FANG Wenfeng, ZHANG Li(Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China)
Corresponding author: Zhang Li
E-mail:[email protected]
Professor Zhang Li
Director of the Department of Internal Medicine, Sun Yat-sen University Cancer Center, doctoral supervisor, second-level professor, chief expert of lung cancer
Chairman of the Cancer Rehabilitation and Palliative Care Committee of the Chinese Anti-Cancer Association (CACA).
He is the chairman-elect of the Oncology Drug Clinical Research Committee of the Chinese Anti-Cancer Association (CACA).
Executive Director of the Chinese Society of Clinical Oncology (CSCO).
He is the chairman-elect of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman of the Non-Small Cell Lung Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman of the Expert Committee of Tumor Support and Rehabilitation Therapy of the Chinese Society of Clinical Oncology (CSCO).
Chairman of the Clinical Research Branch of Guangdong Medical Association
Chairman of the Precision Medicine Branch of Guangdong Clinical Medical Association
Prof. Wenfeng Fang
Chief physician and professor of Sun Yat-sen University Cancer Prevention and Treatment Center, PI of the State Key Laboratory of Zhongma and doctoral supervisor
Young talents of the National High-level Talent Program
Guangdong Province Special Support Program for Millions of Project Young Top-notch Talents
Outstanding Young Medical Talent of Guangdong Province
Guangzhou Pearl River Science and Technology Rising Star
He is a member of the Non-Small Cell Lung Cancer Professional Committee of the Chinese Society of Clinical Oncology (CSCO).
Member of the Nasopharyngeal Carcinoma Professional Committee of the Chinese Society of Clinical Oncology (CSCO).
He is a member of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Nasopharyngeal Cancer Professional Youth Committee of Guangdong Anti-Cancer Association
Vice Chairman of the Precision Medicine and Molecular Diagnosis Professional Committee of Guangdong Medical Association
Vice Chairman of the Real World Clinical Research Professional Committee of Guangdong Clinical Medical Association
【Abstract】In recent years, a revolutionary breakthrough has been made in the treatment of non-small cell lung cancer (NSCLC), and immunotherapy regimens represented by programmed cell death protein 1 and programmed cell death ligand 1 inhibitors run through all stages of NSCLC treatment. From immune monotherapy to combination chemotherapy, the KEYNOTE series of studies has achieved good results, and the 5-year survival data of patients with advanced NSCLC who are negative for driver genes have been continuously refreshed. The studies of CheckMate-9LA and CheckMate-227 further provide a basis for dual immune combination therapy. In addition, the survival data of CheckMate-77T, KEYNOTE-671 and other studies have brought new ideas and new options for the perioperative treatment of NSCLC. Research on new targets, new mechanisms and new treatment strategies is emerging, which can further meet the needs of long-term survival of NSCLC patients. 2023 is a year of rapid development of immunotherapy, with the emergence of new drugs and strategies such as rare mutant targets, antibody-drug conjugates, and mRNA tumor vaccines, bringing more hope to lung cancer patients. The purpose of this article is to summarize the research progress of immunotherapy for NSCLC in 2023.
【Keywords】non-small cell lung cancer, immune checkpoint inhibitors, programmed cell death protein 1, programmed cell death ligand 1, immunotherapy, antibody-drug conjugates
In 2023, many major breakthroughs have been made in the field of lung cancer, and immunotherapy has explored different combination treatment modes in non-small cell lung cancer (NSCLC), showing exciting efficacy. At the same time, in the perioperative field, immunotherapy is advancing even earlier. NSCLC has entered the era of new immunotherapy represented by immune checkpoint inhibitors (ICIs) [1]. From the backline to the first-line, from monotherapy to combination, from late to early, ICIs have made remarkable achievements in the field of NSCLC and have become a new hope for a cure for NSCLC. Every year, exploratory research on immunotherapy for NSCLC emerges one after another, from optimizing immunotherapy models, exploring new therapeutic drugs, analyzing drug resistance mechanisms, formulating coping strategies, to rare target mutations, and developing mRNA tumor vaccines, which bring more hope for the long-term survival of NSCLC patients. The purpose of this article is to summarize the important progress in the field of immunotherapy for NSCLC in 2023, in order to provide a basis for clinical diagnosis and treatment.
