PD-1/PD-L1 blockade therapy with atezolizumab: a new paradigm in the treatment of non-small cell lung cancer (NSCLC).

Introduction

The lung cancer neoplasm is considered to be responsible for almost one-third of cancers and has the highest incidence worldwide. Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death. Cases of lung cancer include NSCLC, adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and large cell carcinoma [ 1 ]. Nearly 80–85% of all lung cancers are NSCLC, and 20% of the cases are diagnosed with the stage of locally advanced NSCLC. Despite significant development in recent years, the prognosis of non-small cell lung cancer remains poor, with elevated rates of local recurrences and metastases [ 2 , 3 ]. Since most of the patients are diagnosed at the latter stage of lung cancer, survival prognosis designation is challenging [ 4 ]. In more than half of patients, recurrences of radically resected NSCLC, often in distant sites, occur 2 years after surgery [ 5 , 6 ]. Epidemiological evidence indicates that if left untreated, the midpoint in the survival of NSCLC cases is < 8 months. Due to the lack of prior diagnosis and following therapy, the 5-year overall survival for NSCLC is < 20% [ 7 ]. The tumor microenvironment (TME) plays a critical role in the start of malignancies through aberrant function command of tissue step by step. In the first steps of tumor growth, a dynamic and mutual connection is made within parts of TME constituent and cancer cells to assist cancer cells' invasion, survival, and metastasis.

The TME components differ based on the type of tumor, but the main constitutive parts are immune cells, stromal cells including fibroblasts, and extracellular matrix (ECM) [ 8 , 9 ]. Clinical outcome and therapeutic response remarkably depend on the TME; its targeting strategies have recently emerged as an encouraging approach for cancer treatment [ 10 – 14 ]. Programmed death-ligand 1 (PD-L1) expression is repeatedly seen in TME of human cancers. PD-L1 (CD274; encoded by the CD274 gene) was the first discovered ligand of PD-1. Its position on the human chromosome is 9 p24.2 and belongs to the B7 family. PD-L1 is widely expressed in lymphocytes, macrophages, dendritic cells (DCs), and activated T cells, which cooperate in the immunosuppressive microenvironment and lead to tumor growth. Furthermore, PD-L1 is also expressed in non-blood cells, including vascular endothelium, mesenchymal stem, reticular fibroblasts, astrocytes, and keratinocytes [ 15 , 16 ]. Tumor immune escape mechanisms, such as immunosuppression, are a climactic approach for tumor survival. The signaling pathway of PD-L1/PD-1 is a significant part of tumor immunosuppression, suppressing T lymphocyte activation, developing tumor cells' immune tolerance, and achieving tumor immune escape [ 16 ]. High levels of PD-L1 are expressed in different cancers, and the PD-L1/PD-1 signaling pathway is exploited to evade T cell immunity [ 17 ]. The blockade of PD-1/ PD-L1 is actively being investigated in non-small-cell lung cancer [ 18 ]. About 16% to 50% response rates have been demonstrated in phase I–III trials studying the efficacy of PD-1/ PD-L1 immune checkpoint inhibitors in NSCLC [ 19 ]. Although notable prolonged overall survival is achieved in patients with NSCLC, a small group could benefit from monotherapy. Therefore, various approaches in combination therapy are used to boost clinical efficacy [ 20 ]. Immunotherapeutic strategies approved for treating patients with NSCLC today include monotherapy and a combination of chemotherapy and immunotherapy [ 21 ]. Additionally, recent immunotherapy approaches, including immune checkpoint inhibitors, have significantly transformed the landscape of NSCLC treatment [ 22 ]. Atezolizumab is effective in multiple treatment settings, including as a first-line therapy for metastatic nonsquamous NSCLC and in subsequent lines of therapy after progression on chemotherapy. This flexibility allows it to be utilized in a broad range of patient scenarios, enhancing its therapeutic value. Herein, we have focused on the clinical data of atezolizumab therapy alone or in combination with other therapeutics for NSCLC therapy.

