytotoxic therapy, with a PFS of 10.3 months observed in pembrolizumab-treated patients compared to 6.0 months in a chemotherapy group. A significant improvement in OS was also observed.[197] A similar comparison of atezolizumab and docetaxel also showed that atezolizumab can increase OS in patients, although how the effects of atezolizumab treatment on the ORR and PFS differ from those of docetaxel still needs further investigation.[198,199] ICIs combined with chemotherapy can act synergistically to improve treatment effects. The combination of pembrolizumab and pemetrexed/platinum-based drugs significantly improved OS and PFS in patients with untreated metastatic nonsquamous NSCLC with no EGFR or ALK mutations.[200]

Durvalumab and avelumab were developed more recently than the three other aforementioned ICIs, so an investigation of their efficacy compared to that of regular chemotherapy is underway. Some evidence already suggests the utility of durvalumab to treat NSCLC patients, as a significantly longer PFS (16.8 months with durvalumab vs. 5.6 months with placebo) was observed in patients with stage III NSCLC without disease progression after platinum-based chemoradiotherapy.[201,202] Another phase III trial showed that avelumab did not increase OS compared to that following docetaxel treatment in PD-L1-positive NSCLC patients previously treated with platinum-based chemoradiotherapy. However, patients undergoing avelumab treatment had fewer adverse reactions, showing the favorable safety profile of avelumab.[203]

Combining anti-PD-(L)1 With anti-CTLA-4

The expression of CTLA-4 delivers an inhibitory signal into T-cells, inhibiting T-cell activation.[204] Thus, the dual targeting of PD-(L)1 and CTLA-4 may produce a greater and more durable tumor response than PD-(L)1 inhibition alone. One critical study showed that nivolumab monotherapy (1-year PFS rate of 29%) was less beneficial in patients with a higher tumor mutational burden (TMB), while the combination of nivolumab and ipilimumab (1-year PFS rate of 42%) was significantly effective.[205] Nivolumab plus ipilimumab was also shown to induce a strong and durable response and exhibited a tolerable safety profile in clinical trials.[206] However, combination therapy with pembrolizumab plus ipilimumab was associated with increased toxicity in 51 patients with advanced NSCLC, despite the high antitumor activity of the two drugs.[207]

When tremelimumab, another CTLA-4 antibody, was used with the PD-L1 inhibitor durvalumab in a phase I study, the complete suppression of PD-L1 was observed in most patients, indicating effective targeting by durvalumab. Additionally, increased peripheral T-cell activation and proliferation were observed in patients treated with durvalumab plus tremelimumab compared with that in patients treated with durvalumab monotherapy, even when tremelimumab was administered at the lowest dose,[208] demonstrating the synergistic effect of dual PD-L1 and CTLA-4 inhibition. Another clinical trial (NCT02352948) of durvalumab plus tremelimumab treatment is ongoing. However, how dual PD-(L)1 and CTLA-4 blockade improves the response rate compared with that following PD-(L)1 blockade monotherapy remains unclear. Table 3 contains information on finished and ongoing anti-PD(L)1/CTLA-4 clinical trials for further reference.[209–211] Recent studies[197,212–215] showed significant correlation between PD-(L)1/CTLA-4 expression levels and the effects of immunotherapy, low PD-(L)1 expression levels were linked with poor responses.

TMB Predicts Responses to Immunotherapy

Immunotherapy has changed the landscape of NSCLC treatment. However, just like ctDNA as a biomarker to predict the response of TKI therapy, novel biomarkers are being evaluated for their potential to provide precise and dynamic prediction of the response to immunotherapy. Although this evaluation is only at its early stage, biomarkers such as PD-(L)1 expression level, the presence of EGFR/ALK mutations, TMB, and microsatellite instability were all associated with the responses to immunotherapy.[216,217] The dynamics of TMB were shown to be independent of PD-L1 expression,[218,219] and greater benefit was consistently observed with high TMB and PD-L1 expression, suggesting the potential of TMB and PD-(L)-1 expression level as independent biomarkers.[220] In patients with stage IV or recurrent NSCLC with a high TMB, the 1-year PFS rate was 43% with nivolumab plus ipilimumab treatment and 13% with chemotherapy. Notably, in patients with a low TMB, the PFS with nivolumab plus ipilimumab treatment was similar to that with chemotherapy, suggesting TMB as a biomarker.[205] Several other studies also noted that higher TMB predicts favorable outcomes such as duration and survival of patients receiving anti-PD-1/PD-L1 therapy in NSCLC.[216,219,221] Furthermore, TMB was significantly lower among patients with EGFR, ALK, or ROS1 mutation compared to wild-type.[216] Unsolved questions on the mechanism of combined PD-(L)1 and CTLA-4 blockade and the synergy of this treatment regime with high TMBs remain.