1. Progress in immunotherapy for patients with advanced NSCLC
ICIs are monoclonal antibody drugs developed for corresponding immune checkpoints, which can relieve the suppression of immune function caused by immune checkpoints by blocking the binding of immune checkpoints to their ligands, and reactivate immune cells to exert anti-tumor effects. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have developed rapidly in the past decade, reshaping the treatment landscape of NSCLC and becoming the first-line standard treatment for advanced NSCLC [2]. In 2023, the data released by various societies will once again consolidate its first-line "hegemon" status. In the European Lung Cancer Conference (ELCC) KEYNOTE-042 study, five-year data updates from the Chinese population showed that pembrolizumab monotherapy doubled overall survival (OS) in ≥ 1 percent of patients with PD-L1, regardless of PD-L1 expression levels [3]. Updated data from the EMPOWER-Lung-1 and EMPOWER-Lung-3 studies suggest a survival benefit in patients with unresectable locally advanced NSCLC who are not candidates for concurrent chemoradiotherapy, either as a single agent or in combination with chemotherapy [4]. For the <1% of PD-L1 patients, the KEYNOTE-189 and KEYNOTE-407 expansion cohort data show that pembrolizumab combined with chemotherapy can improve OS, objective response rate (ORR) and progression-free survival (PFS) in <1% of patients with PD-L1, further supporting the use of pembrolizumab plus chemotherapy as a <1% of PD-L1 First-line standard therapy for metastatic NSCLC [5]. The CheckMate-227 [6] and CheckMate-9LA [7] studies of dual immunotherapy showed a 6-year OS rate of 22 percent and a complete response (CR) or partial response (PR) rate of ≥ 80 percent in patients with stage IV or relapsed NSCLC who received PD-L1≥1 percent in the first line of PD-L1 The six-year OS rate can reach 59 percent, and <1 percent of patients with PD-L1 also demonstrate OS benefits over conventional chemotherapy [6]. Four-year OS follow-up data from CheckMate-9LA [7] demonstrated a survival benefit of dual immunotherapy + chemotherapy for metastatic NSCLC compared with chemotherapy, with a median OS of 11 months and 15.8 months, respectively, regardless of PD-L1 expression level and tissue type.
2. Progress in immunotherapy for patients with early-stage NSCLC
Surgery is the most common treatment for early-stage NSCLC, with a five-year OS rate of 41% (stage III.A) ~ 92% (stage I.A1) [8]. To further reduce the risk of postoperative recurrence and mortality, many clinical trials have attempted to improve the prognosis of patients with early-stage NSCLC by adding adjuvant or neoadjuvant therapy [9-10]. However, the benefits of adjuvant and neoadjuvant treatment of NSCLC with traditional chemotherapy regimens have been limited, with only 5.4 and 5.0 percent of OS rates improved at five years [11-12]. The excellent performance of ICIs in the treatment of advanced NSCLC provides a new direction for the treatment of early-stage NSCLC, and whether moving the line of defense of immunotherapy forward can enable patients with early-stage NSCLC to achieve similar survival benefits is a research hotspot at present.
2.1 Progress in neoadjuvant immunotherapy
As the world's first neoadjuvant phase III clinical study, CheckMate-816 [13] has a challenging pathologic complete response (pCR) rate and event-free survival (EFS) as the primary endpoints of the study. The results of the study were presented at the 2023 annual meeting of the European Society for Medical Oncology (ESMO): with a median follow-up of 49.2 months, compared with chemotherapy, the median EFS time of nivolumab combined with ipilimumab was 20.9 months and 54.8 months (HR=0.77, 95%CI 0.51~1.15), and the 3-year EFS rates were 44% and 56%, respectively The 3-year OS rates were 61% and 73%, respectively.
In addition, the Chinese subgroup data of the CheckMate-816 study, presented at the 2023 American Association for Cancer Research (AACR) annual meeting, were even better: the 3-year EFS rate of nivolumab plus chemotherapy was 60%, compared with chemotherapy alone, the 3-year EFS rate increased by up to 24%, and the risk of disease progression, recurrence or death decreased by 53%; Trends in the EFS benefit of nivolumab plus chemotherapy have been observed in each key subgroup by histological tumor type and PD-L1 expression [14].
2.2 Progress in immunoadjuvant therapy
Neoadjuvant therapy provides an opportunity for early eradication of micrometastases [15], while adjuvant therapy prolongs the overall time to control the disease and provides more recovery time for postoperative patients [16]. RNA sequencing results from the Impower-010 study, presented at the 2023 ESMO Annual Meeting, provide clinical reference for the precise application of immunotherapy for lung cancer [17]. The results of the study of 116 gene tags and other biomarkers associated with cell type and state showed that the biomarker sequencing biomarker evaluable population (BEP) was evaluated for atezolizumab versus the best supportive care for disease-free survival (DFS) (HR=0.71, 95% CI 0.54~0.94) was similar to that of the intention to treat analysis (ITT) population (HR=0.81, 95%CI 0.66~0.99). Transforming growth factor-β β (TGF-β)-mediated tumor-associated fibroblasts (CAFs) are the primary genetic traits influencing the benefit of DFS in patients with RNA-sequencing BEP and grouping according to TGF-β-mediated CAF expression levels (≥ TGF-β median CAF expression is high and TGF-β is < The median CAF expression was low), and the results showed that worse DFS in the best supportive care group was associated with TGF-β-mediated CAF expression, while atezolizumab efficacy was not affected by TGF-β-mediated CAF expression levels. Atezolizumab improved DFS in patients with TGF-β-mediated CAF hyperexpression compared with optimal supportive care. However, due to the limited sample size, the predictive effect of TGF-β-mediated CAF still needs to be further validated.
2.3 Advances in neoadjuvant + adjuvant immunotherapy
The KEYNOTE-091 [18], Impower-010 [19] and CheckMate-816 [13] studies established the role of ICIs in the adjuvant and neoadjuvant treatment of NSCLC, respectively. As for whether the combination of adjuvant therapy and neoadjuvant therapy can further refresh the survival data of NSCLC patients, the study represented by KEYNOTE-671 [20] has preliminarily obtained satisfactory results, which once again proves that the neoadjuvant immunotherapy + adjuvant immunotherapy model can achieve both EFS and OS benefits for perioperative NSCLC patients.