Non-small cell lung cancer (NSCLC) pathogenesis

Lung cancer, as the second most prevalent cancer, is the leading cause of cancer-related deaths in the USA [ 23 ]. Non-small-cell lung cancer is a heterogeneous type of tumor and represents nearly 85% of diagnoses of new lung cancers [ 24 ]. NSCLC incorporates a variety of lung cancers, such as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Adenocarcinoma includes one-half of cases of all lung cancer and is the standard type of this category. Another type of NSCLC, squamous cell carcinoma, generally emerges at the beginning of the tracheobronchial tree, but more cases are now diagnosed in the periphery of the lung [ 25 ]. There are two main histological classifications of lung cancers: small-cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs). Each cancer subtype has various ways of responding to treatment; therefore, they are studied as separate diseases. 15–20% of lung cancers include SCLCs, which proliferate and are represented as moderate or extensive phases [ 26 ].

Regarding the diagnosis, prognosis, and possibility of targeted therapeutic treatment, the molecular characterisation of lung cancer provides important information. In advanced-stage pulmonary adenocarcinomas, many now consider screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements to be the standard of care due to additional proof that targeted therapy is an effective benefit over conventional chemotherapy when applied to the right patients [ 27 ]. About 5% of NSCLCs have an ALK gene rearrangement, which most often results in an EML4-ALK fusion gene [ 28 , 29 ]. Given the availability of crizotinib, a recently authorized targeted medication that exhibits action against the kinases of the products of the ALK, ROS1, and MET genes, it is crucial to identify individuals with this rearrangement. Early research assessing crizotinib's effectiveness in patients with ALK rearrangement revealed a 61% overall response rate [ 30 ]. Phase II and III studies quickly developed as a result, and in 2011, the FDA approved crizotinib expedited based on the first evidence from those trials.

The treatment strategy is selected by considering morphological identification, clinical stage, and patient condition. For early NSCLC, surgery is a treatment choice, although approximately 20% of cases benefit from curative surgery. Biological therapies and chemotherapy are used in the locally advanced and metastatic stages, and recently, immunotherapy is also available [ 31 , 32 ]. In targeted therapy, many specific targets for therapeutic agents are identified due to progress in the study of molecular pathogenesis [ 33 ]. The extensive comprehension of the biology of tumors and improvement in the diagnosis and treatment of cancer has led to a 5% advance in the five-year survival rate over the past two decades [ 34 ]. Five-year survival remains low, although early detection and novel approaches for prevention compensate for short survival rates [ 35 ]. Patients with advanced-stage non-small lung cancer, which was already treated, have poor clinical outcomes. Over the best supportive care and chemotherapy, the survival rate is roughly less than one year [ 36 ]. However, almost 85% of the diagnoses of lung cancer are in advanced stages (III or IV), which is accompanied by the minimum therapeutic choices [ 37 ]. NSCLC may result in some symptoms, including persistent cough, dyspnea, and pain. Acute symptoms are correlated with excess anxiety, impairment in functioning, and decline in health-related quality of life (HRQL) [ 38 ]. Universally, the stage of the patient's tumor and the presence of a residual tumor determine whether the patient receives adjuvant therapy, according to NCCN Guidelines Non-Small Cell Lung Cancer version 7.2021. The size of the tumor determines the cancer stage and if it has spread to other organs. Cancer patients will be monitored or given medication at every stage if no residual tumor is found. Chemotherapy, immunotherapy (atezolizumab), and targeted therapy (osimertinib) are advised for all cancer patients, except for stage IA, who have no residual cancer. Reresection with chemotherapy or RT with chemotherapy is advised for patients in the IB or IIB stages if the remaining tumor is found. Chemoradiation therapy is a further therapeutic option for individuals over stage IIB who had margins that were positive (Fig. 1 ).

