Immunotherapy in non-small cell lung cancer: advancements and challenges

In the past 10 years, immune-checkpoint inhibitors (ICIs), targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, have altered the therapeutic landscape of non-small cell lung cancer (NSCLC) and have resulted in long-term survival benefits in a subset of patients. In this editorial, we focused on recent advancements and challenges of ICIs in patients with NSCLC.

ICIs for First-line Treatment of Advanced NSCLC

The landmark KEYNOTE-024 study demonstrated that pembrolizumab significantly improved progression-free survival (PFS, 10.3 vs. 6.0 months, P < 0.001) and overall survival (OS, 30.0 vs. 14.2 months, P = 0.002) compared with standard chemotherapy in patients with treatment-naïve advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK genetic aberrations.^[1] The KEYNOTE-042 study further demonstrated OS benefits for pembrolizumab monotherapy over chemotherapy in an expanding patient population (OS in PD-L1 TPS ≥1%: 16.7 vs. 12.1 months, P = 0.0018).^[2] However, further exploratory subgroup analysis of KEYNOTE-042 study found no significant benefit in OS in PD-L1 TPS 1–49% population,^[2] suggesting that the survival benefits of pembrolizumab monotherapy may mostly come from higher PD-L1 expression population (≥50%).

ICI in combination with chemotherapy represents another promising treatment paradigm [Supplementary Table 1, http://links.lww.com/CM9/A444].^[3–9] Pembrolizumab combined with chemotherapy has been approved by the National Medical Products Administration (NMPA) for the first-line treatment of advanced squamous and nonsquamous NSCLC without EGFR/ALK genetic aberrations, regardless of PD-L1 expression.^[3,8] Camrelizumab plus pemetrexed/carboplatin also demonstrated significant improvements in terms of objective response rate (ORR; 60.0% vs. 39.1%, P < 0.0001), PFS (11.3 vs. 8.3 months, P = 0.0002) and OS (not reached vs. 20.9 months, P = 0.0272) compared with first-line pemetrexed/carboplatin for Chinese patients with nonsquamous NSCLC without EGFR/ALK genetic aberrations.^[7] Atezolizumab in combination with carboplatin/nab-paclitaxel (IMpower130) or bevacizumab and carboplatin/nab-paclitaxel (IMpower150) also provided PFS and OS superiority over chemotherapy alone in patients with advanced nonsquamous NSCLC.^[4,6]

ICIs in Early-stage Resectable or Locally Advanced, Unresectable NSCLC

Concurrent chemoradiotherapy plays a pivotal role in patients with locally advanced, unresectable NSCLC. How to prevent metastases and improve the survival is essential for these patients after definitive treatment. Recently, the PACIFIC study demonstrated consolidation immunotherapy with durvalumab was effective in patients with locally advanced NSCLC after completed definitive chemoradiotherapy.^[10] In PACIFIC study, durvalumab yielded significant improvements in median PFS compared with placebo (17.2 vs. 5.6 months). The updated OS analyses also demonstrated a clinically meaningful OS benefits with consolidation durvalumab vs. placebo (not reached vs. 29.1 months).^[11] The findings from PACIFIC study established consolidation durvalumab as the standard of care for patients with locally advanced NSCLC after completed definitive chemoradiotherapy.

A previous study has revealed that immune suppression may occur at pre-invasive stages of cancer development,^[12] suggesting a possible role of ICIs in early-stage NSCLC. A pilot study investigated the safety and efficacy of nivolumab as neoadjuvant therapy in resectable early-stage NSCLC.^[13] In 21 patients, 20 achieved complete resection with acceptable side-effect profile. Notably, despite only two patients had partial response, 9 of 20 (45%) patients had a major pathologic response (MPR, defined as 10% residual tumor present). Several studies also demonstrated the promising role of neoadjuvant PD-1/PD-L1 inhibitors either as monotherapy or in combination with ipilimumab or chemotherapy. Although the role of MPR as the primary endpoint is questionable, multiple phase III studies are ongoing to evaluate the long-term benefits of neoadjuvant ICI treatment in patients with early-stage, resectable NSCLC. Furthermore, ongoing studies are also evaluating the role of ICI as adjuvant therapy in stage I-IIIA NSCLC after definitive surgical resection.

Predictive Biomarkers

Despite rapid advances of ICIs in NSCLC, only a minority of patients respond to single-agent ICI treatment. Even in a highly selected patient population (PD-L1 TPS ≥50%), only 44.8% of patients achieved an objective response when treated with pembrolizumab monotherapy.^[1] Due to the complex immune response process, any single biomarker may not be effective and reproducible enough to predict the benefits of ICIs. For instance, although PD-L1 expression has been widely used for patient selection, several limitations make it an imperfect biomarker, including spatial-temporal heterogeneity of PD-L1 expression, high discordance in PD-L1 expression read on immune cells, and different cutoffs used in each assay. Tumor mutation burden (TMB) is another potential biomarker. In CheckMate-227 study, for patients with high TMB (≥10 mutations per megabase), nivolumab plus ipilimumab resulted in longer PFS (7.2 vs. 5.5 months, P < 0.001) and higher ORR (45.3% vs. 26.9%) compared with chemotherapy alone.^[14] However, the OS benefits were independent of TMB level.^[15] Recently, a combined biomarker analysis revealed that T-cell-inflamed gene-expression profile, PD-L1 expression, and TMB may help identify patients who are more likely to derive benefits from ICI treatment.^[16] These findings indicate a direction to pursue predictive biomarkers in further studies. We should integrate multiple biomarkers to better reflect the complex cancer-immune interactions between the tumor, tumor microenvironment and host immunity.