KEYNOTE-671 [20] is currently the only early-stage NSCLC study with dual endpoints of EFS+OS, with interim analysis data from the American Society of Clinical Oncology in 2023 Oncology, ASCO) annual meeting: with a median follow-up of 25.2 months, pembrolizumab combined with neoadjuvant chemotherapy and postoperative single-agent adjuvant therapy for stage II.~III.B NSCLC patients had a 42% lower risk of disease recurrence, progression, or death (HR=0.58, 95%CI 0.46~0.72, P<0.000 01). In the same year, the results of the KEYNOTE-671 [21] study were presented at the annual meeting of ESMO: compared with placebo, pembrolizumab neoadjuvant therapy + adjuvant therapy significantly improved the median OS of patients with resectable stage II.~III.B NSCLC (54.2 months: not reached, HR=0.72, 95%CI 0.56~0.93, P=0.005 17), and the 3-year OS rates were 64.0% and 71.3%, respectively; OS benefit was generally consistent across most of the subgroups analysed. In addition, the EFS data were further updated at the ESMO Congress: the median EFS of pembrolizumab neoadjuvant therapy + adjuvant therapy and placebo group was 47.2 months and 18.3 months, respectively (HR=0.59, 95% CI 0.48~0.72), and the 3-year EFS rates were 54.3% and 35.4%, respectively, and all subgroups achieved a trend of EFS benefit. KEYNOTE-671 is the only study to achieve both OS and EFS endpoint positive, which is a milestone in improving the survival time of patients with resectable NSCLC.
The CheckMate-77T study further demonstrated [22] that although the median EFS time to the primary endpoint of neoadjuvant + adjuvant nivolumab has not yet been reached, the data presented at the ESMO Congress showed that nivolumab + chemotherapy in the perioperative period was significantly reduced by 42% compared with placebo median EFS time was 18.4 months and not reached in the nivolumab and placebo groups, respectively, and the 18-month EFS rate was 70% and 50%, respectively remission (MPR) patients who achieved pCR or MPR had a superior EFS benefit.
The AEGEAN [23] study, which also used a "sandwich" immunotherapy regimen, presented data for the first time at this year's AACR Congress: the pCR rate was 12.9% (17.2% versus 4.3%) higher in the durvalumab group than in the placebo group at a median follow-up of 11.7 months, the median EFS was not reached and 25.9 months, respectively, and the perioperative immunotherapy of durvalumab was safe and tolerable, and there was no adverse effect on the postponement or cancellation of surgery.
In addition, data from the Neotorch study, which innovatively adopted a new model of perioperative immunotherapy using "3+1+13" (i.e., 3 cycles of toripalimab + chemotherapy preoperatively + chemotherapy + 1 cycle of postoperative "toripalimab + chemotherapy" and 13 cycles of "toripalimab" consolidation therapy) were presented at the 2023 ASCO Annual Meeting [24] : With a median follow-up of 18.3 months, toripalimab significantly prolonged median EFS as assessed by both investigators and blinded independent review committees compared with chemotherapy alone, and reduced the risk of disease recurrence, disease progression, or death by 60%; In the subgroup analysis of PD-L1 expression, PD-L1 1%~49% and PD-L1≥50% benefited similar (all HR=0.31), both of which reduced the risk of disease recurrence, disease progression or death by about 70%.
Results from the phase II LCMC3 trial were also presented at the 2023 ELCC Annual Meeting [25]: with a median follow-up of 3.1 years, the 3-year DFS rates were 83% and 64%, and the 3-year OS rates were 89% and 77%, respectively (HR=0.48, 95%CI 0.19~1.21), and the 3-year DFS rates were 75% and 70%, respectively, in patients with stage I., II, and III evaluable The OS rates were 82 and 81 percent, respectively, and adjuvant atezolizumab also conferred a survival benefit in the non-MPR population, with 3-year DFS rates of 80% and 62%, respectively, and 3-year OS rates of 87% and 75%, respectively, with adjuvant atezolizumab and non-adjuvant atezolizumab therapy, respectively.
In addition, a number of clinical trials such as IMpower-030, KEYNOTE-091 and China's self-developed drugs are still in progress, and we look forward to the publication of more research data in the future, which will provide strong evidence-based medical support for immunotherapy in early NSCLC, promote the advancement of immunotherapy, improve patient survival time, and benefit more NSCLC patients.
3. Progress in immunotherapy for special populations
3.1 Immunotherapy exploration for patients with positive gene mutations
Approximately 73.9 percent of NSCLC patients have driver gene mutations, and epidermal growth factor receptor (EGFR) is the most common mutated gene in Chinese NSCLC patients [26-27], and EGFR-tyrosine kinase inhibitors (tyrosine kinase). Inhibitor (TKI) (EGFR-TKI) is the standard of care for patients with advanced EGFR-mutated NSCLC, but most patients develop resistance to TKIs, leading to disease progression [28]. First-line platinum-doublet chemotherapy has limited efficacy, with PFS of only 4~6 months and median OS of less than 1 year [29-30]. How to prolong the survival time after TKI resistance and meet the clinical needs of patients is still being explored.