PD-1/PD-L1 pathway

PD-L1, also known as B7-H1, is a ligand of the programmed death receptor 1 (PD-1) encoded by the CD274 gene, localized on 9p24.1 chromosome [ 39 ]. PD-L1 is demonstrated to mediate tumor immune escape by interacting within the TME [ 40 ]. PD-L1 binding on the surface of tumor cells to PD-1 results in T cell response blockage, promoting the development and function of regulatory T cells, induction of self-tolerance, and immune tolerance to inhibit extreme immune reactions (Fig. 2 ) [ 41 ]. There is a signal sequence defined for PD-L1 consisting of an IgC-like domain, a transmembrane domain, an IgV-like domain, and a short intracellular region with a signal transduction role which has highly conserved motifs needed for interferon-mediated cytotoxicity regulation [ 42 ]. The abnormal function of PD-L1/PD-1 signaling is noticed in chronic Helicobacter pylori infection, inflammatory bowel diseases (IBD), celiac and cancers [ 43 ]. PD-L1 expression is observed in multiple tumors such as glioblastoma, melanoma, lung cancer, gastric cancer, renal cancer, colorectal cancer, breast cancer, pancreatic cancer, and ovarian cancer. PD-L1 is also expressed in hematologic malignancies, including lymphoma, multiple myeloma, and different types of leukemia [ 44 ]. Atezolizumab, durvalumab, and avelumab the therapeutic monoclonal antibodies against PD-L1 have achieved FDA approval [ 45 ]. PD-L1 expression is detected in T cells, B cells, macrophages, and DCs [ 46 ]. Through two main mechanisms, tumor cells express PD-L1, which inhibits immune elimination: innate and adaptive immune resistance [ 47 ]. In innate resistance, PD-L1 is expressed constitutively on tumor cells due to gene amplification of PD-L1 or abnormal emergence of oncogenic signaling pathways. MicroRNA-200/ZEB1 axis activation in NSCLC is reported to lead to PD-L1 upregulation in tumor cells [ 48 ]. In adaptive immune resistance, cytokines such as interferon γ are responsible for developing PD-L1 expression. High levels of PD-L1 are related to effector T cell producing IFNγ in the TME [ 49 ]. It is indicated that two signaling pathways, the Janus kinase (JAK)/STAT and mitogen-activated protein kinase (MAPK), play a pivotal role in PD-L1 expression induced by IFNγ. The binding of the signal transducer and activator of transcription 3 (STAT3) to the promoter of the CD274 gene was correlated with gene expression of PD-L1 [ 50 ]. The discovery of the PD-1/PD-L1 pathway dates back two decades ago, but the therapeutic potential was not recognized immediately. By detecting the immunosuppressive role of the PD-1/PD-L1 signaling pathway, researchers figured that inhibiting this pathway could assist tumor elimination and hinder its metastasis [ 51 ].

PD-L1 as a biomarker

Studies in PD-L1 protein expression in tumors demonstrated encouraging results for applying this protein as a predictive biomarker to PD-L1 blockade [ 52 ]. The expression of PD-L1 in the TME is intricate. Aberrant genetic alterations are linked to its upregulation at transcriptional and posttranscriptional levels or protein levels [ 53 ]. High level of PD-L1 tumors is related to patients who probably respond positively to anti-PD-L1 treatment clinically [ 54 ]. Evaluation of PD-L1 expression is currently being utilized as a routine practice, but challenges accompany it. Knowledge about PD-L1 characteristics plays a vital role in pathologists' accurate interpretation of IHC outcomes and enlightens physicians about the most beneficial treatment choices [ 55 ]. Nevertheless, the predictive role of using PD-L1 is controversial. Because of tumor heterogeneity and individual variability, immunohistochemistry of Anti-PD-L1 may not show the actual status of the tumor. Also, using different assays and antibodies to detect PD-L1 brings about analytical variability [ 56 ]. The use of PD-L1 immunohistochemistry as a prognostic biomarker is accompanied by several unresolved problems: preparation of the tissue, varied IHC cutoffs, variability processing, primary vs metastatic biopsies, and tumor staining vs immune cells staining [ 57 ]. The anti–PD-L1/PD-1 immunotherapies clinical trials that the FDA approved used various platforms of IHC, each with their scoring systems with different antibodies against PD-L1 (22C3, 28–8, SP263, SP142) for analysis of PD-L1 expression on either tumor or immune cells. Investigations for PD-L1 IHC synchronization for staining and antibodies are underway [ 58 ].