Immune-related Adverse Events (irAEs)

With the growing use of ICIs in oncology, awareness and management of irAEs become more important. Unlike the toxicity profiles of classical chemotherapy, irAEs may occur in wide ranges of organs, as consequences of nonspecific and excessive activation of immune system. In a recent meta-analysis involving 16 trials and 6208 patients with advanced NSCLC, the overall incidence of irAEs was 22% for all grades and 4% for grade ≥3 irAEs.^[17] In addition, fatal irAEs were observed in 0.34% of patients and most deaths (79%) were attributed to pneumonitis.^[17] Therefore, ICIs were generally well-tolerated and the majority of irAEs can be successfully managed with corticosteroids or other immunosuppressive agents based on the guidelines on the management of irAEs.

Corticosteroids Use

As mentioned above, corticosteroids are the mainstay for the management of irAEs and commonly used in patients with NSCLC in a variety of conditions. Given the immunosuppressive effects of corticosteroids and pleiotropic impact on T-cell function, concerns regarding the adverse effect of corticosteroids use on the outcomes of ICIs arose. In a recent retrospective study, baseline corticosteroid use of ≥10 mg of prednisone was associated with inferior clinical outcomes in patients with NSCLC when receiving ICIs.^[18] Ricciuti et al^[19] further investigated the effect of different reasons for corticosteroids uses (cancer-related palliative reasons vs. cancer-unrelated indications) on outcomes of patients with advanced NSCLC who were administrated with ICIs. Interestingly, patients who received ≥10 mg of prednisone for cancer-related palliative reasons had poorer outcomes than those who received ≥10 mg of prednisone for cancer-unrelated indications or 0 to 10 mg of prednisone. In light of current evidence, necessary corticosteroid uses therefore should not be decreased or discontinued before the start of ICI treatment.

Hyperprogression and Pseudoprogression

Hyperprogressive disease (HPD) is an atypical response pattern of ICI treatment, characterized by an acceleration of tumor growth kinetics. The incidence of HPD in patients with advanced NSCLC after ICI treatment varied from 9% to 20%.^[20] In a large-sample cohort including 406 advanced NSCLC patients treated with ICIs, 13.8% (56/406) of patients experienced HPD, with a dismal OS of only 3.4 months.^[21] Several clinical or genetic factors have been identified to be associated with HPD, including increased age (>65 years), more than two metastatic sites before ICI treatment, a lower frequency of effector/memory subsets of T cells or EGFR alterations, STK11 mutations, MDM2/4 amplifications.^[22] However, the molecular and immunological bases of HPD remain unclear. A better understanding of the biology of HPD is essential to avoid this detrimental effect of ICI-based therapy on outcomes.

Pseudoprogression represents another atypical response pattern of ICI treatment, which was characterized by initial disease progression but followed by radiologic tumor remission with continued use of ICIs. Pseudoprogression is considered as a result of infiltration of inflammatory cells, hemorrhage, edema or necrosis upon ICI treatment, which lead to accumulated tumor lesions temporarily. This phenomenon was uncommon and found in only 5% of patients with advanced NSCLC treated with ICIs.^[21] In clinical practice, the unidimensional immune-related response criteria or the immune Response Evaluation Criteria in Solid Tumors (RECIST) criteria were helpful in distinguishing radiologic pseudoprogression from true progression. Furthermore, circulating tumor DNA (ctDNA) levels may be useful for early recognition of pseudoprogression in patients during ICI treatment.

Overcoming Primary and Acquired resistance to ICIs

As mentioned above, although predictive biomarker could help identify patients who may benefit from ICI treatment, a substantial number of patients still do not respond to ICIs, namely primary resistance. A characterization of hot, altered (immunosuppressed/excluded) and cold tumor phenotypes on the basis of the level and spatial distribution of CD3+ and CD8+ T cell infiltration may help understand the mechanisms of primary resistance.^[23] Hot tumors, characterized by a high degree of T cell infiltration, represent a tumor phenotype that is suitable for ICI monotherapy or immune-oncology combinations.^[23] For altered-immunosuppressed immune tumors or altered-excluded immune tumors, varied combination therapies are needed to eliminate the immunosuppressed tumor microenvironment (inhibitory molecules, including transforming growth factor-β, interleukin-10 and vascular endothelial growth factor or inhibitory immune cells, including myeloid-derived suppressor cells and Treg cells) and facilitate T cells into the center of tumor (combined with T cell trafficking modulators or physical barrier breakers). For cold tumors, the principle of treatment is to turn cold tumors into hot tumors. ICI in combination with chemotherapy or radiotherapy has been proved effective in patients with NSCLC. Furthermore, how to manage acquired resistance to ICI treatment continues to be a challenge. Varied combinations of PD-1/PD-L1 inhibitors and other checkpoint molecules (cytotoxic T lymphocyte antigen 4 [CTLA-4], T cell immunoglobulin domain and mucin domain-3 [TIM-3], lymphocyte activation gene-3 [LAG-3]), immune-stimulatory agents, metabolic modulators and other immune modulators are being investigated to overcome resistance to ICI treatment.

In the future, a considerable amount of work still needs to be done to maximize the efficacy of ICI treatment and bring about long-term survival in patients with lung cancer.

Funding

This study was partially supported by a grant from the National Natural Science Foundation of China (No. 81703020).

Conflicts of interest

None.

Supplementary Material

cm9-134-1135-s001.pdf ^{(81.2KB, pdf)}