Previous subgroup analyses of the IMpower150 study showed that atezolizumab + bevacizumab + chemotherapy improved the prognosis of patients with NSCLC after EGFR-TKI resistance [31]. To further address the issues of genomic composition and regional differences in clinical practice, a Phase III study of Impower-151 was conducted in China [32]. According to the data reported at the 2023 World Conference on Lung Cance (WCLC) Annual Meeting, in the ITT population, there was no significant PFS benefit of atezolizumab + bevacizumab + carboplatin + paclitaxel or pemetrexed (BCP regimen) compared with bevacizumab + carboplatin + paclitaxel or pemetrexed (ABCP regimen), with median PFS of 7.1 and 9.5 months, respectively (P = 0.183). 8). In the EGFR and anaplastic lymphoma kinase (ALK)-positive subgroups, the PFS was similar between the two groups, with median PFS of 8.5 months and 8.3 months for four-drug and three-drug combinations, respectively.
In addition, the results of the KEYNOTE-789 study updated at the 2023 ASCO Congress showed that although the analysis results were more supportive of the pembrolizumab combination regimen to reduce the risk of mortality (HR=0.84; 95%CI 0.69~1.02, P=0.036 2), the combination of pembrolizumab with chemotherapy did not significantly prolong PFS and OS, with median PFS of 5.6 months and 5.5 months, respectively (HR=0.80, 95% The CI was 0.65~0.97, P=0.012 2), and the median OS was 15.9 months and 14.7 months, respectively (HR=0.84; 95%CI 0.69~1.02, P=0.036 2)[33]. The data from the BACH-NET study reported at the 2023 ELCC Congress also showed that the actual clinical application effect of the four-drug combination of ABCP regimen in patients with EGFR mutations after TKI treatment needs to be further studied [34]. There is still room for exploration on how to further optimize the treatment regimen of immunotherapy combined with chemotherapy after TKI resistance in EGFR-positive patients.
Despite the poor results of classical studies on EGFR mutations, the ATTLAS (KCSG-LU19-04) study reported at the ESMO Congress showed that compared with pemetrexed + carboplatin (PC group), the median PFS of patients with EGFR/ALK-mutant NSCLC who had received TKIs previously treated with TKIs was significantly longer in the ABCP group (5.62 months versus 8.48 months, HR=0.62, P=0.004), and the ORR was significantly higher (41.9%vs. 69.5%) , P<0.001), and the PFS benefit increased with increasing PD-L1 expression [35]. However, whether this regimen can change the treatment options of patients with TKI-resistant EGFR-mutated advanced NSCLC still needs to be explored more deeply.
In addition, the results of the KRYSTAL-7 study targeting KRAS gene mutations were reported at the ESMO Congress, in which Adagrasib + pembrolizumab demonstrated considerable antitumor activity (ORR of 63 percent) and a manageable safety profile in the first-line treatment of 50% of patients with advanced KRAS G12C mutation with PD-L1 ≥ [36]. In another study on the efficacy and safety of the KRAS G12C inhibitor MK-1084 ± pembrolizumab, MK-1084+ pembrolizumab showed promising antitumor activity in first-line treatment of 50% of KRAS G12C-mutant NSCLC patients with PD-L1 TPS ≥ [37].
In recent years, breakthroughs have been made in clinical research on BRAF V600/MET14 exon, RET, KRAS G12C and other gene mutations at home and abroad, so the treatment of TKI resistance needs to be solved urgently.
3.2 Immunotherapy exploration after immunotherapy resistance
Immunotherapy can improve the survival rate and clinical benefit of patients, but drug resistance is also "inevitable", how to break the deadlock of drug resistance, and the exploration of drug resistance mechanisms and coping strategies has never stopped. In an interim analysis of MORPHEUS-Lung in patients with immunotherapy-resistant advanced NSCLC, atezolizumab + bevacizumab was a potential treatment option for ICIs-treated metastatic NSCLC, with median PFS of 6.9 and 4.5 months, respectively (HR = 0.77, 95% CI 0.44~1.34) [38]. In addition, in the SAPPHIRE study, which compared the small molecule inhibitor cestavatinib with nivolumab and chemotherapy, the median OS was 12.2 months and 10.1 months, respectively, but this primary endpoint was not met [39].
3.3 Changed to the exploration of immunotherapy in the elderly population
Previous literature analysis has shown controversy about the efficacy of ICIs in patients aged ≥75 years, leading to limited immunotherapy in older patients [40-41]. A 2023 ESMO Annual Meeting presented an analysis of the efficacy and safety of immunotherapy monotherapy and combination therapy in older patients, which showed that immunotherapy combination therapy was associated with longer OS in older patients [42]. In addition, in a meta-analysis of randomized trials of PD-1 and PD-L1 inhibitors in combination with chemotherapy versus chemotherapy alone in the first-line treatment of older patients with advanced NSCLC, in patients ≥ 65 years of age, the combination was significantly associated with OS and PFS benefits compared with chemotherapy [43]. This suggests that older patients are not contraindicated to immunotherapy.