The correlation between PD-L1 expression in tumor and prognosis

In the number of 158 enrolled patients, 17.1 months of the median progression-free survival (PFS) and 68% of the objective response rate (ORR) were achieved. Evaluations revealed that PFS was remarkably shorter in the group with high PD-L1 expression than in the low or no PD-L1 group. Besides, PD-L1 expression was not correlated to the obtained ORR [ 59 ]. Expression of PD-L1 was analyzed via immunohistochemistry among 108 patients with surgically resected primary NSCLC. Patients with PD-L1 expression had remarkably shorter OS (median OS: 33 months) than those without PD-L1 expression (median OS: 96 months). Multivariate analysis also showed that male sex, expression of PD-L1, and higher metastasis of tumor were notably associated with shorter OS. PD-L1 expression in NSCLC patients is an independent predictive factor for poor survival [ 60 ]. A total of 249 stage III NSCLC patients were stained immunohistochemically with PD-L1, which was evaluated at 68.4%. PD-L1 negative patients had 15.9 months, and PD-L1 positive patients had 16.1 for median PFS and 29.9 to 28.5 months for median OS, respectively. In general, the expression of PD-L1 had no predictive value toward OS and PFS [ 61 ]. A total of 90 patients with operable NSCLC were evaluated with immunohistochemical staining with PD-L1 polyclonal antibody. According to the percentage of PD-L1 staining, its expression was calculated at about 37%. PD-L1 was expressed partly higher in men, smokers, more than 65 years old age, and advanced tumor stage, especially the squamous cell subtype patients. Unlike the median OS, which was significantly longer in the PD-L1 negative group (48 versus 24 months), no considerable difference was obtained from the disease-free survival time compared to the PD-L1 positive and negative groups. In NSCLC patients, PD-L1 expression appears to be a poor prognostic factor [ 62 ]. The result of the IHC analysis of 11 NSCLC patients for PD-L1 expression was acquired. There is a correlation between high expression of PD-L1 and poor prognosis. Patients with low expression of PD-L1 had significantly longer median OS than patients with high expression of PD-L1 (27 to 36 months vs 10 months) [ 63 ]. PD-L1 expression in circulating tumor cells (CTCs) was evaluated by qPCR and immunofluorescence, and PD-L1( +) was calculated at 69.4%. PD-L1 negative patients had a longer PFS than PD-L1 positive patients (median 7.1 months). Assessment of gene expression showed that higher levels of PD-L1 were correlated with poor prognosis [ 64 ]. In NSCLC patients, 170 samples using the clone 22C3 pharmDx kit were probed for PD-L1 expression. Unlike squamous carcinoma patients, who showed significantly higher PD-L1 expression, patients with early-stage resectable lung cancer seem to have lower expression of PDL1. The univariate survival analysis presented longer OS in the PD-L1 negative group. (67.6 months) vs. 57.9 months of the PD-L1 positive group [ 65 ]. 39 Patients with advanced NSCLC were enrolled in a single-center cohort study to assess PD-L1 expression on circulating tumor cells (CTCs). In patients with CTC negative, the median OS was evaluated at 2.2 months versus 16.0 months for patients with CTC positive. There was no correlation between PD-L1 expression of CTCs and tumor tissue. Expression of PD-L1 on CTCs has been managed as a promising biomarker in patients with NSCLC [ 66 ]. 107 patients were analyzed with immunohistochemical staining to evaluate the correlation of PD-L1 expression with clinical parameters. According to the PD-L1 expression, there were no considerable differences in age, gender, and smoking status of the patient. Median PFS was shorter in patients with PD-L1 expression (10.1 months vs 19.9 months). Median OS was 28.4 in patients without PD-L1 expression and 12.1 months in patients with PD-L1 expression. As a result, the expression of PD-L1 was a negative predictive agent for OS and PFS in LA NSCLC [ 67 ]. An immunohistochemical assessment was performed in 211 NSCLC samples of stages I-III squamous cell carcinoma (SQ) and stage I NSCLC. After multivariate analysis, it was revealed that PD-L1 expression is an independent predictor of poor outcome [ 68 ]. Tissue microarrays (TMAs) and immunohistochemical (IHC) analysis of 866 samples of NSCLCs showed PD-L1 expression to be 32.6%. Higher levels of PD-L1 expression in NSCLC cells were associated with higher lymph node status and higher malignancy rate in addition to shorter patient survival, mainly in the adenocarcinoma (AC) group [ 69 ]. An immunohistochemistry assay was used to assess the expression of PD-L1 in 70 NSCLC patients. Outcomes included 87.14% PD-L1 expression and no correlation between PD-L1 with survival or clinicopathological features, and its overexpression was not a remarkable prognostic factor [ 70 ]. In 678 I-III stages of NSCLC, PD-L1 expression was assessed using clone 22C3 immunohistochemistry. Tumors showing PD-L1 expression were considered in 32.8% of cases, and high PD-L1 expression was associated with longer OS, younger patient age, and high tumor grade. In conclusion, PD-L1 seems to be a desirable predictive factor in early-stage disease [ 71 ]. As a result of evaluating tumor cells of 321 clinical patients with NSCLC using immunohistochemistry, PD-L1 expression was shown to be 24% of the NSCLC cases. Interestingly, in tumor cells of pulmonary squamous cell carcinomas, expression of the PD-L1 was correlated with increased overall and positive status of lymph nodes [ 72 ].