4. Progress in immunotherapy combination therapy for NSCLC
4.1 Exploration of new target therapies for NSCLC
As a new type of anti-cancer drug, antibody drug conjugates (ADCs) are gradually applied in the field of NSCLC. The TROP2-ADC data, represented by the TROPION-Lung series of studies, were presented at the 2023 ESMO Annual Meeting, bringing new hope for the treatment of advanced treatment-experienced NSCLC. TROPION-Lung01 is the first phase III study of TROP2-ADC in lung cancer [44]. The results of this study showed that compared with chemotherapy, Dato-DXd significantly prolonged PFS in treatment-treated advanced or metastatic NSCLC, with median PFS of 3.7 months and 4.4 months, respectively (HR=0.75), and the PFS benefit was mainly driven by patients with non-squamous cell carcinoma. In the phase II TROPION-Lung05 study, Dato-DXd demonstrated considerable antitumor activity in patients with severe, treatment-positive advanced NSCLC, with an overall ORR of 35.8 percent [45]. TROPION-Lung04 further explores the application prospect of Dato-DXd in combination with immunotherapy in the treatment of NSCLC, and presented preliminary results at the 2023 WCLC Annual Meeting: when Dato-DXd + durvalumab (double agent) and Dato-DXd + durvalumab + carboplatin (three drugs) are used in combination with advanced or metastatic NSCLC, the ORR is 50% and 76.9%, respectively, and the disease control rate is 92.9%, respectively and 92.3% of patients with PD-L1 expression levels, and the response rate of triple therapy was generally higher than that of dual therapy, showing a manageable safety profile and encouraging anti-tumor activity. In addition, SKB264 (MK-2870), which uses a proprietary toxin-linker strategy, has also begun to evaluate the efficacy and safety of SKB264 in combination with pembrolizumab in the first-line treatment of metastatic NSCLC, so as to further improve the survival of NSCLC patients and achieve clinical cure.
The 2023 Nobel Prize in Physiology or Medicine was announced, and the winners' research direction is in the field of mRNA, which has reinvigorated the confidence of mRNA to overcome cancer. Data from the efficacy and safety analysis of mRNA-4157-P201 in combination with pembrolizumab in the treatment of surgically resected high-risk melanoma were presented at the 2023 ASCO Annual Meeting: mRNA-4157-P201 in combination with pembrolizumab reduced the risk of distant metastasis or death by up to 65% compared with pembrolizumab alone (HR=0.347, 95%CI 0.145~0.828, unilateral P==0.0063) [47]. As a phase II randomized trial in the field of mRNA anti-tumor, KEYNOTE-942 has good results, and the subsequent 3-year follow-up data further confirmed the efficacy advantage of mRNA in the field of anti-tumor. Compared with pembrolizumab monotherapy, mRNA-4157 combined with pembrolizumab treatment could significantly improve recurrence-free survival (RFS), reduce the risk of recurrence or death by 49% (HR=0.510, 95%CI 0.288~0.906, unilateral P=0.0095) and improve distant metastasis-free survival survival (DMFS), which reduced the risk of distant metastasis or death by 62% (HR=0.384, 95%CI 0.172~0.858, unilateral P=0.007 7) [48]. The phase III study of mRNA-4157 for the adjuvant treatment of high-risk melanoma and NSCLC has been initiated, and with the continuous improvement of mRNA technology and the continuous advancement of clinical trials of mRNA tumor vaccines, it is expected that mRNA can make breakthroughs in tumor treatment.
4.2 Progress in new combined immunization strategies
While exploring new drugs and new targets, we have also been exploring new immunotherapy combination strategies. IN 2023, THE RESULTS OF THREE TARGETED BISPECIFIC ANTIBODIES (PAPILLON [49], MARIPOSA [50], MARIPOSA-2 [51]) WERE RELEASED, AND SOME PROGRESS HAS BEEN MADE IN THE TREATMENT OF IMMUNOBISPECIFIC ANTIBODIES BASED ON THE PD-1 AND PD-L1 PATHWAYS.
Data from four studies of KN046, a PD-L1 and CTLA-4 bispecific antibody, were presented at the 2023 ESMO Annual Meeting, and the results showed that KN046 in combination with axitinib in the first-line treatment of PD-L1≥1% advanced NSCLC was 58.6% [52]; There is OS benefit in patients who are resistant to immunotherapy or resistant to EGFR-TKIs in the post-line treatment of KN046 [53]. The combination of SHR-1701, a PD-L1, TGF-β bispecific antibody in combination with bevacizumab demonstrated encouraging antitumor activity in patients with treatment-experienced advanced nonsquamous NSCLC, with a median PFS of 6.2 months [54]. The preliminary efficacy and safety of PD-1 and TIGIT bispecific antibodies AZD2936 [55] and PD-1 and TIM-3 bispecific antibodies AZD7789 in the treatment of immunotherapy-resistant advanced NSCLC have been acceptable [56].