Table 1 summarizes studies evaluating PD-L1 expression in NSCLC patients and its relation to patients' survival.

Atezolizumab as a PD-L1 inhibitor

OAK study analysis

Atezolizumab (anti- PD-L1) was approved for formerly treated advanced non-small-cell lung cancer according to the OAK study, a randomized, open-label phase III trial ( NCT02008227 ) that exhibited remarkably longer survival to the administration of atezolizumab against docetaxel despite of expression of PD-L1 or absence of PD-L1. After almost 2 years of follow-up, characteristics of long-term survivors (LTSs) were attained. The outcomes suggest a stable survival benefit of atezolizumab regardless of histology, PD-L1 expression, or subsequent immunotherapy. Atezolizumab extended, providing long-lasting survival benefits with tolerable safety. The LTSs included high and low PD-L1 expression and PD-L1-negative patients [ 73 ]. In the OAK study, 1225 patients received 1200 mg atezolizumab or 75 mg/m2 docetaxel every 3 weeks. A longer OS (median OS = 13.3) was detected in patients who received atezolizumab compared to docetaxel in all groups of histology and PD-L1 expression. In 16% of 4-year survivors related to atezolizumab treatment, grade 3/4 adverse events happened [ 74 ]. For more validation of the clinical benefit of atezolizumab, patient-reported outcomes (PROs) were gathered. Atezolizumab boosts patients' health-related quality of life (HRQoL) numerically compared to docetaxel. Besides, compared to docetaxel, Atezolizumab delayed the time to deterioration (TTD) of patients' physical functions [ 75 ]. For further analysis of the randomized OAK study, relevant clinical criteria for fast progression (FP) were developed, including the kinetics of tumor growth and early death. FP is described as either death due to cancer development or an increase in the total of the largest diameters. FP rates in atezolizumab and docetaxel administration were the same [ 76 ]. The pooled data from phase III OAK trials suggest that in patients with metastatic NSCLC, antibiotics (ATB) or proton pump inhibitors (PPI) are correlated with poor outcomes. In patients treated with either immune checkpoint inhibitors (ICI) or chemotherapy, it may impact the efficacy of ICI [ 77 ]. The efficacy and safety of atezolizumab and docetaxel in patients in terms of a history of treated brain metastases were assessed in the OAK trial. The prolonged median OS in patients with or without a history of asymptomatic, treated brain metastases (almost 14%) was achieved with atezolizumab compared to docetaxel [ 78 ]. Subgroup analyses of pretreated Japanese patients with NSCLC in the phase 3 OAK studies were performed. Atezolizumab was mainly well tolerated, and no treatment-related deaths were reported. The median OS was 21.3 months, and the outcomes matched the original assessment of OAK [ 79 ].

Monotherapy

The Phase II Trial of BIRCH efficacy of atezolizumab in advanced non-small-cell lung cancer (NSCLC) was examined. BIRCH indicated acceptable tolerability responses with atezolizumab monotherapy. The status of PD-L1 expression acts as a prognostic biomarker to select patients who would likely benefit more from therapy. The 152 patients with advanced NSCLC received atezolizumab. The monotherapy results showed good efficacy and safety and a median OS of 12.8 months [ 80 , 81 ]. A phase I study of single-agent atezolizumab in patients with NSCLC reported that atezolizumab was well tolerated with durable responses and survival benefits. The median duration of response was 16 months, ORR in all patients was 23%, and grade III/IV of treatment-related adverse events (TRAEs) was observed in 11% of patients. With increasing PD-L1 expression, more improved responses were observed in NCT01375842 [ 82 ]. The phase III/IV TAIL study was conducted, and 615 NSCLC patients received 1200 mg intravenous atezolizumab every 3 weeks. In the 12.6-month median follow-up, the median OS and PFS were 11.1 and 2.7 months, respectively. TRAEs occurred in 7.8% NCT03285763 [ 83 ]. In the phase II study, the safety and efficacy of atezolizumab in 138 patients with advanced NSCLC were evaluated. 1200 mg atezolizumab in 21 days was administered. For cohorts 1, 2, and 3, ORR was 32%, 21%, and 23%, respectively, and TRAEs were reported in 81%, 67%, and 69% of patients NCT01846416 [ 84 ].