The median OS of eftilagimod alpha, a soluble LAG-3 protein, in combination with pembrolizumab in patients with PD-1 and PD-L1 inhibitor-resistant metastatic NSCLC was 9.9 months in the phase II TACTI-002 trial [57]. In the INSIGHT-003 study, a confirmed ORR of 66.7 percent was found for first-line treatment of nonsquamous advanced/metastatic NSCLC with Eftilagimod alpha + pembrolizumab + chemotherapy [58]. In addition, the combination of other new target drugs is also being carried out one after another, and the team of immunotherapy research is growing.
5. Summary
From first-line to drug resistance, from monotherapy to combination, from advanced to early, from adjuvant to neoadjuvant, immunotherapy runs through all stages of lung cancer treatment, and constantly refreshes the survival data of patients. The achievements of immunotherapy in the field of NSCLC are exciting, providing a new treatment option for the long-term survival of NSCLC patients and reshaping the treatment landscape. However, the problem of drug resistance caused by immunotherapy still needs to be broken through urgently. In order to meet the different needs of NSCLC patients at different stages, immunotherapy has been gradually explored from the aspects of drug resistance mechanisms and solutions, new targets, and new mechanism drugs. With the continuous development and advancement of a number of clinical studies of immunotherapy, it is believed that NSCLC immunotherapy will continue to be broken through to meet the survival needs of patients in an all-round way.
Bibliography:
[1] Zhang Zhimin, Zhang Bicheng, Xu B, et al.Advances in immunotherapy for advanced non-small cell lung cancer[J].Science & Technology Review,2023,41(18):36-42.
[2] Zou Yifeng, Duan Jianchun.2023 CSCO guideline update interpretation: diagnosis and treatment of driver gene positive non-small cell lung cancer[J].Journal of Practical Oncology,2023,38(5):427-433.
[3] WU Y L, ZHANG L, FAN Y, et al. Pembrolizumab vs chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC) and PD-L1 TPS≥1%: 5-year update from KEYNOTE-042[J]. J Thorac Oncol, 2023, 18(Suppl 4):S65-S66.
[4] KALINKA E, BONDARENKO I, GOGISHVILI M, et al. First-line cemiplimab for locally advanced non-small cell lung cancer: updated subgroup analyses from EMPOWER-Lung 1 and EMPOWER-Lung 3[J]. J Thorac Oncol, 2023, 18(Suppl 4):S106.
[5] GADGEEL S, RODRIGUEZ-ABRE U, HALMOS B, et al. 5-year survival of pembrolizumab plus chemotherapy for metastatic NSCLC with PD-L1 tumor proportion score<1%[J]. J Thorac Oncol, 2023, 18(Suppl 11):S77-S78.
[6] RAMALINGAM S S, CIULEANU T E, BERNABE CARO R, et al. Six-year survival and health-related quality of lifeoutcomes with first-line nivolumab plus ipilimumab inpatients with metastatic NSCLC from CheckMate227[J]. J Thorac Oncol, 2023, 18(Suppl 11):S76-S77
[7] CARBONE D P, CIULEANU T E, SCHENKER M, et al. First-line (1L) nivolumab (N)+ ipilimumab (I)+ chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4-y clinical update and outcomes by tumor histologic subtype (THS)[J]. J Clin Oncol, 2023, 41(Suppl 17):LBA9023-LBA9023.
[8] GOLDSTRAW P, CHANSKY K, CROWLEY J, et al. The IASLC lung cancer staging project: proposals for revision of the tnm stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer[J]. J Thorac Oncol, 2016, 11(1):39-51.
[9] ARRIAGADA R, BERGMAN B, DUNANT A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer[J]. N Engl J Med, 2004, 350(4): 351-360.
[10] VANSTEENKISTE J, WAUTERS E, REYMEN B, et al. Current status of immune checkpoint inhibition in early-stage NSCLC[J]. Ann Oncol, 2019, 30(8):1244-1253.
[11] NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data[J]. Lancet, 2014, 383(9928):1561-1571.
[12] PIGNON J P, TRIBODET H, SCAGLIOTTI G V, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group[J]. J Clin Oncol, 2008, 26(21):3552-3559.
[13] AWAD M M, FORDE P M, GIRARD N, et al. Neoadjuvant nivolumab (N)+ ipilimumab (I) vs chemotherapy (C) in the phase III CheckMate 816 trial[J]. Ann Oncol, 2023, 34(Suppl 2):S731.
[14] WANG C L, CHEN K N, CHEN Q X, et al. Neoadjuvant nivolumab (NIVO)+ chemotherapy (chemo) vs chemo in Chinese patients (pts) with resectable NSCLC in CheckMate 816[J]. Cancer Res, 2023, 83(Suppl 8):CT081.
[15] BLUMENTHAL G M, BUNN P A J R, CHAFT J E, et al. Current status and future perspectives on neoadjuvant therapy in lung cancer[J]. J Thorac Oncol, 2018, 13(12):1818-1831.
[16] OWEN D, CHAFT J E. Immunotherapy in surgically resectable non-small cell lung cancer[J]. J Thorac Dis, 2018, 10(Suppl 3): S404-S411.