Combination with other targeted therapies

In a phase II study, 15 mg/kg bevacizumab and 1200 mg atezolizumab were investigated for advanced nonsquamous NS-NSCLC patients who expressed PD-L1 ≥ 50%. Atezolizumab with bevacizumab as an epidermal growth factor receptor (EGFR) inhibitor prolongs OS and functions as a potential treatment [ 85 ]. The efficacy and safety of 1200 mg atezolizumab plus 600 mg tiragolumab (anti-TIGIT inhibitory agent) as first-line treatment for PD-L1-positive NSCLC patients was assessed in phase 2, randomized CITYSCAPE trial. Atezolizumab plus tiragolumab was well tolerated and significantly improved ORR and PFS, with a median PFS of 5.4 months in the combined group. TRAEs were seen in 21% of patients who received tiragolumab and atezolizumab, and the safety profile was almost the same as that of a single atezolizumab [ 86 ]. In the phase 1b study, the efficacy of atezolizumab and T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitor ipilimumab in 27 melanoma and NSCLC patients was investigated. The median duration of response and OS was 23.0 and 36.9 months, respectively. Atezolizumab plus ipilimumab had a safety profile similar to the individual agents, and no toxicities were seen during dose escalation [ 87 ]. A phase 3 study investigated the efficacy of atezolizumab plus bevacizumab and chemotherapy in patients with nonsquamous metastatic NSCLC. In the combined group, the median PFS and OS were 8.3 months and 19.2 months, respectively, and the safety profile was consistent with each medicine NCT02366143 [ 88 ]. In a phase 1b-2 study in which 99 patients were enrolled daratumumab (anti-CD38-positive cells) plus atezolizumab were administered. The ORR was 4.3% in the combination group compared to 13.0% for individual atezolizumab, and no differences were seen in the median PFS and OS in combined therapy [ 89 ]. A phase 2 study assessed the efficacy of bevacizumab plus atezolizumab in 66 patients with metastatic NSCLC. PFS was 5.6 months and the OS was 14.0 months. Grade 1 or 2 TRAEs occurred in 25% of the patients [ 90 ].

Combination with chemotherapy

In Chinese patients with stage IV, nonsquamous NSCLC efficacy and the safety of atezolizumab, carboplatin, and nab-paclitaxel combination versus carboplatin and nab-paclitaxel was assessed. The PFS (12.98 months) and OS (38.04 months) were enhanced by the addition of atezolizumab and grade ≥ 3 adverse events happened [ 91 ]. IMpower010, the randomized, phase 3 study in patients with resected stage II-IIIA NSCLC, showed promising results after atezolizumab and adjuvant chemotherapy. The disease-free survival was improved with particular benefit in the PD-L1 positive subgroup. NCT02486718 [ 92 ]. IMpower130, the randomized, phase 3 study, evaluated the efficacy of atezolizumab plus chemotherapy compared to single chemotherapy for stage IV nonsquamous NSCLC. A significant improvement in OS and PFS was seen in atezolizumab plus chemotherapy as the first-line treatment. NCT02367781 [ 93 ]. In an open-label phase 2 (POPLAR) trial, patients with NSCLC were assessed after atezolizumab vs docetaxel administration. Single atezolizumab, compared to docetaxel, showed a safety profile and was well tolerated, leading to a significant survival improvement associated with PD-L1 expression on tumor cells. NCT01903993 [ 94 ]. A multicenter Phase II study evaluated the efficacy and safety of metronomic oral vinorelbine chemotherapy plus atezolizumab in advanced NSCLC. Median PFS and median OS are at 4 months NCT03801304 [ 95 ]. 171 metastatic nonsquamous NSCLC who expressed PD-L1 received atezolizumab plus carboplatin and nab-paclitaxel or carboplatin and nab-paclitaxel. The duration of follow-up was 27 months, and the median OS and PFS were 19.9 months and 8.5 months, respectively. The combination had a tolerable safety profile, and AEs were manageable [ 96 ]. A randomized, phase 3 trial aimed to assess the effectiveness of chemotherapy and atezolizumab in patients with metastatic nonsquamous or squamous NSCLC who had PD-L1 expression. The median OS was longer in the atezolizumab group compared to the chemotherapy group (7.1 months). Among all the patients who could be evaluated for safety, AEs happened in 90–94% of the patients. Atezolizumab was shown to have significantly longer OS compared to platinum-based chemotherapy NCT02409342 [ 97 ]. The phase III IMpower131 study assessed atezolizumab plus platinum-based chemotherapy (atezolizumab + carboplatin + nab-paclitaxel) in 1021 stage IV squamous NSCLC. PFS and OS improvement was noticed in the atezolizumab group versus chemotherapy (6.3 vs 5.6 months) (14.2 and 13.5 months) NCT02367794 [ 98 ]. An open-label, phase 3 IMpower132 study evaluated the efficacy of atezolizumab and pemetrexed, cisplatin, and carboplatin chemotherapy as first-line treatment for advanced NSCLC (n = 101). atezolizumab plus platinum-based chemotherapy was well tolerated in advanced NSCLC despite grade 3/4 incidence of TRAEs [ 99 ]. In a phase II study performed in two parts, NSCLC patients received atezolizumab plus chemotherapy. In part 1 (n = 10), median PFS and OS were 18.6 and 22.8 months, and in part 2 (n = 30), PFS was 13.2 months, and OS did not reach [ 100 ]. The 76 NSCLC patients received atezolizumab plus chemotherapy. In carboplatin plus paclitaxel, pemetrexed, and nab-paclitaxel groups, median PFS was 7.1, 8.4, and 5.7 months, and median OS was 12.9, 18.9, and 17.0 months, respectively. The combination was well tolerated NCT01633970 [ 101 ].

A summary of clinical studies based on atezolizumab therapy in NSCLC patients has been cited in Table 2 .

Conclusion

Atezolizumab therapy has made significant strides in the treatment of non-small cell lung cancer (NSCLC), but several future directions and challenges remain that could impact its efficacy and accessibility.

While atezolizumab has shown promise, there is a need to improve its efficacy further. Research is ongoing to identify biomarkers that can predict which patients will benefit most from atezolizumab therapy. Understanding the molecular features of tumors may help tailor treatments more effectively, potentially leading to better outcomes for patients with advanced NSCLC. The integration of atezolizumab with other treatment modalities, such as chemoradiation, is being explored to enhance its effectiveness. For instance, the DETERRED trial is assessing the safety and efficacy of atezolizumab in combination with chemoradiation for unresectable NSCLC, which could pave the way for new treatment protocols.

Future studies may focus on optimizing these combinations to maximize patient benefits.

One of the significant challenges is the limited access to immune checkpoint inhibitors like atezolizumab, particularly in developing countries. The high cost of these therapies can restrict their availability, leading to disparities in treatment outcomes. Addressing these access issues is crucial for ensuring that all patients can benefit from advancements in NSCLC treatment. Atezolizumab also can cause immune-related adverse effects, which may complicate treatment. Ongoing research is needed to better understand these side effects and develop strategies for their management. This includes identifying patients at higher risk for severe reactions and implementing monitoring protocols to mitigate these risks.

The use of atezolizumab in neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings is an area of active investigation. Trials are underway to evaluate its effectiveness in these contexts, which could expand its role in the treatment continuum for NSCLC and potentially improve long-term outcomes. Understanding the long-term outcomes of patients treated with atezolizumab is essential, particularly regarding the development of resistance to therapy. Research into the mechanisms of resistance will be vital for developing strategies to overcome it and improve the durability of responses in NSCLC patients.

In summary, while atezolizumab has established itself as a critical component in the treatment of NSCLC, ongoing research and attention to the challenges of efficacy, access, side effects, and resistance will be essential for optimizing its use and improving patient outcomes in the future.

Author contributions

S.M, P.S, R.J.A, W.M.T, M.A, N.V, M.J.J and H.M wrote the main manuscript text and H.M prepared Figs. 1 and 2. All authors reviewed the manuscript.

Funding

No funders.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.