[17] ALTORKI N K, RECK M, WAKELEE H, et al. Exploratory analysis of disease-free survival (DFS) by TGF-β cancer-associated fibroblast (CAF) gene signature expression in patients (pts) with resected NSCLC treated with atezolizumab (atezo) or best supportive care (BSC)[J]. Anna Oncol, 2023, 34(Suppl 2):S732-S733.
[18] O'BRIEN M, PAZ-ARES L, MARREAUD S, et al. EORTC-1416-LCG/ETOP 8-15–PEARLS/KEYNOTE-091 investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage ⅠB-ⅢA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial[J]. Lancet Oncol, 2022, 23(10):1274-1286.
[19] Wang Changli, Yue Dongsheng, Chen Chen.2022 Research progress in immunotherapy for perioperative non-small cell lung cancer[J].Chinese Journal of Clinical Oncology,2022,49(23):1236-1241.
[20] WAKELEE H A, LIBERMAN M, KATO T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC[J]. J Clin Oncol, 2023, 41(Suppl 17):LBA100-LBA100.
[21] SPICER J D, GAO S, LIBERMAN M, et al. LBA56 Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)[J]. Ann Oncol, 2023, 34(Suppl 2):S1297-S1298.
[22] Cascone T, Awad M M, Spicer J D, et al. LBA1 CheckMate 77T: phase Ⅲ study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage Ⅲa–Ⅲb NSCLC[J]. Ann Oncol, 2023, 34(Suppl 2):S1295.
[23] HAAGER B, HEYMACH J V, HARPOLE D, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab+ chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC[J]. Zentr Fur Chir, 2023,148(Suppl 1):S87-S87.
[24] LU S, WU L, ZHANG W, et al. Perioperative toripalimab+ platinum-doublet chemotherapy vs chemotherapy in resectable stage Ⅱ/Ⅲ non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the phase III Neotorch study[J]. J Clin Oncol, 2023, 41(Suppl 36):425126.
[25] CARBONE D P, WAQAR S N, CHAFT J. Updated survival, efficacy and safety of adjuvant (adj) atezolizumab (atezo) after neoadjuvant (neoadj) atezo in the phase Ⅱ LCMC3 study[J]. J Thorac Oncol, 2023, 18(Suppl 4):S90-S91.
[26] WEN S, DAI L, WANG L, et al. Genomic signature of driver genes identified by target next-generation sequencing in chinese non-small cell lung cancer[J]. Oncologist, 2019, 24(11):e1070-e1081.
[27] SI X, PAN R, MA S, et al. Genomic characteristics of driver genes in Chinese patients with non-small cell lung cancer[J]. Thorac Cancer, 2021, 12(3):357-363.
[28] GOU L Y, WU Y L. Prevalence of driver mutations in non-small-cell lung cancers in the People's Republic of China[J]. Lung Cancer (Auckl), 2014, 5:1-9.
[29] SCHILLER J H,HARRINGTON D, BELANI C P, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer[J]. N Engl J Med, 2002, 346(2):92-98.
[30] PFISTER D G, JOHNSON D H, AZZOLI C G, et al. American Society of Clinical Oncology treatment of unresect non-small-cell lung cancer guideline: update 2003[J]. J Clin Oncol, 2004, 22(2):330-353.
[31] NOGAMI N, BARLESI F, SOCINSKI M A, et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with egfr mutations or metastases in the liver or brain[J]. J Thorac Oncol, 2022, 17(2):309-323.
[32] ZHOU C, DONG X, CHEN G, et al. IMpower151: phase Ⅲ study of atezolizumab+ bevacizumab+ chemotherapy in 1L metastatic nonsquamous NSCLC[J]. J Thorac Oncol, 2023, 18(11):S64-S65.
[33] YANG J C H, LEE D H, LEE J S, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study[J]. J Clin Oncol, 41(Suppl 17):LBA9000-LBA9000.
[34] PASELLO G, LORENZI M, CRIVELLARO G, et al. Bevacizumab plus atezolizumab and chemotherapy in NSCLC harbouring EGFR mutation previously treated with EGFR tyrosine kinase inhibitor: the BACH-NET study[J]. J Thorac Oncol, 2023, 18(4):S52-S53.
[35] PARK S, KIM T M, HAN J Y, et al. Phase Ⅲ, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated non-small-cell lung cancer (ATTLAS, KCSG-LU19-04)[J]. J Clin Oncol, 2023, 2023: JCO2301891.
[36] GARASSINO M C, THEELEN W, JOTTE R, et al. LBA65 KRYSTAL-7: efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation[J]. Ann Oncol, 2023, 34:S1309-S1310.
[37] ROJAS C, LUGOWSKA I, JUERGENS R, et al. Safety and preliminary efficacy of the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC[J]. Ann Oncol, 2023, 34:S466-S467.
[38] GHIRINGHELLI F, FELIP E, ZER A, et al. Atezolizumab and bevacizumab (atezo+ bev)±radiotherapy (RT) vs docetaxel (doc) in checkpoint inhibitor (CPI)–experienced metastatic NSCLC (mNSCLC): results from the phase Ⅰb/Ⅱ MORPHEUS-lung study[J]. Ann Oncol, 2023, 34:S819-S820.
[39] BORGHAEI H, JOHNSON M L, GARON E B, et al. LBA63 SAPPHIRE: phase Ⅲ study of sitravatinib plus nivolumab versus docetaxel in patients with previously treated advanced non-squamous non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2023, 34:S1308.
[40] ZHANG L, SUN L, YU J, et al. Comparison of immune checkpoint inhibitors between older and younger patients with advanced or metastatic lung cancer: a systematic review and meta-analysis[J]. Biomed Res Int, 2019, 2019: 9853701.
[41] NOSAKI K, SAKA H, HOSOMI Y, et al. Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies[J]. Lung Cancer, 2019, 135:188-195.
[42] MAO Y Y, WANG A, ZHAI J, et al. To investigate the differences in efficacy between immunotherapy and combined immunotherapy in elderly patients with non-small cell lung cancer[J]. Ann Oncol, 2023, 34:S841.
[43] LANDRE T, SADAOUI N, BOUHARATI D, et al. Clinical benefit of combination chemo-immunotherapy in first-line treatment for patients over the age of 65 or 75 with metastatic NSCLC[J]. Ann Oncol, 2023, 34(2):S813-S814
[44] AHN M J, LISBERG A, PAZ-ARES L, et al. LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01[J]. Ann Oncol, 2023, 34:S1305-S1306.
[45] PAZ-ARES L, AHN M J, LISBERG A E, et al. TROPION-Lung05: Datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs)[J]. Ann Oncol, 2023, 34:S755-S756.
[46] PAPADOPOULOS K P, BRUNO D, KITAZONO S, et al. Datopotamab deruxtecan (Dato-DXd)+ durvalumab± carboplatin in advanced/mNSCLC: initial results from phase 1b TROPION-Lung04[J]. J Thorac Oncol, 2023, 18(11):S55.
[47] YANG J C H, LEE D H, LEE J S, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: phase 3 KEYNOTE-789 study[J]. J Clin Oncol, 2023, 41(Suppl 17):LBA9000-LBA9000.
[48] Moderna. Moderna and merck announce mRNA-4157 (V940) in combination with KEYTRUDA® (pembrolizumab) demonstrated continued improvement in recurrence-free survival and distant metastasis-free survival in patients with high-risk stage Ⅲ/Ⅳ melanoma following complete resection versus KEYTRUDA at three years[EB/OL]. (2023-02-22) [2023-12-14].https://www.merck.com/news/moderna-and-merck-announce-mrna-4157-v940-in-combination-with-keytruda-pembrolizumab-demonstrated-continued-improvement-in-recurrence-free-survival-and-distant-metastasis-free-survival-in-pa/.
[49] GIRARD N, PARK K, TANG K, et al. LBA5 amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): primary results from PAPILLON, a randomized phase III global study[J]. Ann Oncol, 2023, 34:S1304.
[50] LU S, CHO B C, LEE J S, et al. LBA10 amivantamab plus lazertinib vs osimertinib as first-line treatment among Asian patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): MARIPOSA subgroup analysis[J]. Ann Oncol, 2023, 34:S1661.
[51] PASSARO A, CHO B C, WANG Y, et al. LBA15 Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase Ⅲ, global, randomized, controlled trial[J]. Ann Oncol, 2023, 34:S1307.
[52] ZHAO Y, HUANG Y, FANG W, et al. The preliminary data from a single-arm, open-label, multicenter phase II clinical trial: KN046 combined with axitinib as first-line (1L) treatment for NSCLC[J]. Ann Oncol, 2023, 34:S824.
[53] ZHOU C, XIONG A, FANG J, et al. Updated results of the efficacy and safety of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed prior EGFR-TKI (s)[J]. Ann Oncol, 2023, 34:S767-S768.
[54] FENG J, TANG D, WANG J, et al. SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for recurrent or metastatic cervical cancer: a clinical expansion cohort of a phase I study[J]. Clin Cancer Res, 2022, 28(24):5297-5305.
[55] ROHRBERG K S, BRANDÃO M, CASTANON-ALVAREZ E, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/metastatic non-small-cell lung cancer (NSCLC): first report of ARTEMIDE-01[J]. J Clin Oncol, 2023, 41(Suppl 16):9050-9050.
[56] BESSE B, ITALIANO A, COUSIN S, et al. Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L) 1 therapy[J]. Ann Oncol, 2023, 34:S755.
[57] MAJEM M, FORSTER M D, KREBS M G, et al. Final data from a phase Ⅱ study (TACTI-002) of eftilagimod alpha (soluble LAG-3) and pembrolizumab in 2nd-line metastatic NSCLC pts resistant to PD-1/PD-L1 inhibitors[J]. J Thorac Oncol, 2023, 18(4):S43-S44.
[58] ATMACA A, MÜLLER D W, HABIBZADA T, et al. 1042P INSIGHT 003 evaluating feasibility of eftilagimod alpha (soluble LAG-3) combined with first-line chemo-immunotherapy in metastatic non-small cell lung cancer (NSCLC) adenocarcinomas[J]. Ann Oncol, 2023, 34: S632.